PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (115)
 

Clipboard (0)
None

Select a Filter Below

Journals
more »
Year of Publication
more »
1.  Variants near TERC are associated with mean telomere length. 
Nature genetics  2010;42(3):197-199.
We conducted genome-wide association analyses of mean leukocyte telomere length in 2,917 subjects and follow-up replication analyses in 9,492 and identified a locus on 3q26 encompassing the telomerase RNA component TERC, with compelling evidence for association (rs12696304, combined P value 3.72×10−14). Each copy of the minor allele of rs12696304 was associated with ≈75 base pairs shorter mean telomere length equivalent to ≈3.6 years of age-related attrition of mean telomere length.
doi:10.1038/ng.532
PMCID: PMC3773906  PMID: 20139977
2.  GENETIC ARCHITECTURE OF AMBULATORY BLOOD PRESSURE IN THE GENERAL POPULATION – INSIGHTS FROM CARDIOVASCULAR GENE-CENTRIC ARRAY 
Hypertension  2010;56(6):1069-1076.
Genetic determinants of blood pressure are poorly defined. We undertook a large-scale gene-centric analysis to identify loci and pathways associated with ambulatory systolic and diastolic blood pressure.
We measured 24-hour ambulatory BP in 2020 individuals from 520 white European nuclear families (the GRAPHIC Study) and genotyped their DNA using the Illumina HumanCVD BeadChip array which contains approximately 50000 single nucleotide polymorphisms in >2000 cardiovascular candidate loci. We found a strong association between rs13306560 polymorphism in the promoter region of MTHFR and CLCN6 and mean 24-hour diastolic blood pressure - each minor allele copy of rs13306560 was associated with 2.6 mmHg lower mean 24-hour diastolic blood pressure (P=1.2×10−8). rs13306560 was also associated with clinic diastolic blood pressure in a combined analysis of 8129 subjects from the GRAPHIC Study, the CoLaus Study and the Silesian Cardiovascular Study (P=5.4×10−6). Additional analysis of associations between variants in Gene Ontology-defined pathways and mean 24-hour blood pressure in the GRAPHIC Study showed that cell survival control signalling cascades could play a role in blood pressure regulation. There was also a significant over-representation of rare variants (minor allele frequency <0.05) amongst polymorphisms showing at least nominal association with mean 24-hour blood pressure indicating that a considerable proportion of its heritability may be explained by uncommon alleles.
Through a large scale gene-centric analysis of ambulatory blood pressure, we identified an association of a novel variant at the MTHFR/CLNC6 locus with diastolic blood pressure and provided new insights into the genetic architecture of blood pressure.
doi:10.1161/HYPERTENSIONAHA.110.155721
PMCID: PMC3035934  PMID: 21060006
gene; genetics; blood pressure; single nucleotide polymorphism; association; heritability
3.  Design of the Coronary ARtery DIsease Genome-Wide Replication And Meta-Analysis (CARDIoGRAM) Study 
Background
Recent genome-wide association studies (GWAS) of myocardial infarction (MI) and other forms of coronary artery disease (CAD) have led to the discovery of at least 13 genetic loci. In addition to the effect size, power to detect associations is largely driven by sample size. Therefore, to maximize the chance of finding novel susceptibility loci for CAD and MI, the Coronary ARtery DIsease Genome-wide Replication And Meta-analysis (CARDIoGRAM) consortium was formed.
Methods and Results
CARDIoGRAM combines data from all published and several unpublished GWAS in individuals with European ancestry; includes >22 000 cases with CAD, MI, or both and >60 000 controls; and unifies samples from the Atherosclerotic Disease VAscular functioN and genetiC Epidemiology study, CADomics, Cohorts for Heart and Aging Research in Genomic Epidemiology, deCODE, the German Myocardial Infarction Family Studies I, II, and III, Ludwigshafen Risk and Cardiovascular Heath Study/AtheroRemo, MedStar, Myocardial Infarction Genetics Consortium, Ottawa Heart Genomics Study, PennCath, and the Wellcome Trust Case Control Consortium. Genotyping was carried out on Affymetrix or Illumina platforms followed by imputation of genotypes in most studies. On average, 2.2 million single nucleotide polymorphisms were generated per study. The results from each study are combined using meta-analysis. As proof of principle, we meta-analyzed risk variants at 9p21 and found that rs1333049 confers a 29% increase in risk for MI per copy (P=2×10−20).
Conclusion
CARDIoGRAM is poised to contribute to our understanding of the role of common genetic variation on risk for CAD and MI.
doi:10.1161/CIRCGENETICS.109.899443
PMCID: PMC3070269  PMID: 20923989
coronary artery disease; myocardial infarction; meta-analysis; genetics
4.  Analysis of Gene-Gene Interactions among Common Variants in Candidate Cardiovascular Genes in Coronary Artery Disease 
PLoS ONE  2015;10(2):e0117684.
Objective
Only a small fraction of coronary artery disease (CAD) heritability has been explained by common variants identified to date. Interactions between genes of importance to cardiovascular regulation may account for some of the missing heritability of CAD. This study aimed to investigate the role of gene-gene interactions in common variants in candidate cardiovascular genes in CAD.
Approach and Results
2,101 patients with CAD from the British Heart Foundation Family Heart Study and 2,426 CAD-free controls were included in the discovery cohort. All subjects were genotyped with the Illumina HumanCVD BeadChip enriched for genes and pathways relevant to the cardiovascular system and disease. The primary analysis in the discovery cohort examined pairwise interactions among 913 common (minor allele frequency >0.1) independent single nucleotide polymorphisms (SNPs) with at least nominal association with CAD in single locus analysis. A secondary exploratory interaction analysis was performed among all 11,332 independent common SNPs surviving quality control criteria. Replication analyses were conducted in 2,967 patients and 3,075 controls from the Myocardial Infarction Genetics Consortium. None of the interactions amongst 913 SNPs analysed in the primary analysis was statistically significant after correction for multiple testing (required P<1.2x10-7). Similarly, none of the pairwise gene-gene interactions in the secondary analysis reached statistical significance after correction for multiple testing (required P = 7.8x10-10). None of 36 suggestive interactions from the primary analysis or 31 interactions from the secondary analysis was significant in the replication cohort. Our study had 80% power to detect odds ratios > 1.7 for common variants in the primary analysis.
