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1.  A Multi-Ethnic Meta-Analysis of Genome-Wide Association Studies in Over 100,000 Subjects Identifies 23 Fibrinogen-Associated Loci but no Strong Evidence of a Causal Association between Circulating Fibrinogen and Cardiovascular Disease 
Sabater-Lleal, Maria | Huang, Jie | Chasman, Daniel | Naitza, Silvia | Dehghan, Abbas | Johnson, Andrew D | Teumer, Alexander | Reiner, Alex P | Folkersen, Lasse | Basu, Saonli | Rudnicka, Alicja R | Trompet, Stella | Mälarstig, Anders | Baumert, Jens | Bis, Joshua C. | Guo, Xiuqing | Hottenga, Jouke J | Shin, So-Youn | Lopez, Lorna M | Lahti, Jari | Tanaka, Toshiko | Yanek, Lisa R | Oudot-Mellakh, Tiphaine | Wilson, James F | Navarro, Pau | Huffman, Jennifer E | Zemunik, Tatijana | Redline, Susan | Mehra, Reena | Pulanic, Drazen | Rudan, Igor | Wright, Alan F | Kolcic, Ivana | Polasek, Ozren | Wild, Sarah H | Campbell, Harry | Curb, J David | Wallace, Robert | Liu, Simin | Eaton, Charles B. | Becker, Diane M. | Becker, Lewis C. | Bandinelli, Stefania | Räikkönen, Katri | Widen, Elisabeth | Palotie, Aarno | Fornage, Myriam | Green, David | Gross, Myron | Davies, Gail | Harris, Sarah E | Liewald, David C | Starr, John M | Williams, Frances M.K. | Grant, P.J. | Spector, Timothy D. | Strawbridge, Rona J | Silveira, Angela | Sennblad, Bengt | Rivadeneira, Fernando | Uitterlinden, Andre G | Franco, Oscar H | Hofman, Albert | van Dongen, Jenny | Willemsen, G | Boomsma, Dorret I | Yao, Jie | Jenny, Nancy Swords | Haritunians, Talin | McKnight, Barbara | Lumley, Thomas | Taylor, Kent D | Rotter, Jerome I | Psaty, Bruce M | Peters, Annette | Gieger, Christian | Illig, Thomas | Grotevendt, Anne | Homuth, Georg | Völzke, Henry | Kocher, Thomas | Goel, Anuj | Franzosi, Maria Grazia | Seedorf, Udo | Clarke, Robert | Steri, Maristella | Tarasov, Kirill V | Sanna, Serena | Schlessinger, David | Stott, David J | Sattar, Naveed | Buckley, Brendan M | Rumley, Ann | Lowe, Gordon D | McArdle, Wendy L | Chen, Ming-Huei | Tofler, Geoffrey H | Song, Jaejoon | Boerwinkle, Eric | Folsom, Aaron R. | Rose, Lynda M. | Franco-Cereceda, Anders | Teichert, Martina | Ikram, M Arfan | Mosley, Thomas H | Bevan, Steve | Dichgans, Martin | Rothwell, Peter M. | Sudlow, Cathie L M | Hopewell, Jemma C. | Chambers, John C. | Saleheen, Danish | Kooner, Jaspal S. | Danesh, John | Nelson, Christopher P | Erdmann, Jeanette | Reilly, Muredach P. | Kathiresan, Sekar | Schunkert, Heribert | Morange, Pierre-Emmanuel | Ferrucci, Luigi | Eriksson, Johan G | Jacobs, David | Deary, Ian J | Soranzo, Nicole | Witteman, Jacqueline CM | de Geus, Eco JC | Tracy, Russell P. | Hayward, Caroline | Koenig, Wolfgang | Cucca, Francesco | Jukema, J Wouter | Eriksson, Per | Seshadri, Sudha | Markus, Hugh S. | Watkins, Hugh | Samani, Nilesh J | Wallaschofski, Henri | Smith, Nicholas L. | Tregouet, David | Ridker, Paul M. | Tang, Weihong | Strachan, David P. | Hamsten, Anders | O’Donnell, Christopher J.
Circulation  2013;128(12):10.1161/CIRCULATIONAHA.113.002251.
Background
Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease (CVD), range from 34 to 50%. Genetic variants so far identified by genome-wide association (GWA) studies only explain a small proportion (< 2%) of its variation.
Methods and Results
We conducted a meta-analysis of 28 GWA studies, including more than 90,000 subjects of European ancestry, the first GWA meta-analysis of fibrinogen levels in 7 African Americans studies totaling 8,289 samples, and a GWA study in Hispanic-Americans totaling 1,366 samples. Evaluation for association of SNPs with clinical outcomes included a total of 40,695 cases and 85,582 controls for coronary artery disease (CAD), 4,752 cases and 24,030 controls for stroke, and 3,208 cases and 46,167 controls for venous thromboembolism (VTE). Overall, we identified 24 genome-wide significant (P<5×10−8) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the three structural fibrinogen genes and pathways related to inflammation, adipocytokines and thyrotrophin-releasing hormone signaling. Whereas lead SNPs in a few loci were significantly associated with CAD, the combined effect of all 24 fibrinogen-associated lead SNPs was not significant for CAD, stroke or VTE.
Conclusion
We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and CAD, stroke or VTE.
doi:10.1161/CIRCULATIONAHA.113.002251
PMCID: PMC3842025  PMID: 23969696
Fibrinogen; cardiovascular disease; genome-wide association study
2.  The INTERVAL trial to determine whether intervals between blood donations can be safely and acceptably decreased to optimise blood supply: study protocol for a randomised controlled trial 
Trials  2014;15(1):363.
Background
Ageing populations may demand more blood transfusions, but the blood supply could be limited by difficulties in attracting and retaining a decreasing pool of younger donors. One approach to increase blood supply is to collect blood more frequently from existing donors. If more donations could be safely collected in this manner at marginal cost, then it would be of considerable benefit to blood services. National Health Service (NHS) Blood and Transplant in England currently allows men to donate up to every 12 weeks and women to donate up to every 16 weeks. In contrast, some other European countries allow donations as frequently as every 8 weeks for men and every 10 weeks for women. The primary aim of the INTERVAL trial is to determine whether donation intervals can be safely and acceptably decreased to optimise blood supply whilst maintaining the health of donors.
Methods/Design
INTERVAL is a randomised trial of whole blood donors enrolled from all 25 static centres of NHS Blood and Transplant. Recruitment of about 50,000 male and female donors started in June 2012 and was completed in June 2014. Men have been randomly assigned to standard 12-week versus 10-week versus 8-week inter-donation intervals, while women have been assigned to standard 16-week versus 14-week versus 12-week inter-donation intervals. Sex-specific comparisons will be made by intention-to-treat analysis of outcomes assessed after two years of intervention. The primary outcome is the number of blood donations made. A key secondary outcome is donor quality of life, assessed using the Short Form Health Survey. Additional secondary endpoints include the number of ‘deferrals’ due to low haemoglobin (and other factors), iron status, cognitive function, physical activity, and donor attitudes. A comprehensive health economic analysis will be undertaken.
Discussion
The INTERVAL trial should yield novel information about the effect of inter-donation intervals on blood supply, acceptability, and donors’ physical and mental well-being. The study will generate scientific evidence to help formulate blood collection policies in England and elsewhere.
Trial registration
Current Controlled Trials ISRCTN24760606, 25 January 2012.
doi:10.1186/1745-6215-15-363
PMCID: PMC4177700  PMID: 25230735
whole blood donation; randomised controlled trial; donation frequency; blood supply; donor well-being
3.  Candidate Gene Association Study of Coronary Artery Calcification in Chronic Kidney Disease: Findings from the Chronic Renal Insufficiency Cohort Study 
Objectives
To identify loci for coronary artery calcification (CAC) in patients with chronic kidney disease (CKD).
Background
CKD is associated with increased CAC and subsequent coronary heart disease (CHD) but the mechanisms remain poorly defined. Genetic studies of CAC in CKD may provide a useful strategy for identifying novel pathways in CHD.
Methods
We performed a candidate gene study (~2,100 genes; ~50,000 SNPs) of CAC within the Chronic Renal Insufficiency Cohort (CRIC) Study (n=1,509; 57% European, 43% African ancestry). SNPs with preliminary evidence of association with CAC in CRIC were examined for association with CAC in PennCAC (n=2,560) and Amish Family Calcification Study (AFCS; n=784) samples. SNPs with suggestive replication were further analyzed for association with myocardial infarction (MI) in the Pakistan Risk of Myocardial Infarction study (PROMIS) (n=14,885).
Results
Of 268 SNPs reaching P <5×10−4 for CAC in CRIC, 28 SNPs in 23 loci had nominal support (P <0.05 and in same direction) for CAC in PennCAC or AFCS. Besides chr9p21 and COL4A1, known loci for CHD, these included SNPs having reported GWAS association with hypertension (e.g., ATP2B1). In PROMIS, four of the 23 suggestive CAC loci (chr9p21, COL4A1, ATP2B1 and ABCA4) had significant associations with MI consistent with their direction of effect on CAC.
Conclusions
We identified several loci associated with CAC in CKD that also relate to MI in a general population sample. CKD imparts a high risk of CHD and may provide a useful setting for discovery of novel CHD genes and pathways.
doi:10.1016/j.jacc.2013.01.103
PMCID: PMC3953823  PMID: 23727086
Coronary artery calcification (CAC); chronic kidney disease (CKD); Chronic Renal Insufficiency Cohort Study (CRIC); myocardial infarction (MI); risk factors; candidate genes; single nucleotide polymorphisms (SNPs)
4.  Diabetes Mellitus, Fasting Glucose, and Risk of Cause-Specific Death 
The New England journal of medicine  2011;364(9):829-841.
BACKGROUND
The extent to which diabetes mellitus or hyperglycemia is related to risk of death from cancer or other nonvascular conditions is uncertain.
METHODS
We calculated hazard ratios for cause-specific death, according to baseline diabetes status or fasting glucose level, from individual-participant data on 123,205 deaths among 820,900 people in 97 prospective studies.
RESULTS
After adjustment for age, sex, smoking status, and body-mass index, hazard ratios among persons with diabetes as compared with persons without diabetes were as follows: 1.80 (95% confidence interval [CI], 1.71 to 1.90) for death from any cause, 1.25 (95% CI, 1.19 to 1.31) for death from cancer, 2.32 (95% CI, 2.11 to 2.56) for death from vascular causes, and 1.73 (95% CI, 1.62 to 1.85) for death from other causes. Diabetes (vs. no diabetes) was moderately associated with death from cancers of the liver, pancreas, ovary, colorectum, lung, bladder, and breast. Aside from cancer and vascular disease, diabetes (vs. no diabetes) was also associated with death from renal disease, liver disease, pneumonia and other infectious diseases, mental disorders, nonhepatic digestive diseases, external causes, intentional self-harm, nervous-system disorders, and chronic obstructive pulmonary disease. Hazard ratios were appreciably reduced after further adjustment for glycemia measures, but not after adjustment for systolic blood pressure, lipid levels, inflammation or renal markers. Fasting glucose levels exceeding 100 mg per deciliter (5.6 mmol per liter), but not levels of 70 to 100 mg per deciliter (3.9 to 5.6 mmol per liter), were associated with death. A 50-year-old with diabetes died, on average, 6 years earlier than a counterpart without diabetes, with about 40% of the difference in survival attributable to excess nonvascular deaths.
CONCLUSIONS
In addition to vascular disease, diabetes is associated with substantial premature death from several cancers, infectious diseases, external causes, intentional self-harm, and degenerative disorders, independent of several major risk factors. (Funded by the British Heart Foundation and others.)
doi:10.1056/NEJMoa1008862
PMCID: PMC4109980  PMID: 21366474
5.  Genome-Wide Association Study Identifies a Novel Locus Contributing to Type 2 Diabetes Susceptibility in Sikhs of Punjabi Origin From India 
Diabetes  2013;62(5):1746-1755.
