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1.  Association analyses of 249,796 individuals reveal eighteen new loci associated with body mass index 
Speliotes, Elizabeth K. | Willer, Cristen J. | Berndt, Sonja I. | Monda, Keri L. | Thorleifsson, Gudmar | Jackson, Anne U. | Allen, Hana Lango | Lindgren, Cecilia M. | Luan, Jian’an | Mägi, Reedik | Randall, Joshua C. | Vedantam, Sailaja | Winkler, Thomas W. | Qi, Lu | Workalemahu, Tsegaselassie | Heid, Iris M. | Steinthorsdottir, Valgerdur | Stringham, Heather M. | Weedon, Michael N. | Wheeler, Eleanor | Wood, Andrew R. | Ferreira, Teresa | Weyant, Robert J. | Segré, Ayellet V. | Estrada, Karol | Liang, Liming | Nemesh, James | Park, Ju-Hyun | Gustafsson, Stefan | Kilpeläinen, Tuomas O. | Yang, Jian | Bouatia-Naji, Nabila | Esko, Tõnu | Feitosa, Mary F. | Kutalik, Zoltán | Mangino, Massimo | Raychaudhuri, Soumya | Scherag, Andre | Smith, Albert Vernon | Welch, Ryan | Zhao, Jing Hua | Aben, Katja K. | Absher, Devin M. | Amin, Najaf | Dixon, Anna L. | Fisher, Eva | Glazer, Nicole L. | Goddard, Michael E. | Heard-Costa, Nancy L. | Hoesel, Volker | Hottenga, Jouke-Jan | Johansson, Åsa | Johnson, Toby | Ketkar, Shamika | Lamina, Claudia | Li, Shengxu | Moffatt, Miriam F. | Myers, Richard H. | Narisu, Narisu | Perry, John R.B. | Peters, Marjolein J. | Preuss, Michael | Ripatti, Samuli | Rivadeneira, Fernando | Sandholt, Camilla | Scott, Laura J. | Timpson, Nicholas J. | Tyrer, Jonathan P. | van Wingerden, Sophie | Watanabe, Richard M. | White, Charles C. | Wiklund, Fredrik | Barlassina, Christina | Chasman, Daniel I. | Cooper, Matthew N. | Jansson, John-Olov | Lawrence, Robert W. | Pellikka, Niina | Prokopenko, Inga | Shi, Jianxin | Thiering, Elisabeth | Alavere, Helene | Alibrandi, Maria T. S. | Almgren, Peter | Arnold, Alice M. | Aspelund, Thor | Atwood, Larry D. | Balkau, Beverley | Balmforth, Anthony J. | Bennett, Amanda J. | Ben-Shlomo, Yoav | Bergman, Richard N. | Bergmann, Sven | Biebermann, Heike | Blakemore, Alexandra I.F. | Boes, Tanja | Bonnycastle, Lori L. | Bornstein, Stefan R. | Brown, Morris J. | Buchanan, Thomas A. | Busonero, Fabio | Campbell, Harry | Cappuccio, Francesco P. | Cavalcanti-Proença, Christine | Chen, Yii-Der Ida | Chen, Chih-Mei | Chines, Peter S. | Clarke, Robert | Coin, Lachlan | Connell, John | Day, Ian N.M. | den Heijer, Martin | Duan, Jubao | Ebrahim, Shah | Elliott, Paul | Elosua, Roberto | Eiriksdottir, Gudny | Erdos, Michael R. | Eriksson, Johan G. | Facheris, Maurizio F. | Felix, Stephan B. | Fischer-Posovszky, Pamela | Folsom, Aaron R. | Friedrich, Nele | Freimer, Nelson B. | Fu, Mao | Gaget, Stefan | Gejman, Pablo V. | Geus, Eco J.C. | Gieger, Christian | Gjesing, Anette P. | Goel, Anuj | Goyette, Philippe | Grallert, Harald | Gräßler, Jürgen | Greenawalt, Danielle M. | Groves, Christopher J. | Gudnason, Vilmundur | Guiducci, Candace | Hartikainen, Anna-Liisa | Hassanali, Neelam | Hall, Alistair S. | Havulinna, Aki S. | Hayward, Caroline | Heath, Andrew C. | Hengstenberg, Christian | Hicks, Andrew A. | Hinney, Anke | Hofman, Albert | Homuth, Georg | Hui, Jennie | Igl, Wilmar | Iribarren, Carlos | Isomaa, Bo | Jacobs, Kevin B. | Jarick, Ivonne | Jewell, Elizabeth | John, Ulrich | Jørgensen, Torben | Jousilahti, Pekka | Jula, Antti | Kaakinen, Marika | Kajantie, Eero | Kaplan, Lee M. | Kathiresan, Sekar | Kettunen, Johannes | Kinnunen, Leena | Knowles, Joshua W. | Kolcic, Ivana | König, Inke R. | Koskinen, Seppo | Kovacs, Peter | Kuusisto, Johanna | Kraft, Peter | Kvaløy, Kirsti | Laitinen, Jaana | Lantieri, Olivier | Lanzani, Chiara | Launer, Lenore J. | Lecoeur, Cecile | Lehtimäki, Terho | Lettre, Guillaume | Liu, Jianjun | Lokki, Marja-Liisa | Lorentzon, Mattias | Luben, Robert N. | Ludwig, Barbara | Manunta, Paolo | Marek, Diana | Marre, Michel | Martin, Nicholas G. | McArdle, Wendy L. | McCarthy, Anne | McKnight, Barbara | Meitinger, Thomas | Melander, Olle | Meyre, David | Midthjell, Kristian | Montgomery, Grant W. | Morken, Mario A. | Morris, Andrew P. | Mulic, Rosanda | Ngwa, Julius S. | Nelis, Mari | Neville, Matt J. | Nyholt, Dale R. | ODonnell, Christopher J. | O’Rahilly, Stephen | Ong, Ken K. | Oostra, Ben | Paré, Guillaume | Parker, Alex N. | Perola, Markus | Pichler, Irene | Pietiläinen, Kirsi H. | Platou, Carl G.P. | Polasek, Ozren | Pouta, Anneli | Rafelt, Suzanne | Raitakari, Olli | Rayner, Nigel W. | Ridderstråle, Martin | Rief, Winfried | Ruokonen, Aimo | Robertson, Neil R. | Rzehak, Peter | Salomaa, Veikko | Sanders, Alan R. | Sandhu, Manjinder S. | Sanna, Serena | Saramies, Jouko | Savolainen, Markku J. | Scherag, Susann | Schipf, Sabine | Schreiber, Stefan | Schunkert, Heribert | Silander, Kaisa | Sinisalo, Juha | Siscovick, David S. | Smit, Jan H. | Soranzo, Nicole | Sovio, Ulla | Stephens, Jonathan | Surakka, Ida | Swift, Amy J. | Tammesoo, Mari-Liis | Tardif, Jean-Claude | Teder-Laving, Maris | Teslovich, Tanya M. | Thompson, John R. | Thomson, Brian | Tönjes, Anke | Tuomi, Tiinamaija | van Meurs, Joyce B.J. | van Ommen, Gert-Jan | Vatin, Vincent | Viikari, Jorma | Visvikis-Siest, Sophie | Vitart, Veronique | Vogel, Carla I. G. | Voight, Benjamin F. | Waite, Lindsay L. | Wallaschofski, Henri | Walters, G. Bragi | Widen, Elisabeth | Wiegand, Susanna | Wild, Sarah H. | Willemsen, Gonneke | Witte, Daniel R. | Witteman, Jacqueline C. | Xu, Jianfeng | Zhang, Qunyuan | Zgaga, Lina | Ziegler, Andreas | Zitting, Paavo | Beilby, John P. | Farooqi, I. Sadaf | Hebebrand, Johannes | Huikuri, Heikki V. | James, Alan L. | Kähönen, Mika | Levinson, Douglas F. | Macciardi, Fabio | Nieminen, Markku S. | Ohlsson, Claes | Palmer, Lyle J. | Ridker, Paul M. | Stumvoll, Michael | Beckmann, Jacques S. | Boeing, Heiner | Boerwinkle, Eric | Boomsma, Dorret I. | Caulfield, Mark J. | Chanock, Stephen J. | Collins, Francis S. | Cupples, L. Adrienne | Smith, George Davey | Erdmann, Jeanette | Froguel, Philippe | Grönberg, Henrik | Gyllensten, Ulf | Hall, Per | Hansen, Torben | Harris, Tamara B. | Hattersley, Andrew T. | Hayes, Richard B. | Heinrich, Joachim | Hu, Frank B. | Hveem, Kristian | Illig, Thomas | Jarvelin, Marjo-Riitta | Kaprio, Jaakko | Karpe, Fredrik | Khaw, Kay-Tee | Kiemeney, Lambertus A. | Krude, Heiko | Laakso, Markku | Lawlor, Debbie A. | Metspalu, Andres | Munroe, Patricia B. | Ouwehand, Willem H. | Pedersen, Oluf | Penninx, Brenda W. | Peters, Annette | Pramstaller, Peter P. | Quertermous, Thomas | Reinehr, Thomas | Rissanen, Aila | Rudan, Igor | Samani, Nilesh J. | Schwarz, Peter E.H. | Shuldiner, Alan R. | Spector, Timothy D. | Tuomilehto, Jaakko | Uda, Manuela | Uitterlinden, André | Valle, Timo T. | Wabitsch, Martin | Waeber, Gérard | Wareham, Nicholas J. | Watkins, Hugh | Wilson, James F. | Wright, Alan F. | Zillikens, M. Carola | Chatterjee, Nilanjan | McCarroll, Steven A. | Purcell, Shaun | Schadt, Eric E. | Visscher, Peter M. | Assimes, Themistocles L. | Borecki, Ingrid B. | Deloukas, Panos | Fox, Caroline S. | Groop, Leif C. | Haritunians, Talin | Hunter, David J. | Kaplan, Robert C. | Mohlke, Karen L. | O’Connell, Jeffrey R. | Peltonen, Leena | Schlessinger, David | Strachan, David P. | van Duijn, Cornelia M. | Wichmann, H.-Erich | Frayling, Timothy M. | Thorsteinsdottir, Unnur | Abecasis, Gonçalo R. | Barroso, Inês | Boehnke, Michael | Stefansson, Kari | North, Kari E. | McCarthy, Mark I. | Hirschhorn, Joel N. | Ingelsson, Erik | Loos, Ruth J.F.
Nature genetics  2010;42(11):937-948.
Obesity is globally prevalent and highly heritable, but the underlying genetic factors remain largely elusive. To identify genetic loci for obesity-susceptibility, we examined associations between body mass index (BMI) and ~2.8 million SNPs in up to 123,865 individuals, with targeted follow-up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity-susceptibility loci and identified 18 new loci associated with BMI (P<5×10−8), one of which includes a copy number variant near GPRC5B. Some loci (MC4R, POMC, SH2B1, BDNF) map near key hypothalamic regulators of energy balance, and one is near GIPR, an incretin receptor. Furthermore, genes in other newly-associated loci may provide novel insights into human body weight regulation.
doi:10.1038/ng.686
PMCID: PMC3014648  PMID: 20935630
2.  Fetuin-A and risk of coronary heart disease: a Mendelian randomization analysis and a pooled analysis of AHSG genetic variants in 7 prospective studies 
Atherosclerosis  2015;243(1):44-52.
Background and aims
Fetuin-A has a plausible role in the inhibition of arterial calcification, but its association with risk of coronary heart disease (CHD) in the general population is unclear. We used two common genetic variants in the fetuin-A gene (AHSG) that are strongly associated with circulating fetuin-A levels to investigate the associations with risk of CHD and subclinical cardiovascular measures (intima- media thickness, ankle-arm index, and coronary artery calcification).
Methods
Genetic variation and fetuin-A levels were assessed in 3,299 community-living individuals (2,733 Caucasians and 566 African Americans) 65 years of age or older, free of previous cardiovascular disease, who participated in the Cardiovascular Health Study (CHS) in 1992– 1993.
Results
Among Caucasians, both rs2248690 and rs4917 were associated with 12% lower fetuin-A concentrations per minor allele (P<0.0001). The hazard ratios (HRs) per minor allele for incident CHD were 1.12 (95% CI: 1.00– 1.26) for rs2248690 and 1.02 (0.91- 1.14) for rs4917. Using both genotypes as an instrumental variable for measured fetuin-A, the HRs for one standard deviation increase in genetically determined fetuin-A levels on CHD risk were 0.84 (95% CI: 0.70– 1.00) for rs2248690 and 0.97 (95% CI: 0.82– 1.14) for rs4917, respectively. However, in CHS neither of the genotypes were associated with subclinical cardiovascular measures and when CHS data were meta-analyzed with data from six other prospective studies (totaling 26,702 Caucasian participants and 3,295 CHD cases), the meta-analyzed HRs for incident CHD were 1.12 (0.93– 1.34) and 1.06 (0.93– 1.20) for rs2248690 and rs4917, respectively (p heterogeneity 0.005 and 0.0048).
Conclusion
Common variants in the AHSG gene are strongly associated with fetuin-A levels, but their concurrent association with CHD risk in current prospective studies is inconsistent. Further investigation in studies with measured fetuin-A and AHSG variants is needed to clarify the potential causal association of fetuin-A with CHD risk.
doi:10.1016/j.atherosclerosis.2015.08.031
PMCID: PMC4609621  PMID: 26343871
Fetuin-A; single nucleotide polymorphisms; coronary heart disease; Mendelian randomization; meta-analysis
3.  Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease 
PLoS Genetics  2016;12(10):e1006327.