Conclusions
Moderately large additive interactions between common SNPs in genes relevant to cardiovascular disease do not appear to play a major role in genetic predisposition to CAD. The role of genetic interactions amongst less common SNPs and with medium and small magnitude effects remain to be investigated.
doi:10.1371/journal.pone.0117684
PMCID: PMC4320092  PMID: 25658981
5.  Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization 
Arking, Dan E. | Pulit, Sara L. | Crotti, Lia | van der Harst, Pim | Munroe, Patricia B. | Koopmann, Tamara T. | Sotoodehnia, Nona | Rossin, Elizabeth J. | Morley, Michael | Wang, Xinchen | Johnson, Andrew D. | Lundby, Alicia | Gudbjartsson, Daníel F. | Noseworthy, Peter A. | Eijgelsheim, Mark | Bradford, Yuki | Tarasov, Kirill V. | Dörr, Marcus | Müller-Nurasyid, Martina | Lahtinen, Annukka M. | Nolte, Ilja M. | Smith, Albert Vernon | Bis, Joshua C. | Isaacs, Aaron | Newhouse, Stephen J. | Evans, Daniel S. | Post, Wendy S. | Waggott, Daryl | Lyytikäinen, Leo-Pekka | Hicks, Andrew A. | Eisele, Lewin | Ellinghaus, David | Hayward, Caroline | Navarro, Pau | Ulivi, Sheila | Tanaka, Toshiko | Tester, David J. | Chatel, Stéphanie | Gustafsson, Stefan | Kumari, Meena | Morris, Richard W. | Naluai, Åsa T. | Padmanabhan, Sandosh | Kluttig, Alexander | Strohmer, Bernhard | Panayiotou, Andrie G. | Torres, Maria | Knoflach, Michael | Hubacek, Jaroslav A. | Slowikowski, Kamil | Raychaudhuri, Soumya | Kumar, Runjun D. | Harris, Tamara B. | Launer, Lenore J. | Shuldiner, Alan R. | Alonso, Alvaro | Bader, Joel S. | Ehret, Georg | Huang, Hailiang | Kao, W.H. Linda | Strait, James B. | Macfarlane, Peter W. | Brown, Morris | Caulfield, Mark J. | Samani, Nilesh J. | Kronenberg, Florian | Willeit, Johann | Smith, J. Gustav | Greiser, Karin H. | zu Schwabedissen, Henriette Meyer | Werdan, Karl | Carella, Massimo | Zelante, Leopoldo | Heckbert, Susan R. | Psaty, Bruce M. | Rotter, Jerome I. | Kolcic, Ivana | Polašek, Ozren | Wright, Alan F. | Griffin, Maura | Daly, Mark J. | Arnar, David O. | Hólm, Hilma | Thorsteinsdottir, Unnur | Denny, Joshua C. | Roden, Dan M. | Zuvich, Rebecca L. | Emilsson, Valur | Plump, Andrew S. | Larson, Martin G. | O'Donnell, Christopher J. | Yin, Xiaoyan | Bobbo, Marco | D'Adamo, Adamo P. | Iorio, Annamaria | Sinagra, Gianfranco | Carracedo, Angel | Cummings, Steven R. | Nalls, Michael A. | Jula, Antti | Kontula, Kimmo K. | Marjamaa, Annukka | Oikarinen, Lasse | Perola, Markus | Porthan, Kimmo | Erbel, Raimund | Hoffmann, Per | Jöckel, Karl-Heinz | Kälsch, Hagen | Nöthen, Markus M. | consortium, HRGEN | den Hoed, Marcel | Loos, Ruth J.F. | Thelle, Dag S. | Gieger, Christian | Meitinger, Thomas | Perz, Siegfried | Peters, Annette | Prucha, Hanna | Sinner, Moritz F. | Waldenberger, Melanie | de Boer, Rudolf A. | Franke, Lude | van der Vleuten, Pieter A. | Beckmann, Britt Maria | Martens, Eimo | Bardai, Abdennasser | Hofman, Nynke | Wilde, Arthur A.M. | Behr, Elijah R. | Dalageorgou, Chrysoula | Giudicessi, John R. | Medeiros-Domingo, Argelia | Barc, Julien | Kyndt, Florence | Probst, Vincent | Ghidoni, Alice | Insolia, Roberto | Hamilton, Robert M. | Scherer, Stephen W. | Brandimarto, Jeffrey | Margulies, Kenneth | Moravec, Christine E. | Fabiola Del, Greco M. | Fuchsberger, Christian | O'Connell, Jeffrey R. | Lee, Wai K. | Watt, Graham C.M. | Campbell, Harry | Wild, Sarah H. | El Mokhtari, Nour E. | Frey, Norbert | Asselbergs, Folkert W. | Leach, Irene Mateo | Navis, Gerjan | van den Berg, Maarten P. | van Veldhuisen, Dirk J. | Kellis, Manolis | Krijthe, Bouwe P. | Franco, Oscar H. | Hofman, Albert | Kors, Jan A. | Uitterlinden, André G. | Witteman, Jacqueline C.M. | Kedenko, Lyudmyla | Lamina, Claudia | Oostra, Ben A. | Abecasis, Gonçalo R. | Lakatta, Edward G. | Mulas, Antonella | Orrú, Marco | Schlessinger, David | Uda, Manuela | Markus, Marcello R.P. | Völker, Uwe | Snieder, Harold | Spector, Timothy D. | Ärnlöv, Johan | Lind, Lars | Sundström, Johan | Syvänen, Ann-Christine | Kivimaki, Mika | Kähönen, Mika | Mononen, Nina | Raitakari, Olli T. | Viikari, Jorma S. | Adamkova, Vera | Kiechl, Stefan | Brion, Maria | Nicolaides, Andrew N. | Paulweber, Bernhard | Haerting, Johannes | Dominiczak, Anna F. | Nyberg, Fredrik | Whincup, Peter H. | Hingorani, Aroon | Schott, Jean-Jacques | Bezzina, Connie R. | Ingelsson, Erik | Ferrucci, Luigi | Gasparini, Paolo | Wilson, James F. | Rudan, Igor | Franke, Andre | Mühleisen, Thomas W. | Pramstaller, Peter P. | Lehtimäki, Terho J. | Paterson, Andrew D. | Parsa, Afshin | Liu, Yongmei | van Duijn, Cornelia | Siscovick, David S. | Gudnason, Vilmundur | Jamshidi, Yalda | Salomaa, Veikko | Felix, Stephan B. | Sanna, Serena | Ritchie, Marylyn D. | Stricker, Bruno H. | Stefansson, Kari | Boyer, Laurie A. | Cappola, Thomas P. | Olsen, Jesper V. | Lage, Kasper | Schwartz, Peter J. | Kääb, Stefan | Chakravarti, Aravinda | Ackerman, Michael J. | Pfeufer, Arne | de Bakker, Paul I.W. | Newton-Cheh, Christopher
Nature genetics  2014;46(8):826-836.
The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal Mendelian Long QT Syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals we identified 35 common variant QT interval loci, that collectively explain ∼8-10% of QT variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 novel QT loci in 298 unrelated LQTS probands identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode for proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies novel candidate genes for ventricular arrhythmias, LQTS,and SCD.
doi:10.1038/ng.3014
PMCID: PMC4124521  PMID: 24952745
genome-wide association study; QT interval; Long QT Syndrome; sudden cardiac death; myocardial repolarization; arrhythmias
7.  Shared genetic susceptibility to ischemic stroke and coronary artery disease – a genome-wide analysis of common variants 
Summary
Background and Purpose
Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each have a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases.
Methods
Genome-wide association data were obtained from the METASTROKE, CARDIoGRAM, and C4D consortia. We first analyzed common variants reaching a nominal threshold of significance (p<0.01) for CAD for their association with IS and vice versa. We then examined specific overlap across phenotypes for variants that reached a high threshold of significance. Finally, we conducted a joint meta-analysis on the combined phenotype of IS or CAD. Corresponding analyses were performed restricted to the 2,167 individuals with the ischemic large artery stroke (LAS) subtype.