We performed a genome-wide association study (GWAS) and a multistage meta-analysis of type 2 diabetes (T2D) in Punjabi Sikhs from India. Our discovery GWAS in 1,616 individuals (842 case subjects) was followed by in silico replication of the top 513 independent single nucleotide polymorphisms (SNPs) (P < 10−3) in Punjabi Sikhs (n = 2,819; 801 case subjects). We further replicated 66 SNPs (P < 10−4) through genotyping in a Punjabi Sikh sample (n = 2,894; 1,711 case subjects). On combined meta-analysis in Sikh populations (n = 7,329; 3,354 case subjects), we identified a novel locus in association with T2D at 13q12 represented by a directly genotyped intronic SNP (rs9552911, P = 1.82 × 10−8) in the SGCG gene. Next, we undertook in silico replication (stage 2b) of the top 513 signals (P < 10−3) in 29,157 non-Sikh South Asians (10,971 case subjects) and de novo genotyping of up to 31 top signals (P < 10−4) in 10,817 South Asians (5,157 case subjects) (stage 3b). In combined South Asian meta-analysis, we observed six suggestive associations (P < 10−5 to < 10−7), including SNPs at HMG1L1/CTCFL, PLXNA4, SCAP, and chr5p11. Further evaluation of 31 top SNPs in 33,707 East Asians (16,746 case subjects) (stage 3c) and 47,117 Europeans (8,130 case subjects) (stage 3d), and joint meta-analysis of 128,127 individuals (44,358 case subjects) from 27 multiethnic studies, did not reveal any additional loci nor was there any evidence of replication for the new variant. Our findings provide new evidence on the presence of a population-specific signal in relation to T2D, which may provide additional insights into T2D pathogenesis.
doi:10.2337/db12-1077
PMCID: PMC3636649  PMID: 23300278
6.  Discovery and Refinement of Loci Associated with Lipid Levels 
Willer, Cristen J. | Schmidt, Ellen M. | Sengupta, Sebanti | Peloso, Gina M. | Gustafsson, Stefan | Kanoni, Stavroula | Ganna, Andrea | Chen, Jin | Buchkovich, Martin L. | Mora, Samia | Beckmann, Jacques S. | Bragg-Gresham, Jennifer L. | Chang, Hsing-Yi | Demirkan, Ayşe | Den Hertog, Heleen M. | Do, Ron | Donnelly, Louise A. | Ehret, Georg B. | Esko, Tõnu | Feitosa, Mary F. | Ferreira, Teresa | Fischer, Krista | Fontanillas, Pierre | Fraser, Ross M. | Freitag, Daniel F. | Gurdasani, Deepti | Heikkilä, Kauko | Hyppönen, Elina | Isaacs, Aaron | Jackson, Anne U. | Johansson, Åsa | Johnson, Toby | Kaakinen, Marika | Kettunen, Johannes | Kleber, Marcus E. | Li, Xiaohui | Luan, Jian’an | Lyytikäinen, Leo-Pekka | Magnusson, Patrik K.E. | Mangino, Massimo | Mihailov, Evelin | Montasser, May E. | Müller-Nurasyid, Martina | Nolte, Ilja M. | O’Connell, Jeffrey R. | Palmer, Cameron D. | Perola, Markus | Petersen, Ann-Kristin | Sanna, Serena | Saxena, Richa | Service, Susan K. | Shah, Sonia | Shungin, Dmitry | Sidore, Carlo | Song, Ci | Strawbridge, Rona J. | Surakka, Ida | Tanaka, Toshiko | Teslovich, Tanya M. | Thorleifsson, Gudmar | Van den Herik, Evita G. | Voight, Benjamin F. | Volcik, Kelly A. | Waite, Lindsay L. | Wong, Andrew | Wu, Ying | Zhang, Weihua | Absher, Devin | Asiki, Gershim | Barroso, Inês | Been, Latonya F. | Bolton, Jennifer L. | Bonnycastle, Lori L | Brambilla, Paolo | Burnett, Mary S. | Cesana, Giancarlo | Dimitriou, Maria | Doney, Alex S.F. | Döring, Angela | Elliott, Paul | Epstein, Stephen E. | Ingi Eyjolfsson, Gudmundur | Gigante, Bruna | Goodarzi, Mark O. | Grallert, Harald | Gravito, Martha L. | Groves, Christopher J. | Hallmans, Göran | Hartikainen, Anna-Liisa | Hayward, Caroline | Hernandez, Dena | Hicks, Andrew A. | Holm, Hilma | Hung, Yi-Jen | Illig, Thomas | Jones, Michelle R. | Kaleebu, Pontiano | Kastelein, John J.P. | Khaw, Kay-Tee | Kim, Eric | Klopp, Norman | Komulainen, Pirjo | Kumari, Meena | Langenberg, Claudia | Lehtimäki, Terho | Lin, Shih-Yi | Lindström, Jaana | Loos, Ruth J.F. | Mach, François | McArdle, Wendy L | Meisinger, Christa | Mitchell, Braxton D. | Müller, Gabrielle | Nagaraja, Ramaiah | Narisu, Narisu | Nieminen, Tuomo V.M. | Nsubuga, Rebecca N. | Olafsson, Isleifur | Ong, Ken K. | Palotie, Aarno | Papamarkou, Theodore | Pomilla, Cristina | Pouta, Anneli | Rader, Daniel J. | Reilly, Muredach P. | Ridker, Paul M. | Rivadeneira, Fernando | Rudan, Igor | Ruokonen, Aimo | Samani, Nilesh | Scharnagl, Hubert | Seeley, Janet | Silander, Kaisa | Stančáková, Alena | Stirrups, Kathleen | Swift, Amy J. | Tiret, Laurence | Uitterlinden, Andre G. | van Pelt, L. Joost | Vedantam, Sailaja | Wainwright, Nicholas | Wijmenga, Cisca | Wild, Sarah H. | Willemsen, Gonneke | Wilsgaard, Tom | Wilson, James F. | Young, Elizabeth H. | Zhao, Jing Hua | Adair, Linda S. | Arveiler, Dominique | Assimes, Themistocles L. | Bandinelli, Stefania | Bennett, Franklyn | Bochud, Murielle | Boehm, Bernhard O. | Boomsma, Dorret I. | Borecki, Ingrid B. | Bornstein, Stefan R. | Bovet, Pascal | Burnier, Michel | Campbell, Harry | Chakravarti, Aravinda | Chambers, John C. | Chen, Yii-Der Ida | Collins, Francis S. | Cooper, Richard S. | Danesh, John | Dedoussis, George | de Faire, Ulf | Feranil, Alan B. | Ferrières, Jean | Ferrucci, Luigi | Freimer, Nelson B. | Gieger, Christian | Groop, Leif C. | Gudnason, Vilmundur | Gyllensten, Ulf | Hamsten, Anders | Harris, Tamara B. | Hingorani, Aroon | Hirschhorn, Joel N. | Hofman, Albert | Hovingh, G. Kees | Hsiung, Chao Agnes | Humphries, Steve E. | Hunt, Steven C. | Hveem, Kristian | Iribarren, Carlos | Järvelin, Marjo-Riitta | Jula, Antti | Kähönen, Mika | Kaprio, Jaakko | Kesäniemi, Antero | Kivimaki, Mika | Kooner, Jaspal S. | Koudstaal, Peter J. | Krauss, Ronald M. | Kuh, Diana | Kuusisto, Johanna | Kyvik, Kirsten O. | Laakso, Markku | Lakka, Timo A. | Lind, Lars | Lindgren, Cecilia M. | Martin, Nicholas G. | März, Winfried | McCarthy, Mark I. | McKenzie, Colin A. | Meneton, Pierre | Metspalu, Andres | Moilanen, Leena | Morris, Andrew D. | Munroe, Patricia B. | Njølstad, Inger | Pedersen, Nancy L. | Power, Chris | Pramstaller, Peter P. | Price, Jackie F. | Psaty, Bruce M. | Quertermous, Thomas | Rauramaa, Rainer | Saleheen, Danish | Salomaa, Veikko | Sanghera, Dharambir K. | Saramies, Jouko | Schwarz, Peter E.H. | Sheu, Wayne H-H | Shuldiner, Alan R. | Siegbahn, Agneta | Spector, Tim D. | Stefansson, Kari | Strachan, David P. | Tayo, Bamidele O. | Tremoli, Elena | Tuomilehto, Jaakko | Uusitupa, Matti | van Duijn, Cornelia M. | Vollenweider, Peter | Wallentin, Lars | Wareham, Nicholas J. | Whitfield, John B. | Wolffenbuttel, Bruce H.R. | Ordovas, Jose M. | Boerwinkle, Eric | Palmer, Colin N.A. | Thorsteinsdottir, Unnur | Chasman, Daniel I. | Rotter, Jerome I. | Franks, Paul W. | Ripatti, Samuli | Cupples, L. Adrienne | Sandhu, Manjinder S. | Rich, Stephen S. | Boehnke, Michael | Deloukas, Panos | Kathiresan, Sekar | Mohlke, Karen L. | Ingelsson, Erik | Abecasis, Gonçalo R.
Nature genetics  2013;45(11):10.1038/ng.2797.
Low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, and total cholesterol are heritable, modifiable, risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,578 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5×10−8, including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian, and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipids are often associated with cardiovascular and metabolic traits including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio, and body mass index. Our results illustrate the value of genetic data from individuals of diverse ancestries and provide insights into biological mechanisms regulating blood lipids to guide future genetic, biological, and therapeutic research.
doi:10.1038/ng.2797
PMCID: PMC3838666  PMID: 24097068
7.  Common variants associated with plasma triglycerides and risk for coronary artery disease 
Do, Ron | Willer, Cristen J. | Schmidt, Ellen M. | Sengupta, Sebanti | Gao, Chi | Peloso, Gina M. | Gustafsson, Stefan | Kanoni, Stavroula | Ganna, Andrea | Chen, Jin | Buchkovich, Martin L. | Mora, Samia | Beckmann, Jacques S. | Bragg-Gresham, Jennifer L. | Chang, Hsing-Yi | Demirkan, Ayşe | Den Hertog, Heleen M. | Donnelly, Louise A. | Ehret, Georg B. | Esko, Tõnu | Feitosa, Mary F. | Ferreira, Teresa | Fischer, Krista | Fontanillas, Pierre | Fraser, Ross M. | Freitag, Daniel F. | Gurdasani, Deepti | Heikkilä, Kauko | Hyppönen, Elina | Isaacs, Aaron | Jackson, Anne U. | Johansson, Åsa | Johnson, Toby | Kaakinen, Marika | Kettunen, Johannes | Kleber, Marcus E. | Li, Xiaohui | Luan, Jian'an | Lyytikäinen, Leo-Pekka | Magnusson, Patrik K.E. | Mangino, Massimo | Mihailov, Evelin | Montasser, May E. | Müller-Nurasyid, Martina | Nolte, Ilja M. | O'Connell, Jeffrey R. | Palmer, Cameron D. | Perola, Markus | Petersen, Ann-Kristin | Sanna, Serena | Saxena, Richa | Service, Susan K. | Shah, Sonia | Shungin, Dmitry | Sidore, Carlo | Song, Ci | Strawbridge, Rona J. | Surakka, Ida | Tanaka, Toshiko | Teslovich, Tanya M. | Thorleifsson, Gudmar | Van den Herik, Evita G. | Voight, Benjamin F. | Volcik, Kelly A. | Waite, Lindsay L. | Wong, Andrew | Wu, Ying | Zhang, Weihua | Absher, Devin | Asiki, Gershim | Barroso, Inês | Been, Latonya F. | Bolton, Jennifer L. | Bonnycastle, Lori L | Brambilla, Paolo | Burnett, Mary S. | Cesana, Giancarlo | Dimitriou, Maria | Doney, Alex S.F. | Döring, Angela | Elliott, Paul | Epstein, Stephen E. | Eyjolfsson, Gudmundur Ingi | Gigante, Bruna | Goodarzi, Mark O. | Grallert, Harald | Gravito, Martha L. | Groves, Christopher J. | Hallmans, Göran | Hartikainen, Anna-Liisa | Hayward, Caroline | Hernandez, Dena | Hicks, Andrew A. | Holm, Hilma | Hung, Yi-Jen | Illig, Thomas | Jones, Michelle R. | Kaleebu, Pontiano | Kastelein, John J.P. | Khaw, Kay-Tee | Kim, Eric | Klopp, Norman | Komulainen, Pirjo | Kumari, Meena | Langenberg, Claudia | Lehtimäki, Terho | Lin, Shih-Yi | Lindström, Jaana | Loos, Ruth J.F. | Mach, François | McArdle, Wendy L | Meisinger, Christa | Mitchell, Braxton D. | Müller, Gabrielle | Nagaraja, Ramaiah | Narisu, Narisu | Nieminen, Tuomo V.M. | Nsubuga, Rebecca N. | Olafsson, Isleifur | Ong, Ken K. | Palotie, Aarno | Papamarkou, Theodore | Pomilla, Cristina | Pouta, Anneli | Rader, Daniel J. | Reilly, Muredach P. | Ridker, Paul M. | Rivadeneira, Fernando | Rudan, Igor | Ruokonen, Aimo | Samani, Nilesh | Scharnagl, Hubert | Seeley, Janet | Silander, Kaisa | Stančáková, Alena | Stirrups, Kathleen | Swift, Amy J. | Tiret, Laurence | Uitterlinden, Andre G. | van Pelt, L. Joost | Vedantam, Sailaja | Wainwright, Nicholas | Wijmenga, Cisca | Wild, Sarah H. | Willemsen, Gonneke | Wilsgaard, Tom | Wilson, James F. | Young, Elizabeth H. | Zhao, Jing Hua | Adair, Linda S. | Arveiler, Dominique | Assimes, Themistocles L. | Bandinelli, Stefania | Bennett, Franklyn | Bochud, Murielle | Boehm, Bernhard O. | Boomsma, Dorret I. | Borecki, Ingrid B. | Bornstein, Stefan R. | Bovet, Pascal | Burnier, Michel | Campbell, Harry | Chakravarti, Aravinda | Chambers, John C. | Chen, Yii-Der Ida | Collins, Francis S. | Cooper, Richard S. | Danesh, John | Dedoussis, George | de Faire, Ulf | Feranil, Alan B. | Ferrières, Jean | Ferrucci, Luigi | Freimer, Nelson B. | Gieger, Christian | Groop, Leif C. | Gudnason, Vilmundur | Gyllensten, Ulf | Hamsten, Anders | Harris, Tamara B. | Hingorani, Aroon | Hirschhorn, Joel N. | Hofman, Albert | Hovingh, G. Kees | Hsiung, Chao Agnes | Humphries, Steve E. | Hunt, Steven C. | Hveem, Kristian | Iribarren, Carlos | Järvelin, Marjo-Riitta | Jula, Antti | Kähönen, Mika | Kaprio, Jaakko | Kesäniemi, Antero | Kivimaki, Mika | Kooner, Jaspal S. | Koudstaal, Peter J. | Krauss, Ronald M. | Kuh, Diana | Kuusisto, Johanna | Kyvik, Kirsten O. | Laakso, Markku | Lakka, Timo A. | Lind, Lars | Lindgren, Cecilia M. | Martin, Nicholas G. | März, Winfried | McCarthy, Mark I. | McKenzie, Colin A. | Meneton, Pierre | Metspalu, Andres | Moilanen, Leena | Morris, Andrew D. | Munroe, Patricia B. | Njølstad, Inger | Pedersen, Nancy L. | Power, Chris | Pramstaller, Peter P. | Price, Jackie F. | Psaty, Bruce M. | Quertermous, Thomas | Rauramaa, Rainer | Saleheen, Danish | Salomaa, Veikko | Sanghera, Dharambir K. | Saramies, Jouko | Schwarz, Peter E.H. | Sheu, Wayne H-H | Shuldiner, Alan R. | Siegbahn, Agneta | Spector, Tim D. | Stefansson, Kari | Strachan, David P. | Tayo, Bamidele O. | Tremoli, Elena | Tuomilehto, Jaakko | Uusitupa, Matti | van Duijn, Cornelia M. | Vollenweider, Peter | Wallentin, Lars | Wareham, Nicholas J. | Whitfield, John B. | Wolffenbuttel, Bruce H.R. | Altshuler, David | Ordovas, Jose M. | Boerwinkle, Eric | Palmer, Colin N.A. | Thorsteinsdottir, Unnur | Chasman, Daniel I. | Rotter, Jerome I. | Franks, Paul W. | Ripatti, Samuli | Cupples, L. Adrienne | Sandhu, Manjinder S. | Rich, Stephen S. | Boehnke, Michael | Deloukas, Panos | Mohlke, Karen L. | Ingelsson, Erik | Abecasis, Goncalo R. | Daly, Mark J. | Neale, Benjamin M. | Kathiresan, Sekar
Nature genetics  2013;45(11):1345-1352.
Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiologic studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P<5×10−8 for each) to examine the role of triglycerides on risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglycerides, and show that the direction and magnitude of both are factors in determining CAD risk. Second, we consider loci with only a strong magnitude of association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol, a polymorphism's strength of effect on triglycerides is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
doi:10.1038/ng.2795
PMCID: PMC3904346  PMID: 24097064
8.  Assessing Risk Prediction Models Using Individual Participant Data From Multiple Studies 
Pennells, Lisa | Kaptoge, Stephen | White, Ian R. | Thompson, Simon G. | Wood, Angela M. | Tipping, Robert W. | Folsom, Aaron R. | Couper, David J. | Ballantyne, Christie M. | Coresh, Josef | Goya Wannamethee, S. | Morris, Richard W. | Kiechl, Stefan | Willeit, Johann | Willeit, Peter | Schett, Georg | Ebrahim, Shah | Lawlor, Debbie A. | Yarnell, John W. | Gallacher, John | Cushman, Mary | Psaty, Bruce M. | Tracy, Russ | Tybjærg-Hansen, Anne | Price, Jackie F. | Lee, Amanda J. | McLachlan, Stela | Khaw, Kay-Tee | Wareham, Nicholas J. | Brenner, Hermann | Schöttker, Ben | Müller, Heiko | Jansson, Jan-Håkan | Wennberg, Patrik | Salomaa, Veikko | Harald, Kennet | Jousilahti, Pekka | Vartiainen, Erkki | Woodward, Mark | D'Agostino, Ralph B. | Bladbjerg, Else-Marie | Jørgensen, Torben | Kiyohara, Yutaka | Arima, Hisatomi | Doi, Yasufumi | Ninomiya, Toshiharu | Dekker, Jacqueline M. | Nijpels, Giel | Stehouwer, Coen D. A. | Kauhanen, Jussi | Salonen, Jukka T. | Meade, Tom W. | Cooper, Jackie A. | Cushman, Mary | Folsom, Aaron R. | Psaty, Bruce M. | Shea, Steven | Döring, Angela | Kuller, Lewis H. | Grandits, Greg | Gillum, Richard F. | Mussolino, Michael | Rimm, Eric B. | Hankinson, Sue E. | Manson, JoAnn E. | Pai, Jennifer K. | Kirkland, Susan | Shaffer, Jonathan A. | Shimbo, Daichi | Bakker, Stephan J. L. | Gansevoort, Ron T. | Hillege, Hans L. | Amouyel, Philippe | Arveiler, Dominique | Evans, Alun | Ferrières, Jean | Sattar, Naveed | Westendorp, Rudi G. | Buckley, Brendan M. | Cantin, Bernard | Lamarche, Benoît | Barrett-Connor, Elizabeth | Wingard, Deborah L. | Bettencourt, Richele | Gudnason, Vilmundur | Aspelund, Thor | Sigurdsson, Gunnar | Thorsson, Bolli | Kavousi, Maryam | Witteman, Jacqueline C. | Hofman, Albert | Franco, Oscar H. | Howard, Barbara V. | Zhang, Ying | Best, Lyle | Umans, Jason G. | Onat, Altan | Sundström, Johan | Michael Gaziano, J. | Stampfer, Meir | Ridker, Paul M. | Michael Gaziano, J. | Ridker, Paul M. | Marmot, Michael | Clarke, Robert | Collins, Rory | Fletcher, Astrid | Brunner, Eric | Shipley, Martin | Kivimäki, Mika | Ridker, Paul M. | Buring, Julie | Cook, Nancy | Ford, Ian | Shepherd, James | Cobbe, Stuart M. | Robertson, Michele | Walker, Matthew | Watson, Sarah | Alexander, Myriam | Butterworth, Adam S. | Angelantonio, Emanuele Di | Gao, Pei | Haycock, Philip | Kaptoge, Stephen | Pennells, Lisa | Thompson, Simon G. | Walker, Matthew | Watson, Sarah | White, Ian R. | Wood, Angela M. | Wormser, David | Danesh, John
American Journal of Epidemiology  2013;179(5):621-632.
Individual participant time-to-event data from multiple prospective epidemiologic studies enable detailed investigation into the predictive ability of risk models. Here we address the challenges in appropriately combining such information across studies. Methods are exemplified by analyses of log C-reactive protein and conventional risk factors for coronary heart disease in the Emerging Risk Factors Collaboration, a collation of individual data from multiple prospective studies with an average follow-up duration of 9.8 years (dates varied). We derive risk prediction models using Cox proportional hazards regression analysis stratified by study and obtain estimates of risk discrimination, Harrell's concordance index, and Royston's discrimination measure within each study; we then combine the estimates across studies using a weighted meta-analysis. Various weighting approaches are compared and lead us to recommend using the number of events in each study. We also discuss the calculation of measures of reclassification for multiple studies. We further show that comparison of differences in predictive ability across subgroups should be based only on within-study information and that combining measures of risk discrimination from case-control studies and prospective studies is problematic. The concordance index and discrimination measure gave qualitatively similar results throughout. While the concordance index was very heterogeneous between studies, principally because of differing age ranges, the increments in the concordance index from adding log C-reactive protein to conventional risk factors were more homogeneous.
doi:10.1093/aje/kwt298
PMCID: PMC3927974  PMID: 24366051
C index; coronary heart disease; D measure; individual participant data; inverse variance; meta-analysis; risk prediction; weighting
9.  Adult height and the risk of cause-specific death and vascular morbidity in 1 million people: individual participant meta-analysis 
Wormser, David | Angelantonio, Emanuele Di | Kaptoge, Stephen | Wood, Angela M | Gao, Pei | Sun, Qi | Walldius, Göran | Selmer, Randi | Verschuren, WM Monique | Bueno-de-Mesquita, H Bas | Engström, Gunnar | Ridker, Paul M | Njølstad, Inger | Iso, Hiroyasu | Holme, Ingar | Giampaoli, Simona | Tunstall-Pedoe, Hugh | Gaziano, J Michael | Brunner, Eric | Kee, Frank | Tosetto, Alberto | Meisinger, Christa | Brenner, Hermann | Ducimetiere, Pierre | Whincup, Peter H | Tipping, Robert W | Ford, Ian | Cremer, Peter | Hofman, Albert | Wilhelmsen, Lars | Clarke, Robert | de Boer, Ian H | Jukema, J Wouter | Ibañez, Alejandro Marín | Lawlor, Debbie A | D'Agostino, Ralph B | Rodriguez, Beatriz | Casiglia, Edoardo | Stehouwer, Coen DA | Simons, Leon A | Nietert, Paul J | Barrett-Connor, Elizabeth | Panagiotakos, Demosthenes B | Björkelund, Cecilia | Strandberg, Timo E | Wassertheil-Smoller, Sylvia | Blazer, Dan G | Meade, Tom W | Welin, Lennart | Svärdsudd, Kurt | Woodward, Mark | Nissinen, Aulikki | Kromhout, Daan | Jørgensen, Torben | Tilvis, Reijo S | Guralnik, Jack M | Rosengren, Annika | Taylor, James O | Kiechl, Stefan | Dagenais, Gilles R | Gerry, F | Fowkes, R | Wallace, Robert B | Khaw, Kay-Tee | Shaffer, Jonathan A | Visser, Marjolein | Kauhanen, Jussi | Salonen, Jukka T | Gallacher, John | Ben-Shlomo, Yoav | Kitamura, Akihiko | Sundström, Johan | Wennberg, Patrik | Kiyohara, Yutaka | Daimon, Makoto | de la Cámara, Agustin Gómez | Cooper, Jackie A | Onat, Altan | Devereux, Richard | Mukamal, Kenneth J | Dankner, Rachel | Knuiman, Matthew W | Crespo, Carlos J | Gansevoort, Ron T | Goldbourt, Uri | Nordestgaard, Børge G | Shaw, Jonathan E | Mussolino, Michael | Nakagawa, Hidaeki | Fletcher, Astrid | Kuller, Lewis H | Gillum, Richard F | Gudnason, Vilmundur | Assmann, Gerd | Wald, Nicholas | Jousilahti, Pekka R | Greenland, Philip | Trevisan, Maurizio | Ulmer, Hanno | Butterworth, Adam S | Folsom, Aaron R | Davey-Smith, George | Hu, Frank B | Danesh, John | Tipping, Robert W | Ford, Charles E | Simpson, Lara M | Walldius, Göran | Jungner, Ingmar | Folsom, Aaron R | Demerath, Ellen W | Franceschini, Nora | Lutsey, Pamela L | Panagiotakos, Demosthenes B | Pitsavos, Christos | Chrysohoou, Christina | Stefanadis, Christodoulos | Shaw, Jonathan E | Atkins, Robert | Zimmet, Paul Z | Barr, Elizabeth LM | Knuiman, Matthew W | Whincup, Peter H | Wannamethee, S Goya | Morris, Richard W | Willeit, Johann | Kiechl, Stefan | Weger, Siegfried | Oberhollenzer, Friedrich | Wald, Nicholas | Ebrahim, Shah | Lawlor, Debbie A | Gallacher, John | Ben-Shlomo, Yoav | Yarnell, John WG | Casiglia, Edoardo | Tikhonoff, Valérie | Greenland, Philip | Shay, Christina M | Garside, Daniel B | Nietert, Paul J | Sutherland, Susan E | Bachman, David L | Keil, Julian E | de Boer, Ian H | Kizer, Jorge R | Psaty, Bruce M | Mukamal, Kenneth J | Nordestgaard, Børge G | Tybjærg-Hansen, Anne | Jensen, Gorm B | Schnohr, Peter | Giampaoli, Simona | Palmieri, Luigi | Panico, Salvatore | Pilotto, Lorenza | Vanuzzo, Diego | de la Cámara, Agustin Gómez | Simons, Leon A | Simons, Judith | McCallum, John | Friedlander, Yechiel | Gerry, F | Fowkes, R | Price, Jackie F | Lee, Amanda J | Taylor, James O | Guralnik, Jack M | Phillips, Caroline L | Wallace, Robert B | Kohout, Frank J | Cornoni-Huntley, Joan C | Guralnik, Jack M | Blazer, Dan G | Guralnik, Jack M | Phillips, Caroline L | Phillips, Caroline L | Guralnik, Jack M | Khaw, Kay-Tee | Wareham, Nicholas J | Brenner, Hermann | Schöttker, Ben | Müller, Heiko | Rothenbacher, Dietrich | Wennberg, Patrik | Jansson, Jan-Håkan | Nissinen, Aulikki | Donfrancesco, Chiara | Giampaoli, Simona | Woodward, Mark | Vartiainen, Erkki | Jousilahti, Pekka R | Harald, Kennet | Salomaa, Veikko | D'Agostino, Ralph B | Vasan, Ramachandran S | Fox, Caroline S | Pencina, Michael J | Daimon, Makoto | Oizumi, Toshihide | Kayama, Takamasa | Kato, Takeo | Bladbjerg, Else-Marie | Jørgensen, Torben | Møller, Lars | Jespersen, Jørgen | Dankner, Rachel | Chetrit, Angela | Lubin, Flora | Svärdsudd, Kurt | Eriksson, Henry | Welin, Lennart | Lappas, Georgios | Rosengren, Annika | Lappas, Georgios | Welin, Lennart | Svärdsudd, Kurt | Eriksson, Henry | Lappas, Georgios | Bengtsson, Calle | Lissner, Lauren | Björkelund, Cecilia | Cremer, Peter | Nagel, Dorothea | Strandberg, Timo E | Salomaa, Veikko | Tilvis, Reijo S | Miettinen, Tatu A | Tilvis, Reijo S | Strandberg, Timo E | Kiyohara, Yutaka | Arima, Hisatomi | Doi, Yasufumi | Ninomiya, Toshiharu | Rodriguez, Beatriz | Dekker, Jacqueline M | Nijpels, Giel | Stehouwer, Coen DA | Hu, Frank B | Sun, Qi | Rimm, Eric B | Willett, Walter C | Iso, Hiroyasu | Kitamura, Akihiko | Yamagishi, Kazumasa | Noda, Hiroyuki | Goldbourt, Uri | Vartiainen, Erkki | Jousilahti, Pekka R | Harald, Kennet | Salomaa, Veikko | Kauhanen, Jussi | Salonen, Jukka T | Kurl, Sudhir | Tuomainen, Tomi-Pekka | Poppelaars, Jan L | Deeg, Dorly JH | Visser, Marjolein | Meade, Tom W | De Stavola, Bianca Lucia | Hedblad, Bo | Nilsson, Peter | Engström, Gunnar | Verschuren, WM Monique | Blokstra, Anneke | de Boer, Ian H | Shea, Steven J | Meisinger, Christa | Thorand, Barbara | Koenig, Wolfgang | Döring, Angela | Verschuren, WM Monique | Blokstra, Anneke | Bueno-de-Mesquita, H Bas | Wilhelmsen, Lars | Rosengren, Annika | Lappas, Georgios | Fletcher, Astrid | Nitsch, Dorothea | Kuller, Lewis H | Grandits, Greg | Tverdal, Aage | Selmer, Randi | Nystad, Wenche | Mussolino, Michael | Gillum, Richard F | Hu, Frank B | Sun, Qi | Manson, JoAnn E | Rimm, Eric B | Hankinson, Susan E | Meade, Tom W | De Stavola, Bianca Lucia | Cooper, Jackie A | Bauer, Kenneth A | Davidson, Karina W | Kirkland, Susan | Shaffer, Jonathan A | Shimbo, Daichi | Kitamura, Akihiko | Iso, Hiroyasu | Sato, Shinichi | Holme, Ingar | Selmer, Randi | Tverdal, Aage | Nystad, Wenche | Nakagawa, Hidaeki | Miura, Katsuyuki | Sakurai, Masaru | Ducimetiere, Pierre | Jouven, Xavier | Bakker, Stephan JL | Gansevoort, Ron T | van der Harst, Pim | Hillege, Hans L | Crespo, Carlos J | Garcia-Palmieri, Mario R | Kee, Frank | Amouyel, Philippe | Arveiler, Dominique | Ferrières, Jean | Schulte, Helmut | Assmann, Gerd | Jukema, J Wouter | de Craen, Anton JM | Sattar, Naveed | Stott, David J | Cantin, Bernard | Lamarche, Benoît | Després, Jean-Pierre | Dagenais, Gilles R | Barrett-Connor, Elizabeth | Bergstrom, Jaclyn | Bettencourt, Richele R | Buisson, Catherine | Gudnason, Vilmundur | Aspelund, Thor | Sigurdsson, Gunnar | Thorsson, Bolli | Trevisan, Maurizio | Hofman, Albert | Ikram, M Arfan | Tiemeier, Henning | Witteman, Jacqueline CM | Tunstall-Pedoe, Hugh | Tavendale, Roger | Lowe, Gordon DO | Woodward, Mark | Devereux, Richard | Yeh, Jeun-Liang | Ali, Tauqeer | Calhoun, Darren | Ben-Shlomo, Yoav | Davey-Smith, George | Onat, Altan | Can, Günay | Nakagawa, Hidaeki | Sakurai, Masaru | Nakamura, Koshi | Morikawa, Yuko | Njølstad, Inger | Mathiesen, Ellisiv B | Løchen, Maja-Lisa | Wilsgaard, Tom | Sundström, Johan | Ingelsson, Erik | Michaëlsson, Karl | Cederholm, Tommy | Gaziano, J Michael | Buring, Julie | Ridker, Paul M | Gaziano, J Michael | Ridker, Paul M | Ulmer, Hanno | Diem, Günter | Concin, Hans | Rodeghiero, Francesco | Tosetto, Alberto | Wassertheil-Smoller, Sylvia | Manson, JoAnn E | Marmot, Michael | Clarke, Robert | Fletcher, Astrid | Brunner, Eric | Shipley, Martin | Kivimaki, Mika | Ridker, Paul M | Buring, Julie | Ford, Ian | Robertson, Michele | Ibañez, Alejandro Marín | Feskens, Edith | Geleijnse, Johanna M | Kromhout, Daan | Walker, Matthew | Watson, Sarah | Alexander, Myriam | Butterworth, Adam S | Angelantonio, Emanuele Di | Franco, Oscar H | Gao, Pei | Gobin, Reeta | Haycock, Philip | Kaptoge, Stephen | Seshasai, Sreenivasa R Kondapally | Lewington, Sarah | Pennells, Lisa | Rapsomaniki, Eleni | Sarwar, Nadeem | Thompson, Alexander | Thompson, Simon G | Walker, Matthew | Watson, Sarah | White, Ian R | Wood, Angela M | Wormser, David | Zhao, Xiaohui | Danesh, John
Background The extent to which adult height, a biomarker of the interplay of genetic endowment and early-life experiences, is related to risk of chronic diseases in adulthood is uncertain.
Methods We calculated hazard ratios (HRs) for height, assessed in increments of 6.5 cm, using individual–participant data on 174 374 deaths or major non-fatal vascular outcomes recorded among 1 085 949 people in 121 prospective studies.
Results For people born between 1900 and 1960, mean adult height increased 0.5–1 cm with each successive decade of birth. After adjustment for age, sex, smoking and year of birth, HRs per 6.5 cm greater height were 0.97 (95% confidence interval: 0.96–0.99) for death from any cause, 0.94 (0.93–0.96) for death from vascular causes, 1.04 (1.03–1.06) for death from cancer and 0.92 (0.90–0.94) for death from other causes. Height was negatively associated with death from coronary disease, stroke subtypes, heart failure, stomach and oral cancers, chronic obstructive pulmonary disease, mental disorders, liver disease and external causes. In contrast, height was positively associated with death from ruptured aortic aneurysm, pulmonary embolism, melanoma and cancers of the pancreas, endocrine and nervous systems, ovary, breast, prostate, colorectum, blood and lung. HRs per 6.5 cm greater height ranged from 1.26 (1.12–1.42) for risk of melanoma death to 0.84 (0.80–0.89) for risk of death from chronic obstructive pulmonary disease. HRs were not appreciably altered after further adjustment for adiposity, blood pressure, lipids, inflammation biomarkers, diabetes mellitus, alcohol consumption or socio-economic indicators.
Conclusion Adult height has directionally opposing relationships with risk of death from several different major causes of chronic diseases.
doi:10.1093/ije/dys086
PMCID: PMC3465767  PMID: 22825588
Height; cardiovascular disease; cancer; cause-specific mortality; epidemiological study; meta-analysis
10.  Genome-wide association study in people of South Asian ancestry identifies six novel susceptibility loci for type 2 diabetes 
Nature genetics  2011;43(10):984-989.
We carried out a genome wide association study of type-2 diabetes (T2D) amongst 20,119 people of South Asian ancestry (5,561 with T2D); we identified 20 independent SNPs associated with T2D at P<10−4 for testing amongst a further 38,568 South Asians (13,170 with T2D). In combined analysis, common genetic variants at six novel loci (GRB14, ST6GAL1, VPS26A, HMG20A, AP3S2 and HNF4A) were associated with T2D (P=4.1×10−8 to P=1.9×10−11); SNPs at GRB14 were also associated with insulin sensitivity, and at ST6GAL1 and HNF4A with pancreatic beta-cell function respectively. Our findings provide additional insight into mechanisms underlying T2D, and demonstrate the potential for new discovery from genetic association studies in South Asians who have increased susceptibility to T2D.
doi:10.1038/ng.921
PMCID: PMC3773920  PMID: 21874001
11.  Genetic Associations with Valvular Calcification and Aortic Stenosis 
The New England journal of medicine  2013;368(6):503-512.
BACKGROUND
Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease.
METHODS
We determined genomewide associations with the presence of aorticvalve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis.
RESULTS
One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aorticvalve calcification (odds ratio per allele, 2.05; P = 9.0×10−10), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aorticvalve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P = 1.5×10−8 and P = 1.8×10−8, respectively), but the findings were not replicated consistently.
CONCLUSIONS
Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aorticvalve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.)
doi:10.1056/NEJMoa1109034
PMCID: PMC3766627  PMID: 23388002
12.  GUESS-ing Polygenic Associations with Multiple Phenotypes Using a GPU-Based Evolutionary Stochastic Search Algorithm 
PLoS Genetics  2013;9(8):e1003657.
Genome-wide association studies (GWAS) yielded significant advances in defining the genetic architecture of complex traits and disease. Still, a major hurdle of GWAS is narrowing down multiple genetic associations to a few causal variants for functional studies. This becomes critical in multi-phenotype GWAS where detection and interpretability of complex SNP(s)-trait(s) associations are complicated by complex Linkage Disequilibrium patterns between SNPs and correlation between traits. Here we propose a computationally efficient algorithm (GUESS) to explore complex genetic-association models and maximize genetic variant detection. We integrated our algorithm with a new Bayesian strategy for multi-phenotype analysis to identify the specific contribution of each SNP to different trait combinations and study genetic regulation of lipid metabolism in the Gutenberg Health Study (GHS). Despite the relatively small size of GHS (n = 3,175), when compared with the largest published meta-GWAS (n>100,000), GUESS recovered most of the major associations and was better at refining multi-trait associations than alternative methods. Amongst the new findings provided by GUESS, we revealed a strong association of SORT1 with TG-APOB and LIPC with TG-HDL phenotypic groups, which were overlooked in the larger meta-GWAS and not revealed by competing approaches, associations that we replicated in two independent cohorts. Moreover, we demonstrated the increased power of GUESS over alternative multi-phenotype approaches, both Bayesian and non-Bayesian, in a simulation study that mimics real-case scenarios. We showed that our parallel implementation based on Graphics Processing Units outperforms alternative multi-phenotype methods. Beyond multivariate modelling of multi-phenotypes, our Bayesian model employs a flexible hierarchical prior structure for genetic effects that adapts to any correlation structure of the predictors and increases the power to identify associated variants. This provides a powerful tool for the analysis of diverse genomic features, for instance including gene expression and exome sequencing data, where complex dependencies are present in the predictor space.