We performed an exome-wide association analysis in 1393 late-onset Alzheimer’s disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (~0.5% versus <0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES sub-study, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI) = 7.5 (3.5–15.9), p = 6.6x10-9]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a functionally damaging allele. Our results establish a rare TM2D3 variant in association with LOAD susceptibility, and together with prior work suggests possible links to the β-amyloid cascade.
Author Summary
Alzheimer’s disease (AD) is the most common cause of dementia in the older adult population. There is substantial evidence for an important genetic contribution to AD risk. While prior work has comprehensively evaluated the contribution of common genetic variants in large population-based cohorts, the role of rare variants remains to be defined. Here, we have used a newer genotyping array to characterize less common variants, including those likely to impact the function of encoded proteins, in a combined cohort of 1393 AD cases and 8141 control subjects without AD. Our results implicate a novel, amino acid-changing variant, P155L, in the TM2D3 gene. This variant was discovered to be more common in the Icelandic population, where it was significantly associated with both increased risk and earlier age of onset of AD. Lastly, in order to examine the potential functional impact of the implicated variant, we performed additional studies in the fruit fly. Our results suggest that P155L causes a loss-of-function in TM2D3, in the context of Notch-Presenilin signal transduction. In sum, we identify a novel, rare TM2D3 variant in association with AD risk and highlight functional connections with AD-relevant biology.
doi:10.1371/journal.pgen.1006327
PMCID: PMC5072721  PMID: 27764101
4.  An exome array study of the plasma metabolome 
Nature Communications  2016;7:12360.
The study of rare variants may enhance our understanding of the genetic determinants of the metabolome. Here, we analyze the association between 217 plasma metabolites and exome variants on the Illumina HumanExome Beadchip in 2,076 participants in the Framingham Heart Study, with replication in 1,528 participants of the Atherosclerosis Risk in Communities Study. We identify an association between GMPS and xanthosine using single variant analysis and associations between HAL and histidine, PAH and phenylalanine, and UPB1 and ureidopropionate using gene-based tests (P<5 × 10−8 in meta-analysis), highlighting novel coding variants that may underlie inborn errors of metabolism. Further, we show how an examination of variants across the spectrum of allele frequency highlights independent association signals at select loci and generates a more integrated view of metabolite heritability. These studies build on prior metabolomics genome wide association studies to provide a more complete picture of the genetic architecture of the plasma metabolome.
Several GWAS have identified many common variants associated with blood metabolites. Here, the authors use an exome array to identify low frequency, potentially functional variants that impact human metabolism.
doi:10.1038/ncomms12360
PMCID: PMC4962516  PMID: 27453504
5.  Association of a 62 Variant Type 2 Diabetes Genetic Risk Score with Markers of Subclinical Atherosclerosis: A Transethnic, Multicenter Study 
Background
Type 2 diabetes (T2D) and cardiovascular disease (CVD) share risk factors and subclinical atherosclerosis (SCA) predicts events in those with and without diabetes. T2D genetic risk may predict both T2D and SCA. We hypothesized that greater T2D genetic risk is associated with higher extent of SCA.
Methods and Results
In a cross-sectional analysis including up to 9,210 European Americans, 3,773 African Americans, 1,446 Hispanic Americans and 773 Chinese Americans without known CVD and enrolled in the FHS, CARDIA, MESA and GENOA studies, we tested a 62 T2D-loci genetic risk score (GRS62) for association with measures of SCA, including coronary artery (CACS) or abdominal aortic calcium score, common (CCA-IMT) and internal carotid artery intima-media thickness, and ankle-brachial index (ABI). We used ancestry-stratified linear regression models, with random effects accounting for family relatedness when appropriate, applying a genetic-only (adjusted for sex) and a full SCA risk factors adjusted model (significance = p<0.01 = 0.05/5, number of traits analyzed). An inverse association with CACS in MESA Europeans (fully-adjusted p=0.004) and with CCA-IMT in FHS (p=0.009) was not confirmed in other study cohorts, either separately or in meta-analysis. Secondary analyses showed no consistent associations with β-cell and insulin resistance sub-GRS in FHS and CARDIA.
Conclusions
SCA does not have a major genetic component linked to a burden of 62 T2D loci identified by large genome-wide association studies. A shared T2D-SCA genetic basis, if any, might become apparent from better functional information about both T2D and CVD risk loci.
doi:10.1161/CIRCGENETICS.114.000740
PMCID: PMC4472563  PMID: 25805414
genetic association; risk assessment; subclinical atherosclerosis risk factor; type 2 diabetes mellitus; cardiovascular disease
6.  Gene-centric approach identifies new and known loci for FVIII activity and VWF antigen levels in European Americans and African Americans 
American journal of hematology  2015;90(6):534-540.
Coagulation factor VIII and von Willebrand factor (VWF) are key proteins in procoagulant activation. Higher FVIII coagulant activity (FVIII:C) and VWF antigen (VWF:Ag) are risk factors for cardiovascular disease and venous thromboembolism. Beyond associations with ABO blood group, genetic determinants of FVIII and VWF are not well understood, especially in non European-American populations. We performed a genetic association study of FVIII:C and VWF:Ag that assessed 50,000 gene-centric single nucleotide polymorphisms (SNPs) in 18,556 European Americans (EAs) and 5,047 African Americans (AAs) from five population-based cohorts. Previously unreported associations for FVIII:C were identified in both AAs and EAs with KNG1 (most significantly associated SNP rs710446, Ile581Thr, P=5.10 × 10−7 in EAs and P=3.88 × 10−3 in AAs) and VWF rs7962217 (Gly2705Arg, P=6.30 × 10−9 in EAs and P=2.98 × 10−2 in AAs). Significant associations for FVIII:C were also observed with F8/TMLHE region SNP rs12557310 in EAs (P=8.02 × 10−10), with VWF rs1800380 in AAs (P=5.62 × 10−11), and with MAT1A rs2236568 in AAs (P=1.69 × 10−6). We replicated previously reported associations of FVIII:C and VWF:Ag with the ABO blood group, VWF rs1063856 (Thr789Ala), rs216321 (Ala852Gln), and VWF rs2229446 (Arg2185Gln). Findings from this study expand our understanding of genetic influences for FVIII:C and VWF:Ag in both EAs and AAs.
doi:10.1002/ajh.24005
PMCID: PMC4747096  PMID: 25779970
7.  Design of Pyridopyrazine-1,6-dione γ-Secretase Modulators that Align Potency, MDR Efflux Ratio, and Metabolic Stability 
ACS Medicinal Chemistry Letters  2015;6(5):596-601.