Results
Common variants associated with CAD at p<0.01 were associated with a significant excess risk for IS and for LAS and vice versa. Among the 42 known genome-wide significant loci for CAD, three and five loci were significantly associated with IS and LAS, respectively. In the joint meta-analyses, 15 loci passed genome-wide significance (p<5×10-8) for the combined phenotype of IS or CAD and 17 loci passed genome-wide significance for LAS or CAD. Since these loci had prior evidence for genome-wide significance for CAD we specifically analyzed the respective signals for IS and LAS and found evidence for association at chr12q24/SH2B3 (pIS=1.62×10-07) and ABO (pIS =2.6×10-4) as well as at HDAC9 (pLAS=2.32×10-12), 9p21 (pLAS =3.70×10-6), RAI1-PEMT-RASD1 (pLAS =2.69×10-5), EDNRA (pLAS =7.29×10-4), and CYP17A1-CNNM2-NT5C2 (pLAS =4.9×10-4).
Conclusions
Our results demonstrate substantial overlap in the genetic risk of ischemic stroke and particularly the large artery stroke subtype with coronary artery disease.
doi:10.1161/STROKEAHA.113.002707
PMCID: PMC4112102  PMID: 24262325
8.  Meta-analysis of telomere length in 19 713 subjects reveals high heritability, stronger maternal inheritance and a paternal age effect 
European Journal of Human Genetics  2013;21(10):1163-1168.
Telomere length (TL) has been associated with aging and mortality, but individual differences are also influenced by genetic factors, with previous studies reporting heritability estimates ranging from 34 to 82%. Here we investigate the heritability, mode of inheritance and the influence of parental age at birth on TL in six large, independent cohort studies with a total of 19 713 participants. The meta-analysis estimate of TL heritability was 0.70 (95% CI 0.64–0.76) and is based on a pattern of results that is highly similar for twins and other family members. We observed a stronger mother–offspring (r=0.42; P-value=3.60 × 10−61) than father–offspring correlation (r=0.33; P-value=7.01 × 10−5), and a significant positive association with paternal age at offspring birth (β=0.005; P-value=7.01 × 10−5). Interestingly, a significant and quite substantial correlation in TL between spouses (r=0.25; P-value=2.82 × 10−30) was seen, which appeared stronger in older spouse pairs (mean age ≥55 years; r=0.31; P-value=4.27 × 10−23) than in younger pairs (mean age<55 years; r=0.20; P-value=3.24 × 10−10). In summary, we find a high and very consistent heritability estimate for TL, evidence for a maternal inheritance component and a positive association with paternal age.
doi:10.1038/ejhg.2012.303
PMCID: PMC3778341  PMID: 23321625
telomere length; heritability; paternal age effect
9.  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
10.  Loci influencing blood pressure identified using a cardiovascular gene-centric array 
Ganesh, Santhi K. | Tragante, Vinicius | Guo, Wei | Guo, Yiran | Lanktree, Matthew B. | Smith, Erin N. | Johnson, Toby | Castillo, Berta Almoguera | Barnard, John | Baumert, Jens | Chang, Yen-Pei Christy | Elbers, Clara C. | Farrall, Martin | Fischer, Mary E. | Franceschini, Nora | Gaunt, Tom R. | Gho, Johannes M.I.H. | Gieger, Christian | Gong, Yan | Isaacs, Aaron | Kleber, Marcus E. | Leach, Irene Mateo | McDonough, Caitrin W. | Meijs, Matthijs F.L. | Mellander, Olle | Molony, Cliona M. | Nolte, Ilja M. | Padmanabhan, Sandosh | Price, Tom S. | Rajagopalan, Ramakrishnan | Shaffer, Jonathan | Shah, Sonia | Shen, Haiqing | Soranzo, Nicole | van der Most, Peter J. | Van Iperen, Erik P.A. | Van Setten, Jessica | Vonk, Judith M. | Zhang, Li | Beitelshees, Amber L. | Berenson, Gerald S. | Bhatt, Deepak L. | Boer, Jolanda M.A. | Boerwinkle, Eric | Burkley, Ben | Burt, Amber | Chakravarti, Aravinda | Chen, Wei | Cooper-DeHoff, Rhonda M. | Curtis, Sean P. | Dreisbach, Albert | Duggan, David | Ehret, Georg B. | Fabsitz, Richard R. | Fornage, Myriam | Fox, Ervin | Furlong, Clement E. | Gansevoort, Ron T. | Hofker, Marten H. | Hovingh, G. Kees | Kirkland, Susan A. | Kottke-Marchant, Kandice | Kutlar, Abdullah | LaCroix, Andrea Z. | Langaee, Taimour Y. | Li, Yun R. | Lin, Honghuang | Liu, Kiang | Maiwald, Steffi | Malik, Rainer | Murugesan, Gurunathan | Newton-Cheh, Christopher | O'Connell, Jeffery R. | Onland-Moret, N. Charlotte | Ouwehand, Willem H. | Palmas, Walter | Penninx, Brenda W. | Pepine, Carl J. | Pettinger, Mary | Polak, Joseph F. | Ramachandran, Vasan S. | Ranchalis, Jane | Redline, Susan | Ridker, Paul M. | Rose, Lynda M. | Scharnag, Hubert | Schork, Nicholas J. | Shimbo, Daichi | Shuldiner, Alan R. | Srinivasan, Sathanur R. | Stolk, Ronald P. | Taylor, Herman A. | Thorand, Barbara | Trip, Mieke D. | van Duijn, Cornelia M. | Verschuren, W. Monique | Wijmenga, Cisca | Winkelmann, Bernhard R. | Wyatt, Sharon | Young, J. Hunter | Boehm, Bernhard O. | Caulfield, Mark J. | Chasman, Daniel I. | Davidson, Karina W. | Doevendans, Pieter A. | FitzGerald, Garret A. | Gums, John G. | Hakonarson, Hakon | Hillege, Hans L. | Illig, Thomas | Jarvik, Gail P. | Johnson, Julie A. | Kastelein, John J.P. | Koenig, Wolfgang | März, Winfried | Mitchell, Braxton D. | Murray, Sarah S. | Oldehinkel, Albertine J. | Rader, Daniel J. | Reilly, Muredach P. | Reiner, Alex P. | Schadt, Eric E. | Silverstein, Roy L. | Snieder, Harold | Stanton, Alice V. | Uitterlinden, André G. | van der Harst, Pim | van der Schouw, Yvonne T. | Samani, Nilesh J. | Johnson, Andrew D. | Munroe, Patricia B. | de Bakker, Paul I.W. | Zhu, Xiaofeng | Levy, Daniel | Keating, Brendan J. | Asselbergs, Folkert W.
Human Molecular Genetics  2013;22(16):3394-3395.
doi:10.1093/hmg/ddt177
PMCID: PMC3888295
11.  Integrative Genomics Reveals Novel Molecular Pathways and Gene Networks for Coronary Artery Disease 
PLoS Genetics  2014;10(7):e1004502.