Author Summary
Nowadays, the availability of cheaper and accurate assays to quantify multiple (endo)phenotypes in large population cohorts allows multi-trait studies. However, these studies are limited by the lack of flexible models integrated with efficient computational tools for genome-wide multi SNPs-traits analyses. To overcome this problem, we propose a novel Bayesian analysis strategy and a new algorithmic implementation which exploits parallel processing architecture for fully multivariate modeling of groups of correlated phenotypes at the genome-wide scale. In addition to increased power of our algorithm over alternative Bayesian and well-established non-Bayesian multi-phenotype methods, we provide an application to a real case study of several blood lipid traits, and show how our method recovered most of the major associations and is better at refining multi-trait polygenic associations than alternative methods. We reveal and replicate in independent cohorts new associations with two phenotypic groups that were not detected by competing multivariate approaches and not noticed by a large meta-GWAS. We also discuss the applicability of the proposed method to large meta-analyses involving hundreds of thousands of individuals and to diverse genomic datasets where complex dependencies in the predictor space are present.
doi:10.1371/journal.pgen.1003657
PMCID: PMC3738451  PMID: 23950726
13.  Seventy-five genetic loci influencing the human red blood cell 
van der Harst, Pim | Zhang, Weihua | Leach, Irene Mateo | Rendon, Augusto | Verweij, Niek | Sehmi, Joban | Paul, Dirk S. | Elling, Ulrich | Allayee, Hooman | Li, Xinzhong | Radhakrishnan, Aparna | Tan, Sian-Tsung | Voss, Katrin | Weichenberger, Christian X. | Albers, Cornelis A. | Al-Hussani, Abtehale | Asselbergs, Folkert W. | Ciullo, Marina | Danjou, Fabrice | Dina, Christian | Esko, Tõnu | Evans, David M. | Franke, Lude | Gögele, Martin | Hartiala, Jaana | Hersch, Micha | Holm, Hilma | Hottenga, Jouke-Jan | Kanoni, Stavroula | Kleber, Marcus E. | Lagou, Vasiliki | Langenberg, Claudia | Lopez, Lorna M. | Lyytikäinen, Leo-Pekka | Melander, Olle | Murgia, Federico | Nolte, Ilja M. | O’Reilly, Paul F. | Padmanabhan, Sandosh | Parsa, Afshin | Pirastu, Nicola | Porcu, Eleonora | Portas, Laura | Prokopenko, Inga | Ried, Janina S. | Shin, So-Youn | Tang, Clara S. | Teumer, Alexander | Traglia, Michela | Ulivi, Sheila | Westra, Harm-Jan | Yang, Jian | Zhao, Jing Hua | Anni, Franco | Abdellaoui, Abdel | Attwood, Antony | Balkau, Beverley | Bandinelli, Stefania | Bastardot, François | Benyamin, Beben | Boehm, Bernhard O. | Cookson, William O. | Das, Debashish | de Bakker, Paul I. W. | de Boer, Rudolf A. | de Geus, Eco J. C. | de Moor, Marleen H. | Dimitriou, Maria | Domingues, Francisco S. | Döring, Angela | Engström, Gunnar | Eyjolfsson, Gudmundur Ingi | Ferrucci, Luigi | Fischer, Krista | Galanello, Renzo | Garner, Stephen F. | Genser, Bernd | Gibson, Quince D. | Girotto, Giorgia | Gudbjartsson, Daniel Fannar | Harris, Sarah E. | Hartikainen, Anna-Liisa | Hastie, Claire E. | Hedblad, Bo | Illig, Thomas | Jolley, Jennifer | Kähönen, Mika | Kema, Ido P. | Kemp, John P. | Liang, Liming | Lloyd-Jones, Heather | Loos, Ruth J. F. | Meacham, Stuart | Medland, Sarah E. | Meisinger, Christa | Memari, Yasin | Mihailov, Evelin | Miller, Kathy | Moffatt, Miriam F. | Nauck, Matthias | Novatchkova, Maria | Nutile, Teresa | Olafsson, Isleifur | Onundarson, Pall T. | Parracciani, Debora | Penninx, Brenda W. | Perseu, Lucia | Piga, Antonio | Pistis, Giorgio | Pouta, Anneli | Puc, Ursula | Raitakari, Olli | Ring, Susan M. | Robino, Antonietta | Ruggiero, Daniela | Ruokonen, Aimo | Saint-Pierre, Aude | Sala, Cinzia | Salumets, Andres | Sambrook, Jennifer | Schepers, Hein | Schmidt, Carsten Oliver | Silljé, Herman H. W. | Sladek, Rob | Smit, Johannes H. | Starr, John M. | Stephens, Jonathan | Sulem, Patrick | Tanaka, Toshiko | Thorsteinsdottir, Unnur | Tragante, Vinicius | van Gilst, Wiek H. | van Pelt, L. Joost | van Veldhuisen, Dirk J. | Völker, Uwe | Whitfield, John B. | Willemsen, Gonneke | Winkelmann, Bernhard R. | Wirnsberger, Gerald | Algra, Ale | Cucca, Francesco | d’Adamo, Adamo Pio | Danesh, John | Deary, Ian J. | Dominiczak, Anna F. | Elliott, Paul | Fortina, Paolo | Froguel, Philippe | Gasparini, Paolo | Greinacher, Andreas | Hazen, Stanley L. | Jarvelin, Marjo-Riitta | Khaw, Kay Tee | Lehtimäki, Terho | Maerz, Winfried | Martin, Nicholas G. | Metspalu, Andres | Mitchell, Braxton D. | Montgomery, Grant W. | Moore, Carmel | Navis, Gerjan | Pirastu, Mario | Pramstaller, Peter P. | Ramirez-Solis, Ramiro | Schadt, Eric | Scott, James | Shuldiner, Alan R. | Smith, George Davey | Smith, J. Gustav | Snieder, Harold | Sorice, Rossella | Spector, Tim D. | Stefansson, Kari | Stumvoll, Michael | Wilson Tang, W. H. | Toniolo, Daniela | Tönjes, Anke | Visscher, Peter M. | Vollenweider, Peter | Wareham, Nicholas J. | Wolffenbuttel, Bruce H. R. | Boomsma, Dorret I. | Beckmann, Jacques S. | Dedoussis, George V. | Deloukas, Panos | Ferreira, Manuel A. | Sanna, Serena | Uda, Manuela | Hicks, Andrew A. | Penninger, Josef Martin | Gieger, Christian | Kooner, Jaspal S. | Ouwehand, Willem H. | Soranzo, Nicole | Chambers, John C
Nature  2012;492(7429):369-375.
Anaemia is a chief determinant of globalill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P <10−8, which together explain 4–9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.
doi:10.1038/nature11677
PMCID: PMC3623669  PMID: 23222517
14.  Are Myocardial Infarction–Associated Single-Nucleotide Polymorphisms Associated With Ischemic Stroke? 
Background and Purpose
Ischemic stroke (IS) shares many common risk factors with coronary artery disease (CAD). We hypothesized that genetic variants associated with myocardial infarction (MI) or CAD may be similarly involved in the etiology of IS. To test this hypothesis, we evaluated whether single-nucleotide polymorphisms (SNPs) at 11 different loci recently associated with MI or CAD through genome-wide association studies were associated with IS.
Methods
Meta-analyses of the associations between the 11 MI-associated SNPs and IS were performed using 6865 cases and 11 395 control subjects recruited from 9 studies. SNPs were either genotyped directly or imputed; in a few cases a surrogate SNP in high linkage disequilibrium was chosen. Logistic regression was performed within each study to obtain study-specific βs and standard errors. Meta-analysis was conducted using an inverse variance weighted approach assuming a random effect model.
Results
Despite having power to detect odds ratio of 1.09–1.14 for overall IS and 1.20–1.32 for major stroke subtypes, none of the SNPs were significantly associated with overall IS and/or stroke subtypes after adjusting for multiple comparisons.
Conclusions
Our results suggest that the major common loci associated with MI risk do not have effects of similar magnitude on overall IS but do not preclude moderate associations restricted to specific IS subtypes. Disparate mechanisms may be critical in the development of acute ischemic coronary and cerebrovascular events.
doi:10.1161/STROKEAHA.111.632075
PMCID: PMC3622211  PMID: 22363065
cerebral infarct; genetics; ischemia
15.  Functional IL6R 358Ala Allele Impairs Classical IL-6 Receptor Signaling and Influences Risk of Diverse Inflammatory Diseases 
PLoS Genetics  2013;9(4):e1003444.
Inflammation, which is directly regulated by interleukin-6 (IL-6) signaling, is implicated in the etiology of several chronic diseases. Although a common, non-synonymous variant in the IL-6 receptor gene (IL6R Asp358Ala; rs2228145 A>C) is associated with the risk of several common diseases, with the 358Ala allele conferring protection from coronary heart disease (CHD), rheumatoid arthritis (RA), atrial fibrillation (AF), abdominal aortic aneurysm (AAA), and increased susceptibility to asthma, the variant's effect on IL-6 signaling is not known. Here we provide evidence for the association of this non-synonymous variant with the risk of type 1 diabetes (T1D) in two independent populations and confirm that rs2228145 is the major determinant of the concentration of circulating soluble IL-6R (sIL-6R) levels (34.6% increase in sIL-6R per copy of the minor allele 358Ala; rs2228145 [C]). To further investigate the molecular mechanism of this variant, we analyzed expression of IL-6R in peripheral blood mononuclear cells (PBMCs) in 128 volunteers from the Cambridge BioResource. We demonstrate that, although 358Ala increases transcription of the soluble IL6R isoform (P = 8.3×10−22) and not the membrane-bound isoform, 358Ala reduces surface expression of IL-6R on CD4+ T cells and monocytes (up to 28% reduction per allele; P≤5.6×10−22). Importantly, reduced expression of membrane-bound IL-6R resulted in impaired IL-6 responsiveness, as measured by decreased phosphorylation of the transcription factors STAT3 and STAT1 following stimulation with IL-6 (P≤5.2×10−7). Our findings elucidate the regulation of IL-6 signaling by IL-6R, which is causally relevant to several complex diseases, identify mechanisms for new approaches to target the IL-6/IL-6R axis, and anticipate differences in treatment response to IL-6 therapies based on this common IL6R variant.
Author Summary
Interleukin-6 (IL-6) is a complex cytokine, which plays a critical role in the regulation of inflammatory responses. Genetic variation in the IL-6 receptor gene is associated with the risk of several human diseases with an inflammatory component, including coronary heart disease, rheumatoid arthritis, and asthma. A common non-synonymous single nucleotide polymorphism in this gene (Asp358Ala) has been suggested to be the causal variant in this region by affecting the circulatory concentrations of soluble IL-6R (sIL-6R). In this study we extend the genetic association of this variant to type 1 diabetes and provide evidence that this variant exerts its functional mechanism by regulating the balance between sIL-6R (generated through cleavage of the surface receptor and by alternative splicing of a soluble IL6R isoform) and membrane-bound IL-6R. These data show for the first time that the minor allele of this non-synonymous variant (Ala358) directly controls the surface levels of IL-6R on individual immune cells and that these differences in protein levels translate into a functional impairment in IL-6R signaling. These findings may have implications for clinical trials targeting inflammatory mechanisms involving IL-6R signaling and may provide tools for identifying patients with specific benefit from therapeutic intervention in the IL-6R signaling pathway.
doi:10.1371/journal.pgen.1003444
PMCID: PMC3617094  PMID: 23593036
16.  Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes 
Morris, Andrew P | Voight, Benjamin F | Teslovich, Tanya M | Ferreira, Teresa | Segrè, Ayellet V | Steinthorsdottir, Valgerdur | Strawbridge, Rona J | Khan, Hassan | Grallert, Harald | Mahajan, Anubha | Prokopenko, Inga | Kang, Hyun Min | Dina, Christian | Esko, Tonu | Fraser, Ross M | Kanoni, Stavroula | Kumar, Ashish | Lagou, Vasiliki | Langenberg, Claudia | Luan, Jian'an | Lindgren, Cecilia M | Müller-Nurasyid, Martina | Pechlivanis, Sonali | Rayner, N William | Scott, Laura J | Wiltshire, Steven | Yengo, Loic | Kinnunen, Leena | Rossin, Elizabeth J | Raychaudhuri, Soumya | Johnson, Andrew D | Dimas, Antigone S | Loos, Ruth J F | Vedantam, Sailaja | Chen, Han | Florez, Jose C | Fox, Caroline | Liu, Ching-Ti | Rybin, Denis | Couper, David J | Kao, Wen Hong L | Li, Man | Cornelis, Marilyn C | Kraft, Peter | Sun, Qi | van Dam, Rob M | Stringham, Heather M | Chines, Peter S | Fischer, Krista | Fontanillas, Pierre | Holmen, Oddgeir L | Hunt, Sarah E | Jackson, Anne U | Kong, Augustine | Lawrence, Robert | Meyer, Julia | Perry, John RB | Platou, Carl GP | Potter, Simon | Rehnberg, Emil | Robertson, Neil | Sivapalaratnam, Suthesh | Stančáková, Alena | Stirrups, Kathleen | Thorleifsson, Gudmar | Tikkanen, Emmi | Wood, Andrew R | Almgren, Peter | Atalay, Mustafa | Benediktsson, Rafn | Bonnycastle, Lori L | Burtt, Noël | Carey, Jason | Charpentier, Guillaume | Crenshaw, Andrew T | Doney, Alex S F | Dorkhan, Mozhgan | Edkins, Sarah | Emilsson, Valur | Eury, Elodie | Forsen, Tom | Gertow, Karl | Gigante, Bruna | Grant, George B | Groves, Christopher J | Guiducci, Candace | Herder, Christian | Hreidarsson, Astradur B | Hui, Jennie | James, Alan | Jonsson, Anna | Rathmann, Wolfgang | Klopp, Norman | Kravic, Jasmina | Krjutškov, Kaarel | Langford, Cordelia | Leander, Karin | Lindholm, Eero | Lobbens, Stéphane | Männistö, Satu | Mirza, Ghazala | Mühleisen, Thomas W | Musk, Bill | Parkin, Melissa | Rallidis, Loukianos | Saramies, Jouko | Sennblad, Bengt | Shah, Sonia | Sigurðsson, Gunnar | Silveira, Angela | Steinbach, Gerald | Thorand, Barbara | Trakalo, Joseph | Veglia, Fabrizio | Wennauer, Roman | Winckler, Wendy | Zabaneh, Delilah | Campbell, Harry | van Duijn, Cornelia | Uitterlinden89-, Andre G | Hofman, Albert | Sijbrands, Eric | Abecasis, Goncalo R | Owen, Katharine R | Zeggini, Eleftheria | Trip, Mieke D | Forouhi, Nita G | Syvänen, Ann-Christine | Eriksson, Johan G | Peltonen, Leena | Nöthen, Markus M | Balkau, Beverley | Palmer, Colin N A | Lyssenko, Valeriya | Tuomi, Tiinamaija | Isomaa, Bo | Hunter, David J | Qi, Lu | Shuldiner, Alan R | Roden, Michael | Barroso, Ines | Wilsgaard, Tom | Beilby, John | Hovingh, Kees | Price, Jackie F | Wilson, James F | Rauramaa, Rainer | Lakka, Timo A | Lind, Lars | Dedoussis, George | Njølstad, Inger | Pedersen, Nancy L | Khaw, Kay-Tee | Wareham, Nicholas J | Keinanen-Kiukaanniemi, Sirkka M | Saaristo, Timo E | Korpi-Hyövälti, Eeva | Saltevo, Juha | Laakso, Markku | Kuusisto, Johanna | Metspalu, Andres | Collins, Francis S | Mohlke, Karen L | Bergman, Richard N | Tuomilehto, Jaakko | Boehm, Bernhard O | Gieger, Christian | Hveem, Kristian | Cauchi, Stephane | Froguel, Philippe | Baldassarre, Damiano | Tremoli, Elena | Humphries, Steve E | Saleheen, Danish | Danesh, John | Ingelsson, Erik | Ripatti, Samuli | Salomaa, Veikko | Erbel, Raimund | Jöckel, Karl-Heinz | Moebus, Susanne | Peters, Annette | Illig, Thomas | de Faire, Ulf | Hamsten, Anders | Morris, Andrew D | Donnelly, Peter J | Frayling, Timothy M | Hattersley, Andrew T | Boerwinkle, Eric | Melander, Olle | Kathiresan, Sekar | Nilsson, Peter M | Deloukas, Panos | Thorsteinsdottir, Unnur | Groop, Leif C | Stefansson, Kari | Hu, Frank | Pankow, James S | Dupuis, Josée | Meigs, James B | Altshuler, David | Boehnke, Michael | McCarthy, Mark I
Nature genetics  2012;44(9):981-990.