Herein we describe the design and synthesis of a series of pyridopyrazine-1,6-dione γ-secretase modulators (GSMs) for Alzheimer’s disease (AD) that achieve good alignment of potency, metabolic stability, and low MDR efflux ratios, while also maintaining favorable physicochemical properties. Specifically, incorporation of fluorine enabled design of metabolically less liable lipophilic alkyl substituents to increase potency without compromising the sp3-character. The lead compound 21 (PF-06442609) displayed a favorable rodent pharmacokinetic profile, and robust reductions of brain Aβ42 and Aβ40 were observed in a guinea pig time-course experiment.
doi:10.1021/acsmedchemlett.5b00070
PMCID: PMC4434474  PMID: 26005540
Alzheimer’s disease; gamma secretase modulators; fluorine; lipophilic metabolism efficiency; LipMetE
8.  Identification of Nine Novel Loci Associated with White Blood Cell Subtypes in a Japanese Population 
PLoS Genetics  2011;7(6):e1002067.
White blood cells (WBCs) mediate immune systems and consist of various subtypes with distinct roles. Elucidation of the mechanism that regulates the counts of the WBC subtypes would provide useful insights into both the etiology of the immune system and disease pathogenesis. In this study, we report results of genome-wide association studies (GWAS) and a replication study for the counts of the 5 main WBC subtypes (neutrophils, lymphocytes, monocytes, basophils, and eosinophils) using 14,792 Japanese subjects enrolled in the BioBank Japan Project. We identified 12 significantly associated loci that satisfied the genome-wide significance threshold of P<5.0×10−8, of which 9 loci were novel (the CDK6 locus for the neutrophil count; the ITGA4, MLZE, STXBP6 loci, and the MHC region for the monocyte count; the SLC45A3-NUCKS1, GATA2, NAALAD2, ERG loci for the basophil count). We further evaluated associations in the identified loci using 15,600 subjects from Caucasian populations. These WBC subtype-related loci demonstrated a variety of patterns of pleiotropic associations within the WBC subtypes, or with total WBC count, platelet count, or red blood cell-related traits (n = 30,454), which suggests unique and common functional roles of these loci in the processes of hematopoiesis. This study should contribute to the understanding of the genetic backgrounds of the WBC subtypes and hematological traits.
Author Summary
White blood cells (WBCs) are blood cells that mediate immune systems and defend the body against foreign microorganisms. It is well known that WBCs consist of various subtypes of cells with distinct roles, although the genetic background of each of the WBC subtypes has yet to be examined. In this study, we report genome-wide association studies (GWAS) for the 5 main WBC subtypes (neutrophils, lymphocytes, monocytes, basophils, and eosinophils) using 14,792 Japanese subjects. We identified 12 significantly associated genetic loci, and 9 of them were novel. Evaluation of the associations of these identified loci in cohorts of Caucasian populations demonstrated both ethnically common and divergent genetic backgrounds of the WBC subtypes. These loci also indicated a variety of patterns of pleiotropic associations within the hematological traits, including the other WBC subtypes, total WBC count, platelet count, or red blood cell-related traits, which suggests unique and common functional roles of these loci in the processes of hematopoiesis.
doi:10.1371/journal.pgen.1002067
PMCID: PMC3128095  PMID: 21738478
9.  Low Cardiac Index is Associated with Incident Dementia and Alzheimer’s Disease: The Framingham Heart Study 
Circulation  2015;131(15):1333-1339.
Background
Cross-sectional epidemiological and clinical research suggest lower cardiac index is associated with abnormal brain aging, including smaller brain volumes, increased white matter hyperintensities, and worse cognitive performances. Lower systemic blood flow may have implications for dementia among older adults.
Methods & Results
1039 Framingham Offspring Cohort participants free from clinical stroke, transient ischemic attack, or dementia formed our sample (69±6 years; 53% women). Multivariable-adjusted proportional hazard models adjusting for Framingham Stroke Risk Profile score (age, sex, systolic blood pressure, anti-hypertensive medication, diabetes, cigarette smoking, cardiovascular disease [CVD] history, atrial fibrillation), education, and apolipoprotein E4 status related cardiac MRI-assessed cardiac index (cardiac output/body surface area) to incident all-cause dementia and Alzheimer’s disease (AD). Over the median 7.7 year follow-up period, 32 participants developed dementia, including 26 cases of AD. Each one standard deviation unit decrease in cardiac index increased the relative risk of both dementia (HR=1.66; 95% confidence intervals [CI], 1.11–2.47; p=0.013) and AD (HR=1.65; 95% CI, 1.07–2.54; p=0.022). Compared to normal cardiac index, individuals with clinically low cardiac index had a higher relative risk of dementia (HR=2.07; 95% CI, 1.02–4.19; p=0.044). If participants with clinically prevalent CVD and atrial fibrillation were excluded (n=184), individuals with clinically low cardiac index had a higher relative risk of both dementia (HR=2.92; 95% CI, 1.34–6.36; p=0.007) and AD (HR=2.87; 95% CI, 1.21–6.80; p=0.016) compared to individuals with normal cardiac index.
Conclusions
Lower cardiac index is associated with an increased risk for the development of dementia and AD.
doi:10.1161/CIRCULATIONAHA.114.012438
PMCID: PMC4398627  PMID: 25700178
blood circulation; brain; cardiac output; hemodynamics; dementia; Alzheimer disease
10.  Association Between Interstitial Lung Abnormalities and All-Cause Mortality 
JAMA  2016;315(7):672-681.
IMPORTANCE
Interstitial lung abnormalities have been associated with decreased six-minute walk distance, diffusion capacity for carbon monoxide and total lung capacity; however to our knowledge, an association with mortality has not been previously investigated.
OBJECTIVE
To investigate whether interstitial lung abnormalities are associated with increased mortality.
DESIGN, SETTING, POPULATION
Prospective cohort studies of 2633 participants from the Framingham Heart Study (FHS) (CT scans obtained 9/08–3/11), 5320 from the Age Gene/Environment Susceptibility (AGES)-Reykjavik (recruited 1/02–2/06), 2068 from COPDGene (recruited 11/07–4/10), and 1670 from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) (between 12/05–12/06).
EXPOSURES
Interstitial lung abnormality status as determined by chest CT evaluation.
MAIN OUTCOMES AND MEASURES
All cause mortality over approximately 3 to 9 year median follow up time. Cause-of-death information was also examined in the AGES-Reykjavik cohort.