The majority of the heritability of coronary artery disease (CAD) remains unexplained, despite recent successes of genome-wide association studies (GWAS) in identifying novel susceptibility loci. Integrating functional genomic data from a variety of sources with a large-scale meta-analysis of CAD GWAS may facilitate the identification of novel biological processes and genes involved in CAD, as well as clarify the causal relationships of established processes. Towards this end, we integrated 14 GWAS from the CARDIoGRAM Consortium and two additional GWAS from the Ottawa Heart Institute (25,491 cases and 66,819 controls) with 1) genetics of gene expression studies of CAD-relevant tissues in humans, 2) metabolic and signaling pathways from public databases, and 3) data-driven, tissue-specific gene networks from a multitude of human and mouse experiments. We not only detected CAD-associated gene networks of lipid metabolism, coagulation, immunity, and additional networks with no clear functional annotation, but also revealed key driver genes for each CAD network based on the topology of the gene regulatory networks. In particular, we found a gene network involved in antigen processing to be strongly associated with CAD. The key driver genes of this network included glyoxalase I (GLO1) and peptidylprolyl isomerase I (PPIL1), which we verified as regulatory by siRNA experiments in human aortic endothelial cells. Our results suggest genetic influences on a diverse set of both known and novel biological processes that contribute to CAD risk. The key driver genes for these networks highlight potential novel targets for further mechanistic studies and therapeutic interventions.
Author Summary
Sudden death due to heart attack ranks among the top causes of death in the world, and family studies have shown that genetics has a substantial effect on heart disease risk. Recent studies suggest that multiple genetic factors each with modest effects are necessary for the development of CAD, but the genes and molecular processes involved remain poorly understood. We conducted an integrative genomics study where we used the information of gene-gene interactions to capture groups of genes that are most likely to increase heart disease risk. We not only confirmed the importance of several known CAD risk processes such as the metabolism and transport of cholesterol, immune response, and blood coagulation, but also revealed many novel processes such as neuroprotection, cell cycle, and proteolysis that were not previously implicated in CAD. In particular, we highlight several genes such as GLO1 with key regulatory roles within these processes not detected by the first wave of genetic analyses. These results highlight the value of integrating population genetic data with diverse resources that functionally annotate the human genome. Such integration facilitates the identification of novel molecular processes involved in the pathogenesis of CAD as well as potential novel targets for the development of efficacious therapeutic interventions.
doi:10.1371/journal.pgen.1004502
PMCID: PMC4102418  PMID: 25033284
12.  A sequence variant associated with sortilin-1 (SORT1) on 1p13.3 is independently associated with abdominal aortic aneurysm 
Human Molecular Genetics  2013;22(14):2941-2947.
Abdominal aortic aneurysm (AAA) is a common human disease with a high estimated heritability (0.7); however, only a small number of associated genetic loci have been reported to date. In contrast, over 100 loci have now been reproducibly associated with either blood lipid profile and/or coronary artery disease (CAD) (both risk factors for AAA) in large-scale meta-analyses. This study employed a staged design to investigate whether the loci for these two phenotypes are also associated with AAA. Validated CAD and dyslipidaemia loci underwent screening using the Otago AAA genome-wide association data set. Putative associations underwent staged secondary validation in 10 additional cohorts. A novel association between the SORT1 (1p13.3) locus and AAA was identified. The rs599839 G allele, which has been previously associated with both dyslipidaemia and CAD, reached genome-wide significance in 11 combined independent cohorts (meta-analysis with 7048 AAA cases and 75 976 controls: G allele OR 0.81, 95% CI 0.76–0.85, P = 7.2 × 10−14). Modelling for confounding interactions of concurrent dyslipidaemia, heart disease and other risk factors suggested that this marker is an independent predictor of AAA susceptibility. In conclusion, a genetic marker associated with cardiovascular risk factors, and in particular concurrent vascular disease, appeared to independently contribute to susceptibility for AAA. Given the potential genetic overlap between risk factor and disease phenotypes, the use of well-characterized case–control cohorts allowing for modelling of cardiovascular disease risk confounders will be an important component in the future discovery of genetic markers for conditions such as AAA.
doi:10.1093/hmg/ddt141
PMCID: PMC3690970  PMID: 23535823
13.  A Systems Biology Framework Identifies Molecular Underpinnings of Coronary Heart Disease 
Objective
Genetic approaches have identified numerous loci associated with coronary heart disease (CHD). The molecular mechanisms underlying CHD gene-disease associations, however, remain unclear. We hypothesized that genetic variants with both strong and subtle effects drive gene subnetworks that in turn affect CHD.
Approach and Results
We surveyed CHD-associated molecular interactions by constructing coexpression networks using whole blood gene expression profiles from 188 CHD cases and 188 age- and sex-matched controls. 24 coexpression modules were identified including one case-specific and one control-specific differential module (DM). The DMs were enriched for genes involved in B-cell activation, immune response, and ion transport. By integrating the DMs with altered gene expression associated SNPs (eSNPs) and with results of GWAS of CHD and its risk factors, the control-specific DM was implicated as CHD-causal based on its significant enrichment for both CHD and lipid eSNPs. This causal DM was further integrated with tissue-specific Bayesian networks and protein-protein interaction networks to identify regulatory key driver (KD) genes. Multi-tissue KDs (SPIB and TNFRSF13C) and tissue-specific KDs (e.g. EBF1) were identified.
Conclusions
Our network-driven integrative analysis not only identified CHD-related genes, but also defined network structure that sheds light on the molecular interactions of genes associated with CHD risk.
doi:10.1161/ATVBAHA.112.300112
PMCID: PMC3752786  PMID: 23539213
Gene expression; coronary heart disease; systems biology; coexpression network
14.  Exome sequencing and directed clinical phenotyping diagnose cholesterol ester storage disease presenting as autosomal recessive hypercholesterolemia 
Objective
Autosomal recessive hypercholesterolemia (ARH) is a rare inherited disorder characterized by extremely high total and low-density lipoprotein cholesterol levels that has been previously linked to mutations in LDLRAP1. We identified a family with ARH not explained by mutations in LDLRAP1 or other genes known to cause monogenic hypercholesterolemia. The aim of this study was to identify the molecular etiology of ARH in this family.
Approach and Results
We used exome sequencing to assess all protein coding regions of the genome in three family members and identified a homozygous exon 8 splice junction mutation (c.894G>A, also known as E8SJM) in LIPA that segregated with the diagnosis of hypercholesterolemia. Since homozygosity for mutations in LIPA is known to cause cholesterol ester storage disease (CESD), we performed directed follow-up phenotyping by non-invasively measuring hepatic cholesterol content. We observed abnormal hepatic accumulation of cholesterol in the homozygote individuals, supporting the diagnosis of CESD. Given previous suggestions of cardiovascular disease risk in heterozygous LIPA mutation carriers, we genotyped E8SJM in >27,000 individuals and found no association with plasma lipid levels or risk of myocardial infarction, confirming a true recessive mode of inheritance.