To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip involving 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two demonstrating sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of further common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signalling and cell cycle regulation, in diabetes pathogenesis.
doi:10.1038/ng.2383
PMCID: PMC3442244  PMID: 22885922
17.  Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes 
Morris, Andrew P | Voight, Benjamin F | Teslovich, Tanya M | Ferreira, Teresa | Segré, Ayellet V | Steinthorsdottir, Valgerdur | Strawbridge, Rona J | Khan, Hassan | Grallert, Harald | Mahajan, Anubha | Prokopenko, Inga | Kang, Hyun Min | Dina, Christian | Esko, Tonu | Fraser, Ross M | Kanoni, Stavroula | Kumar, Ashish | Lagou, Vasiliki | Langenberg, Claudia | Luan, Jian’an | Lindgren, Cecilia M | Müller-Nurasyid, Martina | Pechlivanis, Sonali | Rayner, N William | Scott, Laura J | Wiltshire, Steven | Yengo, Loic | Kinnunen, Leena | Rossin, Elizabeth J | Raychaudhuri, Soumya | Johnson, Andrew D | Dimas, Antigone S | Loos, Ruth J F | Vedantam, Sailaja | Chen, Han | Florez, Jose C | Fox, Caroline | Liu, Ching-Ti | Rybin, Denis | Couper, David J | Kao, Wen Hong L | Li, Man | Cornelis, Marilyn C | Kraft, Peter | Sun, Qi | van Dam, Rob M | Stringham, Heather M | Chines, Peter S | Fischer, Krista | Fontanillas, Pierre | Holmen, Oddgeir L | Hunt, Sarah E | Jackson, Anne U | Kong, Augustine | Lawrence, Robert | Meyer, Julia | Perry, John R B | Platou, Carl G P | Potter, Simon | Rehnberg, Emil | Robertson, Neil | Sivapalaratnam, Suthesh | Stančáková, Alena | Stirrups, Kathleen | Thorleifsson, Gudmar | Tikkanen, Emmi | Wood, Andrew R | Almgren, Peter | Atalay, Mustafa | Benediktsson, Rafn | Bonnycastle, Lori L | Burtt, Noël | Carey, Jason | Charpentier, Guillaume | Crenshaw, Andrew T | Doney, Alex S F | Dorkhan, Mozhgan | Edkins, Sarah | Emilsson, Valur | Eury, Elodie | Forsen, Tom | Gertow, Karl | Gigante, Bruna | Grant, George B | Groves, Christopher J | Guiducci, Candace | Herder, Christian | Hreidarsson, Astradur B | Hui, Jennie | James, Alan | Jonsson, Anna | Rathmann, Wolfgang | Klopp, Norman | Kravic, Jasmina | Krjutškov, Kaarel | Langford, Cordelia | Leander, Karin | Lindholm, Eero | Lobbens, Stéphane | Männistö, Satu | Mirza, Ghazala | Mühleisen, Thomas W | Musk, Bill | Parkin, Melissa | Rallidis, Loukianos | Saramies, Jouko | Sennblad, Bengt | Shah, Sonia | Sigurðsson, Gunnar | Silveira, Angela | Steinbach, Gerald | Thorand, Barbara | Trakalo, Joseph | Veglia, Fabrizio | Wennauer, Roman | Winckler, Wendy | Zabaneh, Delilah | Campbell, Harry | van Duijn, Cornelia | Uitterlinden, Andre G | Hofman, Albert | Sijbrands, Eric | Abecasis, Goncalo R | Owen, Katharine R | Zeggini, Eleftheria | Trip, Mieke D | Forouhi, Nita G | Syvänen, Ann-Christine | Eriksson, Johan G | Peltonen, Leena | Nöthen, Markus M | Balkau, Beverley | Palmer, Colin N A | Lyssenko, Valeriya | Tuomi, Tiinamaija | Isomaa, Bo | Hunter, David J | Qi, Lu | Shuldiner, Alan R | Roden, Michael | Barroso, Ines | Wilsgaard, Tom | Beilby, John | Hovingh, Kees | Price, Jackie F | Wilson, James F | Rauramaa, Rainer | Lakka, Timo A | Lind, Lars | Dedoussis, George | Njølstad, Inger | Pedersen, Nancy L | Khaw, Kay-Tee | Wareham, Nicholas J | Keinanen-Kiukaanniemi, Sirkka M | Saaristo, Timo E | Korpi-Hyövälti, Eeva | Saltevo, Juha | Laakso, Markku | Kuusisto, Johanna | Metspalu, Andres | Collins, Francis S | Mohlke, Karen L | Bergman, Richard N | Tuomilehto, Jaakko | Boehm, Bernhard O | Gieger, Christian | Hveem, Kristian | Cauchi, Stephane | Froguel, Philippe | Baldassarre, Damiano | Tremoli, Elena | Humphries, Steve E | Saleheen, Danish | Danesh, John | Ingelsson, Erik | Ripatti, Samuli | Salomaa, Veikko | Erbel, Raimund | Jöckel, Karl-Heinz | Moebus, Susanne | Peters, Annette | Illig, Thomas | de Faire, Ulf | Hamsten, Anders | Morris, Andrew D | Donnelly, Peter J | Frayling, Timothy M | Hattersley, Andrew T | Boerwinkle, Eric | Melander, Olle | Kathiresan, Sekar | Nilsson, Peter M | Deloukas, Panos | Thorsteinsdottir, Unnur | Groop, Leif C | Stefansson, Kari | Hu, Frank | Pankow, James S | Dupuis, Josée | Meigs, James B | Altshuler, David | Boehnke, Michael | McCarthy, Mark I
Nature genetics  2012;44(9):981-990.
To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip involving 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two demonstrating sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of further common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signalling and cell cycle regulation, in diabetes pathogenesis.
doi:10.1038/ng.2383
PMCID: PMC3442244  PMID: 22885922
18.  Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes 
Strawbridge, Rona J. | Dupuis, Josée | Prokopenko, Inga | Barker, Adam | Ahlqvist, Emma | Rybin, Denis | Petrie, John R. | Travers, Mary E. | Bouatia-Naji, Nabila | Dimas, Antigone S. | Nica, Alexandra | Wheeler, Eleanor | Chen, Han | Voight, Benjamin F. | Taneera, Jalal | Kanoni, Stavroula | Peden, John F. | Turrini, Fabiola | Gustafsson, Stefan | Zabena, Carina | Almgren, Peter | Barker, David J.P. | Barnes, Daniel | Dennison, Elaine M. | Eriksson, Johan G. | Eriksson, Per | Eury, Elodie | Folkersen, Lasse | Fox, Caroline S. | Frayling, Timothy M. | Goel, Anuj | Gu, Harvest F. | Horikoshi, Momoko | Isomaa, Bo | Jackson, Anne U. | Jameson, Karen A. | Kajantie, Eero | Kerr-Conte, Julie | Kuulasmaa, Teemu | Kuusisto, Johanna | Loos, Ruth J.F. | Luan, Jian'an | Makrilakis, Konstantinos | Manning, Alisa K. | Martínez-Larrad, María Teresa | Narisu, Narisu | Nastase Mannila, Maria | Öhrvik, John | Osmond, Clive | Pascoe, Laura | Payne, Felicity | Sayer, Avan A. | Sennblad, Bengt | Silveira, Angela | Stančáková, Alena | Stirrups, Kathy | Swift, Amy J. | Syvänen, Ann-Christine | Tuomi, Tiinamaija | van 't Hooft, Ferdinand M. | Walker, Mark | Weedon, Michael N. | Xie, Weijia | Zethelius, Björn | Ongen, Halit | Mälarstig, Anders | Hopewell, Jemma C. | Saleheen, Danish | Chambers, John | Parish, Sarah | Danesh, John | Kooner, Jaspal | Östenson, Claes-Göran | Lind, Lars | Cooper, Cyrus C. | Serrano-Ríos, Manuel | Ferrannini, Ele | Forsen, Tom J. | Clarke, Robert | Franzosi, Maria Grazia | Seedorf, Udo | Watkins, Hugh | Froguel, Philippe | Johnson, Paul | Deloukas, Panos | Collins, Francis S. | Laakso, Markku | Dermitzakis, Emmanouil T. | Boehnke, Michael | McCarthy, Mark I. | Wareham, Nicholas J. | Groop, Leif | Pattou, François | Gloyn, Anna L. | Dedoussis, George V. | Lyssenko, Valeriya | Meigs, James B. | Barroso, Inês | Watanabe, Richard M. | Ingelsson, Erik | Langenberg, Claudia | Hamsten, Anders | Florez, Jose C.
Diabetes  2011;60(10):2624-2634.
OBJECTIVE
Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology.
RESEARCH DESIGN AND METHODS
We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates.
RESULTS
Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10−8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10−4), improved β-cell function (P = 1.1 × 10−5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10−6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets.
CONCLUSIONS
We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.
doi:10.2337/db11-0415
PMCID: PMC3178302  PMID: 21873549
19.  Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study 
Voight, Benjamin F | Peloso, Gina M | Orho-Melander, Marju | Frikke-Schmidt, Ruth | Barbalic, Maja | Jensen, Majken K | Hindy, George | Hólm, Hilma | Ding, Eric L | Johnson, Toby | Schunkert, Heribert | Samani, Nilesh J | Clarke, Robert | Hopewell, Jemma C | Thompson, John F | Li, Mingyao | Thorleifsson, Gudmar | Newton-Cheh, Christopher | Musunuru, Kiran | Pirruccello, James P | Saleheen, Danish | Chen, Li | Stewart, Alexandre FR | Schillert, Arne | Thorsteinsdottir, Unnur | Thorgeirsson, Gudmundur | Anand, Sonia | Engert, James C | Morgan, Thomas | Spertus, John | Stoll, Monika | Berger, Klaus | Martinelli, Nicola | Girelli, Domenico | McKeown, Pascal P | Patterson, Christopher C | Epstein, Stephen E | Devaney, Joseph | Burnett, Mary-Susan | Mooser, Vincent | Ripatti, Samuli | Surakka, Ida | Nieminen, Markku S | Sinisalo, Juha | Lokki, Marja-Liisa | Perola, Markus | Havulinna, Aki | de Faire, Ulf | Gigante, Bruna | Ingelsson, Erik | Zeller, Tanja | Wild, Philipp | de Bakker, Paul I W | Klungel, Olaf H | Maitland-van der Zee, Anke-Hilse | Peters, Bas J M | de Boer, Anthonius | Grobbee, Diederick E | Kamphuisen, Pieter W | Deneer, Vera H M | Elbers, Clara C | Onland-Moret, N Charlotte | Hofker, Marten H | Wijmenga, Cisca | Verschuren, WM Monique | Boer, Jolanda MA | van der Schouw, Yvonne T | Rasheed, Asif | Frossard, Philippe | Demissie, Serkalem | Willer, Cristen | Do, Ron | Ordovas, Jose M | Abecasis, Gonçalo R | Boehnke, Michael | Mohlke, Karen L | Daly, Mark J | Guiducci, Candace | Burtt, Noël P | Surti, Aarti | Gonzalez, Elena | Purcell, Shaun | Gabriel, Stacey | Marrugat, Jaume | Peden, John | Erdmann, Jeanette | Diemert, Patrick | Willenborg, Christina | König, Inke R | Fischer, Marcus | Hengstenberg, Christian | Ziegler, Andreas | Buysschaert, Ian | Lambrechts, Diether | Van de Werf, Frans | Fox, Keith A | El Mokhtari, Nour Eddine | Rubin, Diana | Schrezenmeir, Jürgen | Schreiber, Stefan | Schäfer, Arne | Danesh, John | Blankenberg, Stefan | Roberts, Robert | McPherson, Ruth | Watkins, Hugh | Hall, Alistair S | Overvad, Kim | Rimm, Eric | Boerwinkle, Eric | Tybjaerg-Hansen, Anne | Cupples, L Adrienne | Reilly, Muredach P | Melander, Olle | Mannucci, Pier M | Ardissino, Diego | Siscovick, David | Elosua, Roberto | Stefansson, Kari | O'Donnell, Christopher J | Salomaa, Veikko | Rader, Daniel J | Peltonen, Leena | Schwartz, Stephen M | Altshuler, David | Kathiresan, Sekar
Lancet  2012;380(9841):572-580.