RESULTS
Interstitial lung abnormalities were present in 177 (7%) of the participants from FHS, 378 (7%) from AGES-Reykjavik, 156 (8%) from COPDGene, and in 157 (9%) from ECLIPSE. Over median follow-up times of ~3–9 years there were more deaths (and a greater absolute rate of mortality) among those with interstitial lung abnormalities compared to those without interstitial lung abnormalities in each cohort; 7% compared to 1% in FHS (6% difference, 95% confidence interval [CI] 2%, 10%), 56% compared to 33% in AGES-Reykjavik (23% difference, 95% CI 18%, 28%), 16% compared to 11% in COPDGene (5% difference, 95% CI −1%, 11%) and 11% compared to 5% in ECLIPSE (6% difference, 95% CI 1%, 11%). After adjustment for covariates, interstitial lung abnormalities were associated with an increase in the risk of death in the FHS (HR=2.7, 95% CI, 1.1–65, P=0.030), AGES-Reykjavik (HR 1.3, 95% CI 1.2–1.4, P<0.001), COPDGene (HR=1.8, 95% CI, 1.1, 2.8, P=0.014), and ECLIPSE (HR=1.4, 95% CI, 1.1–2, P=0.022) cohorts. In the AGES-Reykjavik cohort the higher rate of mortality could be explained by a higher rate of death due to respiratory disease, specifically pulmonary fibrosis.
CONCLUSIONS AND RELEVANCE
In four separate research cohorts, interstitial lung abnormalities were associated with a higher risk of all-cause mortality. The clinical implications of this association require further investigation.
doi:10.1001/jama.2016.0518
PMCID: PMC4828973  PMID: 26881370
Idiopathic pulmonary fibrosis; interstitial lung disease; interstitial lung abnormalities (ILA); undiagnosed; subclinical
11.  Future Translational Applications From the Contemporary Genomics Era 
Circulation  2015;131(19):1715-1736.
The field of genetics and genomics has advanced considerably with the achievement of recent milestones encompassing the identification of many loci for cardiovascular disease and variable drug responses. Despite this achievement, a gap exists in the understanding and advancement to meaningful translation that directly affects disease prevention and clinical care. The purpose of this scientific statement is to address the gap between genetic discoveries and their practical application to cardiovascular clinical care. In brief, this scientific statement assesses the current timeline for effective translation of basic discoveries to clinical advances, highlighting past successes. Current discoveries in the area of genetics and genomics are covered next, followed by future expectations, tools, and competencies for achieving the goal of improving clinical care.
doi:10.1161/CIR.0000000000000211
PMCID: PMC4825323  PMID: 25882488
AHA Scientific Statements; adrenergic beta-antagonists; DNA; genetics; genome-wide association study; HapMap Project; Human Genome Project; PCSK9 protein; mouse; polymorphism; single nucleotide
12.  Impact of Age, Sex and Indexation Method on MR Left Ventricular Reference Values in the Framingham Heart Study Offspring Cohort 
Purpose
To determine normative values for left ventricular (LV) volumes, mass, concentricity and ejection fraction (EF) and investigate associations between sex, age and body size with LV parameters in community dwelling adults.
Materials and Methods
1794 Framingham Heart Study Offspring cohort members underwent LV short-axis oriented, contiguous multislice ciné SSFP MR of the left ventricle; from these a healthy referent group (N=852, 61±9 years, 40% men) free of clinical cardiac disease and hypertension (SBP<140, DBP<90 mmHg, never used antihypertensive medication ≥ 30 years prior to scanning) was identified. Referent participants were stratified by sex and age group (≤55, 56-65, >65 years); LV parameters were indexed to measures of body size.
Results
Men have greater LV volumes and mass than women both before and after indexation to height, powers of height, and body surface area (p<0.01 all), but indexation to fat-free mass yielded greater LV volume and mass in women. In both sexes, LV volumes and mass decrease with advancing age, though indexation attenuates this association. LVEF is greater in women than men (68±5% vs. 66±5%, p<0.01) and increases with age in both sexes (p<0.05).
Conclusion
Among non-hypertensive adults free of cardiac disease, men have greater LV volumes and mass with sex differences generally persisting after indexation to body size. LV volumes and mass tend to decrease with greater age in both sexes. Female sex and advanced age were both associated with greater LVEF.
doi:10.1002/jmri.24649
PMCID: PMC4248013  PMID: 24817313
magnetic resonance imaging; left ventricle; aging; sex differences; population study; reference values
13.  Dissecting the Roles of microRNAs in Coronary Heart Disease via Integrative Genomics Analyses 
Objective
The roles of microRNAs (miRNAs) in coronary heart disease (CHD) have not been well characterized. This study sought to systematically characterize the complex genomic architecture of CHD by integrating whole blood miRNA and mRNA expression with genetic variation in 186 CHD cases and 186 controls.
Approach and Results
At FDR<0.2, 15 miRNAs were differentially expressed between CHD cases and controls. To explore regulatory mechanisms, we integrated miRNA and mRNA expression with genotype data genome-wide to investigate miRNA and mRNA associations and relations of genetic variation to miRNAs. We identified a large number of correlated miRNA-mRNA pairs and genetic loci that appear to regulate miRNA levels. Subsequently, we explored the relations of these complex molecular associations to CHD status. We identified a large difference in miRNA-mRNA associations between CHD cases and controls, as demonstrated by a significantly higher proportion of inversely correlated miRNA-mRNA pairs in cases vs. controls (80% vs. 30%; p<1e-16), suggesting a genome-wide shift in the regulatory structure of the transcriptome in CHD. The differentially co-expressed miRNA-mRNA pairs showed enrichment for CHD risk genetic variants affecting both miRNA and mRNA expression levels, implicating a putatively causal role in CHD. Furthermore, three miRNAs (miR-1275, miR-365a-3p, and miR-150-5p) were associated with an mRNA co-expression module that was causally linked to CHD and reflected dysregulation of B-cell centered immune function.
Conclusions
Our results provide novel evidence that miRNAs are important regulators of biological processes involved in CHD via genetic control and via their tight co-expression with mRNAs.