Conclusions
By integrating observations from Mendelian and population genetics along with directed clinical phenotyping, we diagnosed clinically unapparent CESD in the affected individuals from this kindred and addressed an outstanding question regarding risk of cardiovascular disease in LIPA E8SJM heterozygous carriers.
doi:10.1161/ATVBAHA.113.302426
PMCID: PMC4002172  PMID: 24072694
hypercholesterolemia; genetics; myocardial infarction
15.  Genetic predisposition to higher blood pressure increases coronary artery disease risk 
Hypertension  2013;61(5):10.1161/HYPERTENSIONAHA.111.00275.
Hypertension is a risk factor for coronary artery disease. Recent genome-wide association studies have identified 30 genetic variants associated with higher blood pressure at genome-wide significance (p<5×10−8). If elevated blood pressure is a causative factor for coronary artery disease, these variants should also increase coronary artery disease risk. Analyzing genome-wide association data from 22,233 coronary artery disease cases and 64,762 controls, we observed in the Coronary artery disease Genome-Wide Replication And Meta-Analysis (CARDIoGRAM) consortium that 88% of these blood pressure-associated polymorphisms were likewise positively associated with coronary artery disease, i.e. they had an odds ratio >1 for coronary artery disease, a proportion much higher than expected by chance (p=4.10−5). The average relative coronary artery disease risk increase per each of the multiple blood pressure-raising alleles observed in the consortium was 3.0% for systolic blood pressure-associated polymorphisms (95% confidence interval, 1.8 to 4.3%) and 2.9% for diastolic blood pressure-associated polymorphisms (95% confidence interval, 1.7 to 4.1%). In sub-studies, individuals carrying most systolic blood pressure- and diastolic blood pressure-related risk alleles (top quintile of a genetic risk score distribution) had 70% (95% confidence interval, 50-94%) and 59% (95% confidence interval, 40-81%) higher odds of having coronary artery disease, respectively, as compared to individuals in the bottom quintile. In conclusion, most blood pressure-associated polymorphisms also confer an increased risk for coronary artery disease. These findings are consistent with a causal relationship of increasing blood pressure to coronary artery disease. Genetic variants primarily affecting blood pressure contribute to the genetic basis of coronary artery disease.
doi:10.1161/HYPERTENSIONAHA.111.00275
PMCID: PMC3855241  PMID: 23478099
Blood pressure; polymorphism; genetics; coronary artery disease
16.  Identification of seven loci affecting mean telomere length and their association with disease 
Codd, Veryan | Nelson, Christopher P. | Albrecht, Eva | Mangino, Massimo | Deelen, Joris | Buxton, Jessica L. | Jan Hottenga, Jouke | Fischer, Krista | Esko, Tõnu | Surakka, Ida | Broer, Linda | Nyholt, Dale R. | Mateo Leach, Irene | Salo, Perttu | Hägg, Sara | Matthews, Mary K. | Palmen, Jutta | Norata, Giuseppe D. | O’Reilly, Paul F. | Saleheen, Danish | Amin, Najaf | Balmforth, Anthony J. | Beekman, Marian | de Boer, Rudolf A. | Böhringer, Stefan | Braund, Peter S. | Burton, Paul R. | de Craen, Anton J. M. | Denniff, Matthew | Dong, Yanbin | Douroudis, Konstantinos | Dubinina, Elena | Eriksson, Johan G. | Garlaschelli, Katia | Guo, Dehuang | Hartikainen, Anna-Liisa | Henders, Anjali K. | Houwing-Duistermaat, Jeanine J. | Kananen, Laura | Karssen, Lennart C. | Kettunen, Johannes | Klopp, Norman | Lagou, Vasiliki | van Leeuwen, Elisabeth M. | Madden, Pamela A. | Mägi, Reedik | Magnusson, Patrik K.E. | Männistö, Satu | McCarthy, Mark I. | Medland, Sarah E. | Mihailov, Evelin | Montgomery, Grant W. | Oostra, Ben A. | Palotie, Aarno | Peters, Annette | Pollard, Helen | Pouta, Anneli | Prokopenko, Inga | Ripatti, Samuli | Salomaa, Veikko | Suchiman, H. Eka D. | Valdes, Ana M. | Verweij, Niek | Viñuela, Ana | Wang, Xiaoling | Wichmann, H.-Erich | Widen, Elisabeth | Willemsen, Gonneke | Wright, Margaret J. | Xia, Kai | Xiao, Xiangjun | van Veldhuisen, Dirk J. | Catapano, Alberico L. | Tobin, Martin D. | Hall, Alistair S. | Blakemore, Alexandra I.F. | van Gilst, Wiek H. | Zhu, Haidong | Erdmann, Jeanette | Reilly, Muredach P. | Kathiresan, Sekar | Schunkert, Heribert | Talmud, Philippa J. | Pedersen, Nancy L. | Perola, Markus | Ouwehand, Willem | Kaprio, Jaakko | Martin, Nicholas G. | van Duijn, Cornelia M. | Hovatta, Iiris | Gieger, Christian | Metspalu, Andres | Boomsma, Dorret I. | Jarvelin, Marjo-Riitta | Slagboom, P. Eline | Thompson, John R. | Spector, Tim D. | van der Harst, Pim | Samani, Nilesh J.
Nature genetics  2013;45(4):422-427e2.
Inter-individual variation in mean leukocyte telomere length (LTL) is associated with cancer and several age-associated diseases. Here, in a genome-wide meta-analysis of 37,684 individuals with replication of selected variants in a further 10,739 individuals, we identified seven loci, including five novel loci, associated with mean LTL (P<5x10−8). Five of the loci contain genes (TERC, TERT, NAF1, OBFC1, RTEL1) that are known to be involved in telomere biology. Lead SNPs at two loci (TERC and TERT) associate with several cancers and other diseases, including idiopathic pulmonary fibrosis. Moreover, a genetic risk score analysis combining lead variants at all seven loci in 22,233 coronary artery disease cases and 64,762 controls showed an association of the alleles associated with shorter LTL with increased risk of CAD (21% (95% CI: 5–35%) per standard deviation in LTL, p=0.014). Our findings support a causal role of telomere length variation in some age-related diseases.