Summary
Background
High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal.
Methods
We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20 913 myocardial infarction cases, 95 407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12 482 cases of myocardial infarction and 41 331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol.
Findings
Carriers of the LIPG 396Ser allele (2·6% frequency) had higher HDL cholesterol (0·14 mmol/L higher, p=8×10−13) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with non-carriers. This difference in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84–0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88–1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58–0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68–1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45–1·63) was concordant with that from genetic score (OR 2·13, 95% CI 1·69–2·69, p=2×10−10).
Interpretation
Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction.
Funding
US National Institutes of Health, The Wellcome Trust, European Union, British Heart Foundation, and the German Federal Ministry of Education and Research.
doi:10.1016/S0140-6736(12)60312-2
PMCID: PMC3419820  PMID: 22607825
20.  BRCA2 Variants and cardiovascular disease in a multi-ethnic study 
BMC Medical Genetics  2012;13:56.
Background
Germline mutations of BRCA1/2 are associated with hereditary breast and ovarian cancer. Recent data suggests excess mortality in mutation carriers beyond that conferred by neoplasia, and recent in vivo and in vitro studies suggest a modulatory role for BRCA proteins in endothelial and cardiomyocyte function. We therefore tested the association of BRCA2 variants with clinical cardiovascular disease (CVD).
Methods
Using data from 1,170 individuals included in two multi-ethnic population-based studies (SHARE and SHARE-AP), the association between BRCA2 variants and CVD was evaluated. 15 SNPs in BRCA2 with minor allele frequencies (MAF) > 0.01 had been previously genotyped using the cardiovascular gene-centric 50 k SNP array. 115 individuals (9.8%) reported a CVD event, defined as myocardial infarction (MI), angina, silent MI, stroke, and angioplasty or coronary artery bypass surgery. Analyses were adjusted for age and sex. The SNPs rs11571836 and rs1799943 were subsequently genotyped using the MassARRAY platform in 1,045 cases of incident MI and 1,135 controls from the South Asian subset of an international case-control study of acute MI (INTERHEART), and rs11571836 was imputed in 4,686 cases and 4500 controls from the Pakistan Risk of Myocardial Infarction Study (PROMIS).
Results
Two BRCA2 SNPs, rs11571836 and rs1799943, both located in untranslated regions, were associated with lower risk of CVD (OR 0.47 p = 0.01 and OR 0.56 p = 0.03 respectively) in the SHARE studies. Analysis by specific ethnicities demonstrated an association with CVD for both SNPs in Aboriginal People, and for rs11571836 only in South Asians. No association was observed in the European and Chinese subgroups. A non-significant trend towards an association between rs11571836 and lower risk of MI was observed in South Asians from INTERHEART [OR = 0.87 (95% CI: 0.75-1.01) p = 0.068], but was not evident in PROMIS [OR = 0.96 (95% CI: 0.90-1.03) p = 0.230]. Meta-analysis of both case-control studies resulted in a combined OR of 0.94 (95% CI: 0.89-1.004, p = 0.06).
Conclusions
Although there was an association between two SNPs in BRCA2 and CVD in a multi-ethnic population, these results were not replicated in two South Asian case-control studies of incident MI. Future studies exploring the association between BRCA variants and cardiovascular disorders are needed to clarify the role, if any, for BRCA variants in CVD pathogenesis.
doi:10.1186/1471-2350-13-56
PMCID: PMC3464815  PMID: 22809218
21.  Fruit and vegetable intake and mortality from ischaemic heart disease: results from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heart study 
European Heart Journal  2011;32(10):1235-1243.
Aims
A higher intake of fruits and vegetables has been associated with a lower risk of ischaemic heart disease (IHD), but there is some uncertainty about the interpretation of this association. The objective was to assess the relation between fruit and vegetable intake and risk of mortality from IHD in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heart study.
Methods and results
After an average of 8.4 years of follow-up, there were 1636 deaths from IHD among 313 074 men and women without previous myocardial infarction or stroke from eight European countries. Participants consuming at least eight portions (80 g each) of fruits and vegetables a day had a 22% lower risk of fatal IHD [relative risk (RR) = 0.78, 95% confidence interval (CI): 0.65–0.95] compared with those consuming fewer than three portions a day. After calibration of fruit and vegetable intake to account for differences in dietary assessment between the participating centres, a one portion (80 g) increment in fruit and vegetable intake was associated with a 4% lower risk of fatal IHD (RR = 0.96, 95% CI: 0.92–1.00, P for trend = 0.033).
Conclusion
Results from this large observational study suggest that a higher intake of fruits and vegetables is associated with a reduced risk of IHD mortality. Whether this association is causal and, if so, the biological mechanism(s) by which fruits and vegetables operate to lower IHD risks remains unclear.
doi:10.1093/eurheartj/ehq465
PMCID: PMC3094548  PMID: 21245490
Fruits; Vegetables; Coronary disease; Prospective cohort studies
22.  Homocysteine and Coronary Heart Disease: Meta-analysis of MTHFR Case-Control Studies, Avoiding Publication Bias 
PLoS Medicine  2012;9(2):e1001177.
Robert Clarke and colleagues conduct a meta-analysis of unpublished datasets to examine the causal relationship between elevation of homocysteine levels in the blood and the risk of coronary heart disease. Their data suggest that an increase in homocysteine levels is not likely to result in an increase in risk of coronary heart disease.
Background
Moderately elevated blood levels of homocysteine are weakly correlated with coronary heart disease (CHD) risk, but causality remains uncertain. When folate levels are low, the TT genotype of the common C677T polymorphism (rs1801133) of the methylene tetrahydrofolate reductase gene (MTHFR) appreciably increases homocysteine levels, so “Mendelian randomization” studies using this variant as an instrumental variable could help test causality.
Methods and Findings
Nineteen unpublished datasets were obtained (total 48,175 CHD cases and 67,961 controls) in which multiple genetic variants had been measured, including MTHFR C677T. These datasets did not include measurements of blood homocysteine, but homocysteine levels would be expected to be about 20% higher with TT than with CC genotype in the populations studied. In meta-analyses of these unpublished datasets, the case-control CHD odds ratio (OR) and 95% CI comparing TT versus CC homozygotes was 1.02 (0.98–1.07; p = 0.28) overall, and 1.01 (0.95–1.07) in unsupplemented low-folate populations. By contrast, in a slightly updated meta-analysis of the 86 published studies (28,617 CHD cases and 41,857 controls), the OR was 1.15 (1.09–1.21), significantly discrepant (p = 0.001) with the OR in the unpublished datasets. Within the meta-analysis of published studies, the OR was 1.12 (1.04–1.21) in the 14 larger studies (those with variance of log OR<0.05; total 13,119 cases) and 1.18 (1.09–1.28) in the 72 smaller ones (total 15,498 cases).
Conclusions
The CI for the overall result from large unpublished datasets shows lifelong moderate homocysteine elevation has little or no effect on CHD. The discrepant overall result from previously published studies reflects publication bias or methodological problems.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Coronary heart disease (CHD) is the leading cause of death among adults in developed countries. With age, fatty deposits (atherosclerotic plaques) coat the walls of the coronary arteries, the blood vessels that supply the heart with oxygen and nutrients. The resultant restriction of the heart's blood supply causes shortness of breath, angina (chest pains that are usually relieved by rest), and sometimes fatal heart attacks. Many established risk factors for CHD, including smoking, physical inactivity, being overweight, and eating a fat-rich diet, can be modified by lifestyle changes. Another possible modifiable risk factor for CHD is a high blood level of the amino acid homocysteine. Methylene tetrahydofolate reductase, which is encoded by the MTHFR gene, uses folate to break down and remove homocysteine so fortification of cereals with folate can reduce population homocysteine blood levels. Pooled results from prospective observational studies that have looked for an association between homocysteine levels and later development of CHD suggest that the reduction in homocysteine levels that can be achieved by folate supplementation is associated with an 11% lower CHD risk.
Why Was This Study Done?
Prospective observational studies cannot prove that high homocysteine levels cause CHD because of confounding, the potential presence of other unknown shared characteristics that really cause CHD. However, an approach called “Mendelian randomization” can test whether high blood homocysteine causes CHD. A common genetic variant of the MTHFR gene—the C677T polymorphism—reduces MTHFR efficiency so TT homozygotes (individuals in whom both copies of the MTHFR gene have the nucleotide thymine at position 677; the human genome contains two copies of most genes) have 25% higher blood homocysteine levels than CC homozygotes. In meta-analyses (statistical pooling of the results of several studies) of published Mendelian randomized studies, TT homozygotes have a higher CHD risk than CC homozygotes. Because gene variants are inherited randomly, they are not subject to confounding, so this result suggests that high blood homocysteine causes CHD. But what if only Mendelian randomization studies that found an association have been published? Such publication bias would affect this aggregate result. Here, the researchers investigate the association of the MTHFR C677T polymorphism with CHD in unpublished datasets that have analyzed this polymorphism incidentally during other genetic studies.
What Did the Researchers Do and Find?
The researchers obtained 19 unpublished datasets that contained data on the MTHFR C677T polymorphism in thousands of people with and without CHD. Meta-analysis of these datasets indicates that the excess CHD risk in TT homozygotes compared to CC homozygotes was 2% (much lower than predicted from the prospective observational studies), a nonsignificant difference (that is, it could have occurred by chance). When the probable folate status of the study populations (based on when national folic acid fortification legislation came into effect) was taken into account, there was still no evidence that TT homozygotes had an excess CHD risk. By contrast, in an updated meta-analysis of 86 published studies of the association of the polymorphism with CHD, the excess CHD risk in TT homozygotes compared to CC homozygotes was 15%. Finally, in a meta-analysis of randomized trials on the use of vitamin B supplements for homocysteine reduction, folate supplementation had no significant effect on the 5-year incidence of CHD.
What Do These Findings Mean?
These analyses of unpublished datasets are consistent with lifelong moderate elevation of homocysteine levels having no significant effect on CHD risk. In other words, these findings indicate that circulating homocysteine levels within the normal range are not causally related to CHD risk. The meta-analysis of the randomized trials of folate supplementation also supports this conclusion. So why is there a discrepancy between these findings and those of meta-analyses of published Mendelian randomization studies? The discrepancy is too large to be dismissed as a chance finding, suggest the researchers, but could be the result of publication bias—some studies might have been prioritized for publication because of the positive nature of their results whereas the unpublished datasets used in this study would not have been affected by any failure to publish null results. Overall, these findings reveal a serious example of publication bias and argue against the use of folate supplements as a means of reducing CHD risk.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001177.
The American Heart Association provides information about CHD and tips on keeping the heart healthy; it also provides information on homocysteine, folic acid, and CHD, general information on supplements and heart health, and personal stories about CHD
The UK National Health Service Choices website provides information about CHD, including personal stories about CHD
Information is available from the British Heart Foundation on heart disease and keeping the heart healthy
The US National Heart Lung and Blood Institute also provides information on CHD (in English and Spanish)
MedlinePlus provides links to many other sources of information on CHD (in English and Spanish)
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001177
PMCID: PMC3283559  PMID: 22363213
23.  Association between Walking Speed and Age in Healthy, Free-Living Individuals Using Mobile Accelerometry—A Cross-Sectional Study 
PLoS ONE  2011;6(8):e23299.
Context
Walking speed is a fundamental parameter of human motion and is increasingly considered as an important indicator of individuals' health status.
Objective
To evaluate the relationship of gait parameters, and demographic and physical characteristics in healthy men and women.
Design, Setting, and Participants
Recruitment of a subsample (n = 358) of male and female blood donors taking part in the Cambridge CardioResource study. Collection of demographic data, measurement of physical characteristics (height, weight and blood pressure) and assessment of 7-day, free-living activity parameters using accelerometry and a novel algorithm to measure walking speed. Participants were a median (interquartile range[IQR]) age of 49 (16) years; 45% women; and had a median (IQR) BMI of 26 (5.4).