doi:10.1161/ATVBAHA.114.305176
PMCID: PMC4376567  PMID: 25657313
microRNA expression; coronary heart disease; systems biology; genetics
14.  A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease 
Nikpay, Majid | Goel, Anuj | Won, Hong-Hee | Hall, Leanne M | Willenborg, Christina | Kanoni, Stavroula | Saleheen, Danish | Kyriakou, Theodosios | Nelson, Christopher P | Hopewell, Jemma C | Webb, Thomas R | Zeng, Lingyao | Dehghan, Abbas | Alver, Maris | Armasu, Sebastian M | Auro, Kirsi | Bjonnes, Andrew | Chasman, Daniel I | Chen, Shufeng | Ford, Ian | Franceschini, Nora | Gieger, Christian | Grace, Christopher | Gustafsson, Stefan | Huang, Jie | Hwang, Shih-Jen | Kim, Yun Kyoung | Kleber, Marcus E | Lau, King Wai | Lu, Xiangfeng | Lu, Yingchang | Lyytikäinen, Leo-Pekka | Mihailov, Evelin | Morrison, Alanna C | Pervjakova, Natalia | Qu, Liming | Rose, Lynda M | Salfati, Elias | Saxena, Richa | Scholz, Markus | Smith, Albert V | Tikkanen, Emmi | Uitterlinden, Andre | Yang, Xueli | Zhang, Weihua | Zhao, Wei | de Andrade, Mariza | de Vries, Paul S | van Zuydam, Natalie R | Anand, Sonia S | Bertram, Lars | Beutner, Frank | Dedoussis, George | Frossard, Philippe | Gauguier, Dominique | Goodall, Alison H | Gottesman, Omri | Haber, Marc | Han, Bok-Ghee | Huang, Jianfeng | Jalilzadeh, Shapour | Kessler, Thorsten | König, Inke R | Lannfelt, Lars | Lieb, Wolfgang | Lind, Lars | Lindgren, Cecilia M | Lokki, Marja-Liisa | Magnusson, Patrik K | Mallick, Nadeem H | Mehra, Narinder | Meitinger, Thomas | Memon, Fazal-ur-Rehman | Morris, Andrew P | Nieminen, Markku S | Pedersen, Nancy L | Peters, Annette | Rallidis, Loukianos S | Rasheed, Asif | Samuel, Maria | Shah, Svati H | Sinisalo, Juha | Stirrups, Kathleen E | Trompet, Stella | Wang, Laiyuan | Zaman, Khan S | Ardissino, Diego | Boerwinkle, Eric | Borecki, Ingrid B | Bottinger, Erwin P | Buring, Julie E | Chambers, John C | Collins, Rory | Cupples, L Adrienne | Danesh, John | Demuth, Ilja | Elosua, Roberto | Epstein, Stephen E | Esko, Tõnu | Feitosa, Mary F | Franco, Oscar H | Franzosi, Maria Grazia | Granger, Christopher B | Gu, Dongfeng | Gudnason, Vilmundur | Hall, Alistair S | Hamsten, Anders | Harris, Tamara B | Hazen, Stanley L | Hengstenberg, Christian | Hofman, Albert | Ingelsson, Erik | Iribarren, Carlos | Jukema, J Wouter | Karhunen, Pekka J | Kim, Bong-Jo | Kooner, Jaspal S | Kullo, Iftikhar J | Lehtimäki, Terho | Loos, Ruth J F | Melander, Olle | Metspalu, Andres | März, Winfried | Palmer, Colin N | Perola, Markus | Quertermous, Thomas | Rader, Daniel J | Ridker, Paul M | Ripatti, Samuli | Roberts, Robert | Salomaa, Veikko | Sanghera, Dharambir K | Schwartz, Stephen M | Seedorf, Udo | Stewart, Alexandre F | Stott, David J | Thiery, Joachim | Zalloua, Pierre A | ODonnell, Christopher J | Reilly, Muredach P | Assimes, Themistocles L | Thompson, John R | Erdmann, Jeanette | Clarke, Robert | Watkins, Hugh | Kathiresan, Sekar | McPherson, Ruth | Deloukas, Panos | Schunkert, Heribert | Samani, Nilesh J | Farrall, Martin
Nature genetics  2015;47(10):1121-1130.
Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association studies (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of 185 thousand CAD cases and controls, interrogating 6.7 million common (MAF>0.05) as well as 2.7 million low frequency (0.005
doi:10.1038/ng.3396
PMCID: PMC4589895  PMID: 26343387
There is increasing evidence that bone and vascular calcification share common pathogenesis. Little is known about potential links between bone and valvular calcification. The purpose of this study was to determine the association between spine bone mineral density (BMD) and vascular and valvular calcification. Participants included 1317 participants (689 women, 628 men) in the Framingham Offspring Study (mean age 60 years). Integral, trabecular, and cortical volumetric bone density (vBMD) and arterial and valvular calcification were measured from computed tomography (CT) scans and categorized by sex-specific quartiles (Q4 = high vBMD). Calcification of the coronary arteries (CAC), abdominal aorta (AAC), aortic valve (AVC), and mitral valve (MVC) were quantified using the Agatston Score (AS). Prevalence of any calcium (AS >0) was 69% for CAC, 81% for AAC, 39% for AVC, and 20% for MVC. In women, CAC increased with decreasing quartile of trabecular vBMD: adjusted mean CAC = 2.1 (Q4), 2.2 (Q3), 2.5 (Q2), 2.6 (Q1); trend p = 0.04. However, there was no inverse trend between CAC and trabecular vBMD in men: CAC = 4.3 (Q4), 4.3 (Q3), 4.2 (Q2), 4.3 (Q1); trend p = 0.92. AAC increased with decreasing quartile of trabecular vBMD in both women (AAC = 4.5 [Q4], 4.8 [Q3], 5.4 [Q2], 5.1 [Q1]; trend p = 0.01) and men (AAC = 5.5 [Q4], 5.8 [Q3], 5.9 [Q2], 6.2 [Q1]; trend p = 0.01). We observed no association between trabecular vBMD and AVC or MVC in women or men. Finally, cortical vBMD was unrelated to vascular calcification and valvular calcification in women and men. Women and men with low spine vBMD have greater severity of vascular calcification, particularly at the abdominal aorta. The inverse relation between AAC and spine vBMD in women and men may be attributable to shared etiology and may be an important link on which to focus treatment efforts that can target individuals at high risk of both fracture and cardiovascular events.
doi:10.1002/jbmr.2530
PMCID: PMC4809363  PMID: 25871790
BONE; AGING; QCT; OSTEOPOROSIS; VASCULAR CALCIFICATION; VALVULAR CALCIFICATION; EPIDEMIOLOGY
Objective
Determine the prevalence and risk factor (RF) correlates of aortic plaque (AP) detected by cardiovascular magnetic resonance (CMR), which mainly shows noncalcified plaques, and by noncontrast computed tomography (CT), which best depicts calcified plaques, in community-dwelling adults.
Approach and Results
1016 Framingham Offspring cohort members (64±9y, 474 men) underwent CMR and CT of the aorta. Potential RFs for AP (age; sex; BMI; blood pressure; LDL and HDL cholesterol; fasting glucose; C-reactive protein; prevalent hypertension, diabetes, smoking; use of antihypertensive, diabetes or lipid-lowering drugs) were compared between participants with zero versus nonzero AP by CMR and by CT. Candidate RFs attaining p<0.05 for difference with either imaging modality were entered into multivariable logistic regression models adjusting for age, sex and other RFs. Odds ratios were calculated for modality-specific prevalence of AP. Associations between RFs and continuous measures of AP were assessed using Tobit regression. Prevalences of CMR and CT AP were 49% and 82% respectively. AP burdens by CMR and CT were correlated, r=0.28, p<0.0001. Increasing age and smoking were associated with prevalent AP by both CMR and CT. Additionally, prevalent AP by CMR was associated with female sex and fasting glucose, prevalent AP by CT with hypertension treatment and with adverse lipid profile.