doi:10.1038/ng.2528
PMCID: PMC4006270  PMID: 23535734
17.  Loci influencing blood pressure identified using a cardiovascular gene-centric array 
Ganesh, Santhi K. | Tragante, Vinicius | Guo, Wei | Guo, Yiran | Lanktree, Matthew B. | Smith, Erin N. | Johnson, Toby | Castillo, Berta Almoguera | Barnard, John | Baumert, Jens | Chang, Yen-Pei Christy | Elbers, Clara C. | Farrall, Martin | Fischer, Mary E. | Franceschini, Nora | Gaunt, Tom R. | Gho, Johannes M.I.H. | Gieger, Christian | Gong, Yan | Isaacs, Aaron | Kleber, Marcus E. | Leach, Irene Mateo | McDonough, Caitrin W. | Meijs, Matthijs F.L. | Mellander, Olle | Molony, Cliona M. | Nolte, Ilja M. | Padmanabhan, Sandosh | Price, Tom S. | Rajagopalan, Ramakrishnan | Shaffer, Jonathan | Shah, Sonia | Shen, Haiqing | Soranzo, Nicole | van der Most, Peter J. | Van Iperen, Erik P.A. | Van Setten, Jessic A. | Vonk, Judith M. | Zhang, Li | Beitelshees, Amber L. | Berenson, Gerald S. | Bhatt, Deepak L. | Boer, Jolanda M.A. | Boerwinkle, Eric | Burkley, Ben | Burt, Amber | Chakravarti, Aravinda | Chen, Wei | Cooper-DeHoff, Rhonda M. | Curtis, Sean P. | Dreisbach, Albert | Duggan, David | Ehret, Georg B. | Fabsitz, Richard R. | Fornage, Myriam | Fox, Ervin | Furlong, Clement E. | Gansevoort, Ron T. | Hofker, Marten H. | Hovingh, G. Kees | Kirkland, Susan A. | Kottke-Marchant, Kandice | Kutlar, Abdullah | LaCroix, Andrea Z. | Langaee, Taimour Y. | Li, Yun R. | Lin, Honghuang | Liu, Kiang | Maiwald, Steffi | Malik, Rainer | Murugesan, Gurunathan | Newton-Cheh, Christopher | O'Connell, Jeffery R. | Onland-Moret, N. Charlotte | Ouwehand, Willem H. | Palmas, Walter | Penninx, Brenda W. | Pepine, Carl J. | Pettinger, Mary | Polak, Joseph F. | Ramachandran, Vasan S. | Ranchalis, Jane | Redline, Susan | Ridker, Paul M. | Rose, Lynda M. | Scharnag, Hubert | Schork, Nicholas J. | Shimbo, Daichi | Shuldiner, Alan R. | Srinivasan, Sathanur R. | Stolk, Ronald P. | Taylor, Herman A. | Thorand, Barbara | Trip, Mieke D. | van Duijn, Cornelia M. | Verschuren, W. Monique | Wijmenga, Cisca | Winkelmann, Bernhard R. | Wyatt, Sharon | Young, J. Hunter | Boehm, Bernhard O. | Caulfield, Mark J. | Chasman, Daniel I. | Davidson, Karina W. | Doevendans, Pieter A. | FitzGerald, Garret A. | Gums, John G. | Hakonarson, Hakon | Hillege, Hans L. | Illig, Thomas | Jarvik, Gail P. | Johnson, Julie A. | Kastelein, John J.P. | Koenig, Wolfgang | März, Winfried | Mitchell, Braxton D. | Murray, Sarah S. | Oldehinkel, Albertine J. | Rader, Daniel J. | Reilly, Muredach P. | Reiner, Alex P. | Schadt, Eric E. | Silverstein, Roy L. | Snieder, Harold | Stanton, Alice V. | Uitterlinden, André G. | van der Harst, Pim | van der Schouw, Yvonne T. | Samani, Nilesh J. | Johnson, Andrew D. | Munroe, Patricia B. | de Bakker, Paul I.W. | Zhu, Xiaofeng | Levy, Daniel | Keating, Brendan J. | Asselbergs, Folkert W.
Human Molecular Genetics  2013;22(8):1663-1678.
Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped ∼50 000 single-nucleotide polymorphisms (SNPs) that capture variation in ∼2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P < 2.4 × 10−6). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.
doi:10.1093/hmg/dds555
PMCID: PMC3657476  PMID: 23303523
18.  Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age 
Deelen, Joris | Beekman, Marian | Uh, Hae-Won | Broer, Linda | Ayers, Kristin L. | Tan, Qihua | Kamatani, Yoichiro | Bennet, Anna M. | Tamm, Riin | Trompet, Stella | Guðbjartsson, Daníel F. | Flachsbart, Friederike | Rose, Giuseppina | Viktorin, Alexander | Fischer, Krista | Nygaard, Marianne | Cordell, Heather J. | Crocco, Paolina | van den Akker, Erik B. | Böhringer, Stefan | Helmer, Quinta | Nelson, Christopher P. | Saunders, Gary I. | Alver, Maris | Andersen-Ranberg, Karen | Breen, Marie E. | van der Breggen, Ruud | Caliebe, Amke | Capri, Miriam | Cevenini, Elisa | Collerton, Joanna C. | Dato, Serena | Davies, Karen | Ford, Ian | Gampe, Jutta | Garagnani, Paolo | de Geus, Eco J.C. | Harrow, Jennifer | van Heemst, Diana | Heijmans, Bastiaan T. | Heinsen, Femke-Anouska | Hottenga, Jouke-Jan | Hofman, Albert | Jeune, Bernard | Jonsson, Palmi V. | Lathrop, Mark | Lechner, Doris | Martin-Ruiz, Carmen | Mcnerlan, Susan E. | Mihailov, Evelin | Montesanto, Alberto | Mooijaart, Simon P. | Murphy, Anne | Nohr, Ellen A. | Paternoster, Lavinia | Postmus, Iris | Rivadeneira, Fernando | Ross, Owen A. | Salvioli, Stefano | Sattar, Naveed | Schreiber, Stefan | Stefánsson, Hreinn | Stott, David J. | Tiemeier, Henning | Uitterlinden, André G. | Westendorp, Rudi G.J. | Willemsen, Gonneke | Samani, Nilesh J. | Galan, Pilar | Sørensen, Thorkild I.A. | Boomsma, Dorret I. | Jukema, J. Wouter | Rea, Irene Maeve | Passarino, Giuseppe | de Craen, Anton J.M. | Christensen, Kaare | Nebel, Almut | Stefánsson, Kári | Metspalu, Andres | Magnusson, Patrik | Blanché, Hélène | Christiansen, Lene | Kirkwood, Thomas B.L. | van Duijn, Cornelia M. | Franceschi, Claudio | Houwing-Duistermaat, Jeanine J. | Slagboom, P. Eline
Human Molecular Genetics  2014;23(16):4420-4432.
The genetic contribution to the variation in human lifespan is ∼25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality. We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (≥85 years) and 16 121 younger controls (<65 years) followed by replication in an additional set of 13 060 long-lived individuals and 61 156 controls. In addition, we performed a subset analysis in cases aged ≥90 years. We observed genome-wide significant association with longevity, as reflected by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3 (OR = 1.10, P = 1.74 × 10−8). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR = 0.72, P = 3.40 × 10−36), representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis (n = 34 103), the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival (HR = 0.95, P = 0.003). This allele has previously been reported to associate with low blood pressure in middle age. Interestingly, the minor allele (T) associates with decreased cardiovascular mortality risk, independent of blood pressure. We report on the first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population. The minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure. Hence, the pleiotropic mechanisms by which this intragenic variation contributes to lifespan regulation have to be elucidated.