Main Outcome Measure
Walking speed.
Results
In this study, the hypothesis that walking speed declines with age was generated using an initial ‘open’ dataset. This was subsequently validated in a separate ‘closed’ dataset that showed a decrease of walking speed of −0.0037 m/s per year. This is equivalent to a difference of 1.2 minutes, when walking a distance of 1 km aged 20 compared to 60 years. Associations between walking speed and other participant characteristics (i.e. gender, BMI and blood pressure) were non-significant. BMI was negatively correlated with the number of walking and running steps and longest non-stop distance.
Conclusion
This is the first study using accelerometry which shows an association between walking speed and age in free-living, healthy individuals. Absolute values of gait speed are comparable to published normal ranges in clinical settings. This study highlights the potential use of mobile accelerometry to assess gait parameters which may be indicative of future health outcomes in healthy individuals.
doi:10.1371/journal.pone.0023299
PMCID: PMC3154324  PMID: 21853107
24.  Prospective study of insulin-like growth factor-I, insulin-like growth factor-binding protein 3, genetic variants in the IGF1 and IGFBP3 genes and risk of coronary artery disease 
Although experimental studies have suggested that insulin-like growth factor I (IGF-I) and its binding protein IGFBP-3 might have a role in the aetiology of coronary artery disease (CAD), the relevance of circulating IGFs and their binding proteins in the development of CAD in human populations is unclear. We conducted a nested case-control study, with a mean follow-up of six years, within the EPIC-Norfolk cohort to assess the association between circulating levels of IGF-I and IGFBP-3 and risk of CAD in up to 1,013 cases and 2,055 controls matched for age, sex and study enrolment date. After adjustment for cardiovascular risk factors, we found no association between circulating levels of IGF-I or IGFBP-3 and risk of CAD (odds ratio: 0.98 (95% Cl 0.90-1.06) per 1 SD increase in circulating IGF-I; odds ratio: 1.02 (95% Cl 0.94-1.12) for IGFBP-3). We examined associations between tagging single nucleotide polymorphisms (tSNPs) at the IGF1 and IGFBP3 loci and circulating IGF-I and IGFBP-3 levels in up to 1,133 cases and 2,223 controls and identified three tSNPs (rs1520220, rs3730204, rs2132571) that showed independent association with either circulating IGF-I or IGFBP-3 levels. In an assessment of 31 SNPs spanning the IGF1 or IGFBP3 loci, none were associated with risk of CAD in a meta-analysis that included EPIC-Norfolk and eight additional studies comprising up to 9,319 cases and 19,964 controls. Our results indicate that IGF-I and IGFBP-3 are unlikely to be importantly involved in the aetiology of CAD in human populations.
PMCID: PMC3166154  PMID: 21915365
Epidemiology; Genetics of cardiovascular disease; Risk factors; IGF1; IGFBP3
25.  Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study 
Fox, Ervin R. | Young, J. Hunter | Li, Yali | Dreisbach, Albert W. | Keating, Brendan J. | Musani, Solomon K. | Liu, Kiang | Morrison, Alanna C. | Ganesh, Santhi | Kutlar, Abdullah | Ramachandran, Vasan S. | Polak, Josef F. | Fabsitz, Richard R. | Dries, Daniel L. | Farlow, Deborah N. | Redline, Susan | Adeyemo, Adebowale | Hirschorn, Joel N. | Sun, Yan V. | Wyatt, Sharon B. | Penman, Alan D. | Palmas, Walter | Rotter, Jerome I. | Townsend, Raymond R. | Doumatey, Ayo P. | Tayo, Bamidele O. | Mosley, Thomas H. | Lyon, Helen N. | Kang, Sun J. | Rotimi, Charles N. | Cooper, Richard S. | Franceschini, Nora | Curb, J. David | Martin, Lisa W. | Eaton, Charles B. | Kardia, Sharon L.R. | Taylor, Herman A. | Caulfield, Mark J. | Ehret, Georg B. | Johnson, Toby | Chakravarti, Aravinda | Zhu, Xiaofeng | Levy, Daniel | Munroe, Patricia B. | Rice, Kenneth M. | Bochud, Murielle | Johnson, Andrew D. | Chasman, Daniel I. | Smith, Albert V. | Tobin, Martin D. | Verwoert, Germaine C. | Hwang, Shih-Jen | Pihur, Vasyl | Vollenweider, Peter | O'Reilly, Paul F. | Amin, Najaf | Bragg-Gresham, Jennifer L. | Teumer, Alexander | Glazer, Nicole L. | Launer, Lenore | Zhao, Jing Hua | Aulchenko, Yurii | Heath, Simon | Sõber, Siim | Parsa, Afshin | Luan, Jian'an | Arora, Pankaj | Dehghan, Abbas | Zhang, Feng | Lucas, Gavin | Hicks, Andrew A. | Jackson, Anne U. | Peden, John F. | Tanaka, Toshiko | Wild, Sarah H. | Rudan, Igor | Igl, Wilmar | Milaneschi, Yuri | Parker, Alex N. | Fava, Cristiano | Chambers, John C. | Kumari, Meena | JinGo, Min | van der Harst, Pim | Kao, Wen Hong Linda | Sjögren, Marketa | Vinay, D.G. | Alexander, Myriam | Tabara, Yasuharu | Shaw-Hawkins, Sue | Whincup, Peter H. | Liu, Yongmei | Shi, Gang | Kuusisto, Johanna | Seielstad, Mark | Sim, Xueling | Nguyen, Khanh-Dung Hoang | Lehtimäki, Terho | Matullo, Giuseppe | Wu, Ying | Gaunt, Tom R. | Charlotte Onland-Moret, N. | Cooper, Matthew N. | Platou, Carl G.P. | Org, Elin | Hardy, Rebecca | Dahgam, Santosh | Palmen, Jutta | Vitart, Veronique | Braund, Peter S. | Kuznetsova, Tatiana | Uiterwaal, Cuno S.P.M. | Campbell, Harry | Ludwig, Barbara | Tomaszewski, Maciej | Tzoulaki, Ioanna | Palmer, Nicholette D. | Aspelund, Thor | Garcia, Melissa | Chang, Yen-Pei C. | O'Connell, Jeffrey R. | Steinle, Nanette I. | Grobbee, Diederick E. | Arking, Dan E. | Hernandez, Dena | Najjar, Samer | McArdle, Wendy L. | Hadley, David | Brown, Morris J. | Connell, John M. | Hingorani, Aroon D. | Day, Ian N.M. | Lawlor, Debbie A. | Beilby, John P. | Lawrence, Robert W. | Clarke, Robert | Collins, Rory | Hopewell, Jemma C. | Ongen, Halit | Bis, Joshua C. | Kähönen, Mika | Viikari, Jorma | Adair, Linda S. | Lee, Nanette R. | Chen, Ming-Huei | Olden, Matthias | Pattaro, Cristian | Hoffman Bolton, Judith A. | Köttgen, Anna | Bergmann, Sven | Mooser, Vincent | Chaturvedi, Nish | Frayling, Timothy M. | Islam, Muhammad | Jafar, Tazeen H. | Erdmann, Jeanette | Kulkarni, Smita R. | Bornstein, Stefan R. | Grässler, Jürgen | Groop, Leif | Voight, Benjamin F. | Kettunen, Johannes | Howard, Philip | Taylor, Andrew | Guarrera, Simonetta | Ricceri, Fulvio | Emilsson, Valur | Plump, Andrew | Barroso, Inês | Khaw, Kay-Tee | Weder, Alan B. | Hunt, Steven C. | Bergman, Richard N. | Collins, Francis S. | Bonnycastle, Lori L. | Scott, Laura J. | Stringham, Heather M. | Peltonen, Leena | Perola, Markus | Vartiainen, Erkki | Brand, Stefan-Martin | Staessen, Jan A. | Wang, Thomas J. | Burton, Paul R. | SolerArtigas, Maria | Dong, Yanbin | Snieder, Harold | Wang, Xiaoling | Zhu, Haidong | Lohman, Kurt K. | Rudock, Megan E. | Heckbert, Susan R. | Smith, Nicholas L. | Wiggins, Kerri L. | Shriner, Daniel | Veldre, Gudrun | Viigimaa, Margus | Kinra, Sanjay | Prabhakaran, Dorairajan | Tripathy, Vikal | Langefeld, Carl D. | Rosengren, Annika | Thelle, Dag S. | MariaCorsi, Anna | Singleton, Andrew | Forrester, Terrence | Hilton, Gina | McKenzie, Colin A. | Salako, Tunde | Iwai, Naoharu | Kita, Yoshikuni | Ogihara, Toshio | Ohkubo, Takayoshi | Okamura, Tomonori | Ueshima, Hirotsugu | Umemura, Satoshi | Eyheramendy, Susana | Meitinger, Thomas | Wichmann, H.-Erich | Cho, Yoon Shin | Kim, Hyung-Lae | Lee, Jong-Young | Scott, James | Sehmi, Joban S. | Zhang, Weihua | Hedblad, Bo | Nilsson, Peter | Smith, George Davey | Wong, Andrew | Narisu, Narisu | Stančáková, Alena | Raffel, Leslie J. | Yao, Jie | Kathiresan, Sekar | O'Donnell, Chris | Schwartz, Steven M. | Arfan Ikram, M. | Longstreth, Will T. | Seshadri, Sudha | Shrine, Nick R.G. | Wain, Louise V. | Morken, Mario A. | Swift, Amy J. | Laitinen, Jaana | Prokopenko, Inga | Zitting, Paavo | Cooper, Jackie A. | Humphries, Steve E. | Danesh, John | Rasheed, Asif | Goel, Anuj | Hamsten, Anders | Watkins, Hugh | Bakker, Stephan J.L. | van Gilst, Wiek H. | Janipalli, Charles S. | Radha Mani, K. | Yajnik, Chittaranjan S. | Hofman, Albert | Mattace-Raso, Francesco U.S. | Oostra, Ben A. | Demirkan, Ayse | Isaacs, Aaron | Rivadeneira, Fernando | Lakatta, Edward G. | Orru, Marco | Scuteri, Angelo | Ala-Korpela, Mika | Kangas, Antti J. | Lyytikäinen, Leo-Pekka | Soininen, Pasi | Tukiainen, Taru | Würz, Peter | Twee-Hee Ong, Rick | Dörr, Marcus | Kroemer, Heyo K. | Völker, Uwe | Völzke, Henry | Galan, Pilar | Hercberg, Serge | Lathrop, Mark | Zelenika, Diana | Deloukas, Panos | Mangino, Massimo | Spector, Tim D. | Zhai, Guangju | Meschia, James F. | Nalls, Michael A. | Sharma, Pankaj | Terzic, Janos | Kranthi Kumar, M.J. | Denniff, Matthew | Zukowska-Szczechowska, Ewa | Wagenknecht, Lynne E. | Fowkes, Gerald R. | Charchar, Fadi J. | Schwarz, Peter E.H. | Hayward, Caroline | Guo, Xiuqing | Bots, Michiel L. | Brand, Eva | Samani, Nilesh J. | Polasek, Ozren | Talmud, Philippa J. | Nyberg, Fredrik | Kuh, Diana | Laan, Maris | Hveem, Kristian | Palmer, Lyle J. | van der Schouw, Yvonne T. | Casas, Juan P. | Mohlke, Karen L. | Vineis, Paolo | Raitakari, Olli | Wong, Tien Y. | Shyong Tai, E. | Laakso, Markku | Rao, Dabeeru C. | Harris, Tamara B. | Morris, Richard W. | Dominiczak, Anna F. | Kivimaki, Mika | Marmot, Michael G. | Miki, Tetsuro | Saleheen, Danish | Chandak, Giriraj R. | Coresh, Josef | Navis, Gerjan | Salomaa, Veikko | Han, Bok-Ghee | Kooner, Jaspal S. | Melander, Olle | Ridker, Paul M. | Bandinelli, Stefania | Gyllensten, Ulf B. | Wright, Alan F. | Wilson, James F. | Ferrucci, Luigi | Farrall, Martin | Tuomilehto, Jaakko | Pramstaller, Peter P. | Elosua, Roberto | Soranzo, Nicole | Sijbrands, Eric J.G. | Altshuler, David | Loos, Ruth J.F. | Shuldiner, Alan R. | Gieger, Christian | Meneton, Pierre | Uitterlinden, Andre G. | Wareham, Nicholas J. | Gudnason, Vilmundur | Rettig, Rainer | Uda, Manuela | Strachan, David P. | Witteman, Jacqueline C.M. | Hartikainen, Anna-Liisa | Beckmann, Jacques S. | Boerwinkle, Eric | Boehnke, Michael | Larson, Martin G. | Järvelin, Marjo-Riitta | Psaty, Bruce M. | Abecasis, Gonçalo R. | Elliott, Paul | van Duijn , Cornelia M. | Newton-Cheh, Christopher
Human Molecular Genetics  2011;20(11):2273-2284.
The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10−8) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10−8). The top IBC association for SBP was rs2012318 (P= 6.4 × 10−6) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10−6) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity.
doi:10.1093/hmg/ddr092
PMCID: PMC3090190  PMID: 21378095

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