Conclusions
AP by CMR and CT are both associated with smoking and increasing age, but other risk factors differ between calcified and noncalcified AP. The relative predictive value of AP detected by CMR versus by CT for incident cardiovascular events remains to be determined.
doi:10.1161/ATVBAHA.114.303600
PMCID: PMC4099001  PMID: 24833796
aortic atherosclerosis; epidemiology; risk factors; magnetic resonance imaging; computed tomography
PLoS ONE  2016;11(3):e0144997.
Background
Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting.
Methods
We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5×10−6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up.
Results
In Stage I 15 loci passed the threshold of 5×10−6; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8×10−3) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2×10−9). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2×10−3).
Conclusions
QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.
doi:10.1371/journal.pone.0144997
PMCID: PMC4780701  PMID: 26950853
Human genetics  2015;134(3):343-358.
Genome-wide expression quantitative trait locus (eQTL) mapping may reveal common genetic variants regulating gene expression. In addition to mapping eQTLs, we systematically evaluated the heritability of the whole blood transcriptome in 5626 participants from the Framingham Heart Study. Of all gene expression measurements, about 40% exhibit evidence of being heritable (hgeneExp2>0, (p<0.05]), the average heritability was estimated to be 0.13, and 10% display hgeneExp2>0.2. In order to identify the role of eQTLs in promoting phenotype differences and disease susceptibility, we investigated the proportion of cis/trans eQTLs in different heritability categories and discovered that genes with higher heritability are more likely to have cis eQTLs that explain large proportions of variance in the expression of the corresponding genes. Single cis eQTLs explain 0.33–0.53 of variance in transcripts on average, whereas single trans eQTLs only explain 0.02–0.07. The top cis eQTLs tend to explain more variance in the corresponding gene when its hgeneExp2 is greater. Taking body mass index (BMI) as a case study, we cross-linked cis/trans eQTLs with both GWAS SNPs and differentially expressed genes for BMI. We discovered that BMI GWAS SNPs in 16p11.2 (e.g., rs7359397) are associated with several BMI differentially expressed genes in a cis manner (e.g. SULT1A1, SPNS1, and TUFM). These BMI signature genes explain a much larger proportion of variance in BMI than do the GWAS SNPs. Our results shed light the impact of eQTLs on the heritability of the human whole blood transcriptome and its relations to phenotype differences.
doi:10.1007/s00439-014-1524-3
PMCID: PMC4339826  PMID: 25585846
heritability; eQTL; transcriptome; gene expression
JAMA  2015;314(2):134-141.
IMPORTANCE
The 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for cholesterol management defined new eligibility criteria for statin therapy. However, it is unclear whether this approach improves identification of adults at higher risk of cardiovascular events.
OBJECTIVE
To determine whether the ACC/AHA guidelines improve identification of individuals who develop incident cardiovascular disease (CVD) and/or have coronary artery calcification (CAC) compared with the National Cholesterol Education Program’s 2004 Updated Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III) guidelines.
DESIGN, SETTING, AND PARTICIPANTS
Longitudinal community-based cohort study, with participants for this investigation drawn from the offspring and third-generation cohorts of the Framingham Heart Study. Participants underwent multidetector computed tomography for CAC between 2002 and 2005 and were followed up for a median of 9.4 years for incident CVD.
EXPOSURES
Statin eligibility was determined based on Framingham risk factors and low-density lipoprotein thresholds for ATP III, whereas the pooled cohort calculator was used for ACC/AHA.
MAIN OUTCOMES AND MEASURES
The primary outcome was incident CVD (myocardial infarction, death due to coronary heart disease [CHD], or ischemic stroke). Secondary outcomes were CHD and CAC (as measured by the Agatston score).
RESULTS
Among 2435 statin-naive participants (mean age, 51.3 [SD, 8.6] years; 56% female), 39% (941/2435) were statin eligible by ACC/AHA compared with 14% (348/2435) by ATP III (P < .001). There were 74 incident CVD events (40 nonfatal myocardial infarctions, 31 nonfatal ischemic strokes, and 3 fatal CHD events). Participants who were statin eligible by ACC/AHA had increased hazard ratios for incident CVD compared with those eligible by ATP III: 6.8 (95% CI, 3.8–11.9) vs 3.1 (95% CI, 1.9–5.0), respectively (P <.001). Similar results were seen for CVD in participants with intermediate Framingham Risk Scores and for CHD. Participants who were newly statin eligible (n = 593 [24%]) had an incident CVD rate of 5.7%, yielding a number needed to treat of 39 to 58. Participants with CAC were more likely to be statin eligible by ACC/AHA than by ATP III: CAC score >0 (n = 1015): 63% vs 23%; CAC score >100 (n = 376): 80% vs 32%; and CAC score >300 (n = 186): 85% vs 34% (all P < .001). A CAC score of 0 identified a low-risk group among ACC/AHA statin-eligible participants (306/941 [33%]) with a CVD rate of 1.6%.
CONCLUSIONS AND RELEVANCE
In this community-based primary prevention cohort, the ACC/AHA guidelines for determining statin eligibility, compared with the ATP III, were associated with greater accuracy and efficiency in identifying increased risk of incident CVD and subclinical coronary artery disease, particularly in intermediate-risk participants.
doi:10.1001/jama.2015.7515
PMCID: PMC4754085  PMID: 26172893
Huang, Jie | Huffman, Jennifer E. | Yamkauchi, Munekazu | Trompet, Stella | Asselbergs, Folkert W. | Sabater-Lleal, Maria | Trégouët, David-Alexandre | Chen, Wei-Min | Smith, Nicholas L. | Kleber, Marcus E. | Shin, So-Youn | Becker, Diane M. | Tang, Weihong | Dehghan, Abbas | Johnson, Andrew D. | Truong, Vinh | Folkersen, Lasse | Yang, Qiong | Oudot-Mellakh, Tiphaine | Buckley, Brendan M. | Moore, Jason H. | Williams, Frances M.K. | Campbell, Harry | Silbernagel, Günther | Vitart, Veronique | Rudan, Igor | Tofler, Geoffrey H. | Navis, Gerjan J. | DeStefano, Anita | Wright, Alan F. | Chen, Ming-Huei | de Craen, Anton J.M. | Worrall, Bradford B. | Rudnicka, Alicja R. | Rumley, Ann | Bookman, Ebony B. | Psaty, Bruce M. | Chen, Fang | Keene, Keith L. | Franco, Oscar H. | Böhm, Bernhard O. | Uitterlinden, Andre G. | Carter, Angela M. | Jukema, J. Wouter | Sattar, Naveed | Bis, Joshua C. | Ikram, Mohammad A. | Sale, Michèle M. | McKnight, Barbara | Fornage, Myriam | Ford, Ian | Taylor, Kent | Slagboom, P. Eline | McArdle, Wendy L. | Hsu, Fang-Chi | Franco-Cereceda, Anders | Goodall, Alison H. | Yanek, Lisa R. | Furie, Karen L. | Cushman, Mary | Hofman, Albert | Witteman, Jacqueline CM. | Folsom, Aaron R. | Basu, Saonli | Matijevic, Nena | van Gilst, Wiek H. | Wilson, James F. | Westendorp, Rudi G.J. | Kathiresan, Sekar | Reilly, Muredach P. | Tracy, Russell P. | Polasek, Ozren | Winkelmann, Bernhard R. | Grant, Peter J. | Hillege, Hans L. | Cambien, Francois | Stott, David J. | Lowe, Gordon D. | Spector, Timothy D. | Meigs, James B. | Marz, Winfried | Eriksson, Per | Becker, Lewis C. | Morange, Pierre-Emmanuel | Soranzo, Nicole | Williams, Scott M. | Hayward, Caroline | van der Harst, Pim | Hamsten, Anders | Lowenstein, Charles J. | Strachan, David P. | O'Donnell, Christopher J.