doi:10.1093/hmg/ddu139
PMCID: PMC4103672  PMID: 24688116
19.  Distinct Loci in the CHRNA5/CHRNA3/CHRNB4 Gene Cluster Are Associated With Onset of Regular Smoking 
Stephens, Sarah H. | Hartz, Sarah M. | Hoft, Nicole R. | Saccone, Nancy L. | Corley, Robin C. | Hewitt, John K. | Hopfer, Christian J. | Breslau, Naomi | Coon, Hilary | Chen, Xiangning | Ducci, Francesca | Dueker, Nicole | Franceschini, Nora | Frank, Josef | Han, Younghun | Hansel, Nadia N. | Jiang, Chenhui | Korhonen, Tellervo | Lind, Penelope A. | Liu, Jason | Lyytikäinen, Leo-Pekka | Michel, Martha | Shaffer, John R. | Short, Susan E. | Sun, Juzhong | Teumer, Alexander | Thompson, John R. | Vogelzangs, Nicole | Vink, Jacqueline M. | Wenzlaff, Angela | Wheeler, William | Yang, Bao-Zhu | Aggen, Steven H. | Balmforth, Anthony J. | Baumeister, Sebastian E. | Beaty, Terri H. | Benjamin, Daniel J. | Bergen, Andrew W. | Broms, Ulla | Cesarini, David | Chatterjee, Nilanjan | Chen, Jingchun | Cheng, Yu-Ching | Cichon, Sven | Couper, David | Cucca, Francesco | Dick, Danielle | Foroud, Tatiana | Furberg, Helena | Giegling, Ina | Gillespie, Nathan A. | Gu, Fangyi | Hall, Alistair S. | Hällfors, Jenni | Han, Shizhong | Hartmann, Annette M. | Heikkilä, Kauko | Hickie, Ian B. | Hottenga, Jouke Jan | Jousilahti, Pekka | Kaakinen, Marika | Kähönen, Mika | Koellinger, Philipp D. | Kittner, Stephen | Konte, Bettina | Landi, Maria-Teresa | Laatikainen, Tiina | Leppert, Mark | Levy, Steven M. | Mathias, Rasika A. | McNeil, Daniel W. | Medland, Sarah E. | Montgomery, Grant W. | Murray, Tanda | Nauck, Matthias | North, Kari E. | Paré, Peter D. | Pergadia, Michele | Ruczinski, Ingo | Salomaa, Veikko | Viikari, Jorma | Willemsen, Gonneke | Barnes, Kathleen C. | Boerwinkle, Eric | Boomsma, Dorret I. | Caporaso, Neil | Edenberg, Howard J. | Francks, Clyde | Gelernter, Joel | Grabe, Hans Jörgen | Hops, Hyman | Jarvelin, Marjo-Riitta | Johannesson, Magnus | Kendler, Kenneth S. | Lehtimäki, Terho | Magnusson, Patrik K.E. | Marazita, Mary L. | Marchini, Jonathan | Mitchell, Braxton D. | Nöthen, Markus M. | Penninx, Brenda W. | Raitakari, Olli | Rietschel, Marcella | Rujescu, Dan | Samani, Nilesh J. | Schwartz, Ann G. | Shete, Sanjay | Spitz, Margaret | Swan, Gary E. | Völzke, Henry | Veijola, Juha | Wei, Qingyi | Amos, Chris | Cannon, Dale S. | Grucza, Richard | Hatsukami, Dorothy | Heath, Andrew | Johnson, Eric O. | Kaprio, Jaakko | Madden, Pamela | Martin, Nicholas G. | Stevens, Victoria L. | Weiss, Robert B. | Kraft, Peter | Bierut, Laura J. | Ehringer, Marissa A.
Genetic epidemiology  2013;37(8):846-859.
Neuronal nicotinic acetylcholine receptor (nAChR) genes (CHRNA5/CHRNA3/CHRNB4) have been reproducibly associated with nicotine dependence, smoking behaviors, and lung cancer risk. Of the few reports that have focused on early smoking behaviors, association results have been mixed. This meta-analysis examines early smoking phenotypes and SNPs in the gene cluster to determine: (1) whether the most robust association signal in this region (rs16969968) for other smoking behaviors is also associated with early behaviors, and/or (2) if additional statistically independent signals are important in early smoking. We focused on two phenotypes: age of tobacco initiation (AOI) and age of first regular tobacco use (AOS). This study included 56,034 subjects (41 groups) spanning nine countries and evaluated five SNPs including rs1948, rs16969968, rs578776, rs588765, and rs684513. Each dataset was analyzed using a centrally generated script. Meta-analyses were conducted from summary statistics. AOS yielded significant associations with SNPs rs578776 (beta = 0.02, P = 0.004), rs1948 (beta = 0.023, P = 0.018), and rs684513 (beta = 0.032, P = 0.017), indicating protective effects. There were no significant associations for the AOI phenotype. Importantly, rs16969968, the most replicated signal in this region for nicotine dependence, cigarettes per day, and cotinine levels, was not associated with AOI (P = 0.59) or AOS (P = 0.92). These results provide important insight into the complexity of smoking behavior phenotypes, and suggest that association signals in the CHRNA5/A3/B4 gene cluster affecting early smoking behaviors may be different from those affecting the mature nicotine dependence phenotype.
doi:10.1002/gepi.21760
PMCID: PMC3947535  PMID: 24186853
CHRNA5; CHRNA3; CHRNB4; meta-analysis; nicotine; smoke
20.  Genome-wide association study in Han Chinese identifies four new susceptibility loci for coronary artery disease 
Nature genetics  2012;44(8):890-894.
We performed a meta-analysis of 2 genome-wide association studies of coronary artery disease comprising 1,515 cases with coronary artery disease and 5,019 controls, followed by de novo replication studies in 15,460 cases and 11,472 controls, all of Chinese Han descent. We successfully identified four new loci for coronary artery disease reaching genome-wide significance (P < 5 × 10−8), which mapped in or near TTC32-WDR35, GUCY1A3, C6orf10-BTNL2 and ATP2B1. We also replicated four loci previously identified in European populations (PHACTR1, TCF21, CDKN2A/B and C12orf51). These findings provide new insights into biological pathways for the susceptibility of coronary artery disease in Chinese Han population.
doi:10.1038/ng.2337
PMCID: PMC3927410  PMID: 22751097
21.  The Relation of Rapid Changes in Obesity Measures to Lipid Profile - Insights from a Nationwide Metabolic Health Survey in 444 Polish Cities 
PLoS ONE  2014;9(1):e86837.
Objective
The impact of fast changes in obesity indices on other measures of metabolic health is poorly defined in the general population. Using the Polish accession to the European Union as a model of political and social transformation we examined how an expected rapid increase in body mass index (BMI) and waist circumference relates to changes in lipid profile, both at the population and personal level.
Methods
Through primary care centres in 444 Polish cities, two cross-sectional nationwide population-based surveys (LIPIDOGRAM 2004 and LIPIDOGRAM 2006) examined 15,404 and 15,453 adult individuals in 2004 and 2006, respectively. A separate prospective sample of 1,840 individuals recruited in 2004 had a follow-up in 2006 (LIPIDOGRAM PLUS).
Results
Two years after Polish accession to European Union, mean population BMI and waist circumference increased by 0.6% and 0.9%, respectively. This tracked with a 7.6% drop in HDL-cholesterol and a 2.1% increase in triglycerides (all p<0.001) nationwide. The direction and magnitude of the population changes were replicated at the personal level in LIPIDOGRAM PLUS (0.7%, 0.3%, 8.6% and 1.8%, respectively). However, increases in BMI and waist circumference were both only weakly associated with HDL-cholesterol and triglycerides changes prospectively. The relation of BMI to the magnitude of change in both lipid fractions was comparable to that of waist circumference.
Conclusions
Moderate changes in obesity measures tracked with a significant deterioration in measures of pro-atherogenic dyslipidaemia at both personal and population level. These associations were predominantly driven by factors not measureable directly through either BMI or waist circumference.
doi:10.1371/journal.pone.0086837
PMCID: PMC3908946  PMID: 24497983
22.  Genetic variants influencing circulating lipid levels and risk of coronary artery disease 
Objectives
Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of LDL-c, HDL-c and triglycerides.
Methods and results
We combined genome-wide association data from eight studies, comprising up to 17,723 participants with information on circulating lipid concentrations. We did independent replication studies in up to 37,774 participants from eight populations and also in a population of Indian Asian descent. We also assessed the association between SNPs at lipid loci and risk of CAD in up to 9,633 cases and 38,684 controls.
We identified four novel genetic loci that showed reproducible associations with lipids (P values 1.6 × 10−8 to 3.1 × 10−10). These include a potentially functional SNP in the SLC39A8 gene for HDL-c, a SNP near the MYLIP/GMPR and PPP1R3B genes for LDL-c and at the AFF1 gene for triglycerides. SNPs showing strong statistical association with one or more lipid traits at the CELSR2, APOB, APOE-C1-C4-C2 cluster, LPL, ZNF259-APOA5-A4-C3-A1 cluster and TRIB1 loci were also associated with CAD risk (P values 1.1 × 10−3 to 1.2 × 10−9).
Conclusions
We have identified four novel loci associated with circulating lipids. We also show that in addition to those that are largely associated with LDL-c, genetic loci mainly associated with circulating triglycerides and HDL-c are also associated with risk of CAD. These findings potentially provide new insights into the biological mechanisms underlying lipid metabolism and CAD risk.
doi:10.1161/ATVBAHA.109.201020
PMCID: PMC3891568  PMID: 20864672
lipids; lipoproteins; genetics; epidemiology
23.  Leukocyte telomere length associates with prospective mortality independent of immune-related parameters and known genetic markers 
Background: Human leukocyte telomere length (LTL) decreases with age and shorter LTL has previously been associated with increased prospective mortality. However, it is not clear whether LTL merely marks the health status of an individual by its association with parameters of immune function, for example, or whether telomere shortening also contributes causally to lifespan variation in humans.
Methods: We measured LTL in 870 nonagenarian siblings (mean age 93 years), 1580 of their offspring and 725 spouses thereof (mean age 59 years) from the Leiden Longevity Study (LLS).
Results: We found that shorter LTL is associated with increased prospective mortality in middle (30–80 years; hazard ratio (HR) = 0.75, P = 0.001) and highly advanced age (≥90 years; HR = 0.92, P = 0.028), and show that this association cannot be explained by the association of LTL with the immune-related markers insulin-like growth factor 1 to insulin-like growth factor binding protein 3 molar ratio, C-reactive protein, interleukin 6, cytomegalovirus serostatus or white blood cell counts. We found no difference in LTL between the middle-aged LLS offspring and their spouses (β = 0.006, P = 0.932). Neither did we observe an association of LTL-associated genetic variants with mortality in a prospective meta-analysis of multiple cohorts (n = 8165).
Conclusions: We confirm LTL to be a marker of prospective mortality in middle and highly advanced age and additionally show that this association could not be explained by the association of LTL with various immune-related markers. Furthermore, the approaches performed here do not further support the hypothesis that LTL variation contributes to the genetic propensity for longevity.
doi:10.1093/ije/dyt267
PMCID: PMC4052133  PMID: 24425829
Leukocyte telomere length; prospective mortality; immune-related markers; familial longevity; genetics; human
24.  Urotensin-II System in Genetic Control of Blood Pressure and Renal Function 
PLoS ONE  2013;8(12):e83137.
Urotensin-II controls ion/water homeostasis in fish and vascular tone in rodents. We hypothesised that common genetic variants in urotensin-II pathway genes are associated with human blood pressure or renal function. We performed family-based analysis of association between blood pressure, glomerular filtration and genes of the urotensin-II pathway (urotensin-II, urotensin-II related peptide, urotensin-II receptor) saturated with 28 tagging single nucleotide polymorphisms in 2024 individuals from 520 families; followed by an independent replication in 420 families and 7545 unrelated subjects. The expression studies of the urotensin-II pathway were carried out in 97 human kidneys. Phylogenetic evolutionary analysis was conducted in 17 vertebrate species. One single nucleotide polymorphism (rs531485 in urotensin-II gene) was associated with adjusted estimated glomerular filtration rate in the discovery cohort (p = 0.0005). It showed no association with estimated glomerular filtration rate in the combined replication resource of 8724 subjects from 6 populations. Expression of urotensin-II and its receptor showed strong linear correlation (r = 0.86, p<0.0001). There was no difference in renal expression of urotensin-II system between hypertensive and normotensive subjects. Evolutionary analysis revealed accumulation of mutations in urotensin-II since the divergence of primates and weaker conservation of urotensin-II receptor in primates than in lower vertebrates. Our data suggest that urotensin-II system genes are unlikely to play a major role in genetic control of human blood pressure or renal function. The signatures of evolutionary forces acting on urotensin-II system indicate that it may have evolved towards loss of function since the divergence of primates.
doi:10.1371/journal.pone.0083137
PMCID: PMC3877024  PMID: 24391740
25.  Rationale and design of the PRognostic Importance of MIcrovascular Dysfunction in asymptomatic patients with Aortic Stenosis (PRIMID-AS): a multicentre observational study with blinded investigations 
BMJ Open  2013;3(12):e004348.
Introduction
Aortic stenosis (AS) is the commonest valve disorder in the developed world requiring surgery. Surgery in patients with severe asymptomatic AS remains controversial. Exercise testing can identify asymptomatic patients at increased risk of death and symptom development, but with limited specificity, especially in older adults. Cardiac MRI (CMR), including myocardial perfusion reserve (MPR) may be a novel imaging biomarker in AS.
Aims
(1) To improve risk stratification in asymptomatic patients with AS and (2) to determine whether MPR is a better predictor of outcome than exercise testing and brain natriuretic peptide (BNP).
Method/design
Multicentre, prospective observational study in the UK, comparing MPR with exercise testing and BNP (with blinded CMR analysis) for predicting outcome.
Population
170 asymptomatic patients with moderate-to-severe AS, who would be considered for aortic valve replacement (AVR).
Primary outcome
Composite of: typical symptoms necessitating referral for AVR and major adverse cardiovascular events. Follow-up: 12–30 months (minimum 12 months).
Primary hypothesis
MPR will be a better predictor of outcome than exercise testing and BNP.
Ethics/dissemination
The study has full ethical approval and is actively recruiting patients. Data collection will be completed in November 2014 and the study results will be submitted for publication within 6 months of completion.
ClinicalTrials.gov identifier
NCT01658345.
doi:10.1136/bmjopen-2013-004348
PMCID: PMC3884636  PMID: 24353258

Results 1-25 (115)