Objective
Tissue plasminogen activator (tPA), a serine protease, catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for endogenous fibrinolysis. In some populations, elevated plasma levels of tPA have been associated with myocardial infarction and other cardiovascular diseases (CVD). We conducted a meta-analysis of genome-wide association studies (GWAS) to identify novel correlates of circulating levels of tPA.
Approach and Results
Fourteen cohort studies with tPA measures (N=26,929) contributed to the meta-analysis. Three loci were significantly associated with circulating tPA levels (P <5.0×10−8). The first locus is on 6q24.3, with the lead SNP (rs9399599, P=2.9×10−14) within STXBP5. The second locus is on 8p11.21. The lead SNP (rs3136739, P=1.3×10−9) is intronic to POLB and less than 200kb away from the tPA encoding gene PLAT. We identified a non-synonymous SNP (rs2020921) in modest LD with rs3136739 (r2 = 0.50) within exon 5 of PLAT (P=2.0×10−8). The third locus is on 12q24.33, with the lead SNP (rs7301826, P=1.0×10−9) within intron 7 of STX2. We further found evidence for association of lead SNPs in STXBP5 and STX2 with expression levels of the respective transcripts. In in vitro cell studies, silencing STXBP5 decreased release of tPA from vascular endothelial cells, while silencing of STX2 increased tPA release. Through an in-silico lookup, we found no associations of the three lead SNPs with coronary artery disease or stroke.
Conclusions
We identified three loci associated with circulating tPA levels, the PLAT region, STXBP5 and STX2. Our functional studies implicate a novel role for STXBP5 and STX2 in regulating tPA release.
doi:10.1161/ATVBAHA.113.302088
PMCID: PMC4009733  PMID: 24578379
tissue plasminogen activator; genome-wide association study; meta-analysis; cardiovascular disease risk; fibrinolysis; hemostasis
Background
We determined whether vascular and valvular calcification predicted incident major coronary heart disease, cardiovascular disease (CVD), and all‐cause mortality independent of Framingham risk factors in the community‐based Framingham Heart Study.
Methods and Results
Coronary artery calcium (CAC), thoracic and abdominal aortic calcium, and mitral or aortic valve calcium were measured by cardiac computed tomography in participants free of CVD. Participants were followed for a median of 8 years. Multivariate Cox proportional hazards models were used to determine association of CAC, thoracic and abdominal aortic calcium, and mitral and aortic valve calcium with end points. Improvement in discrimination beyond risk factors was tested via the C‐statistic and net reclassification index. In this cohort of 3486 participants (mean age 50±10 years; 51% female), CAC was most strongly associated with major coronary heart disease, followed by major CVD, and all‐cause mortality independent of Framingham risk factors. Among noncoronary calcifications, mitral valve calcium was associated with major CVD and all‐cause mortality independent of Framingham risk factors and CAC. CAC significantly improved discriminatory value beyond risk factors for coronary heart disease (area under the curve 0.78–0.82; net reclassification index 32%, 95% CI 11–53) but not for CVD. CAC accurately reclassified 85% of the 261 patients who were at intermediate (5–10%) 10‐year risk for coronary heart disease based on Framingham risk factors to either low risk (n=172; no events observed) or high risk (n=53; observed event rate 8%).
Conclusions
CAC improves discrimination and risk reclassification for major coronary heart disease and CVD beyond risk factors in asymptomatic community‐dwelling persons and accurately reclassifies two‐thirds of the intermediate‐risk population.
doi:10.1161/JAHA.115.003144
PMCID: PMC4802453  PMID: 26903006
coronary disease; prognosis; risk factors; Computerized Tomography (CT); Cardiovascular Disease; Prognosis
Nalls, Michael A. | Couper, David J. | Tanaka, Toshiko | van Rooij, Frank J. A. | Chen, Ming-Huei | Smith, Albert V. | Toniolo, Daniela | Zakai, Neil A. | Yang, Qiong | Greinacher, Andreas | Wood, Andrew R. | Garcia, Melissa | Gasparini, Paolo | Liu, Yongmei | Lumley, Thomas | Folsom, Aaron R. | Reiner, Alex P. | Gieger, Christian | Lagou, Vasiliki | Felix, Janine F. | Völzke, Henry | Gouskova, Natalia A. | Biffi, Alessandro | Döring, Angela | Völker, Uwe | Chong, Sean | Wiggins, Kerri L. | Rendon, Augusto | Dehghan, Abbas | Moore, Matt | Taylor, Kent | Wilson, James G. | Lettre, Guillaume | Hofman, Albert | Bis, Joshua C. | Pirastu, Nicola | Fox, Caroline S. | Meisinger, Christa | Sambrook, Jennifer | Arepalli, Sampath | Nauck, Matthias | Prokisch, Holger | Stephens, Jonathan | Glazer, Nicole L. | Cupples, L. Adrienne | Okada, Yukinori | Takahashi, Atsushi | Kamatani, Yoichiro | Matsuda, Koichi | Tsunoda, Tatsuhiko | Tanaka, Toshihiro | Kubo, Michiaki | Nakamura, Yusuke | Yamamoto, Kazuhiko | Kamatani, Naoyuki | Stumvoll, Michael | Tönjes, Anke | Prokopenko, Inga | Illig, Thomas | Patel, Kushang V. | Garner, Stephen F. | Kuhnel, Brigitte | Mangino, Massimo | Oostra, Ben A. | Thein, Swee Lay | Coresh, Josef | Wichmann, H.-Erich | Menzel, Stephan | Lin, JingPing | Pistis, Giorgio | Uitterlinden, André G. | Spector, Tim D. | Teumer, Alexander | Eiriksdottir, Gudny | Gudnason, Vilmundur | Bandinelli, Stefania | Frayling, Timothy M. | Chakravarti, Aravinda | van Duijn, Cornelia M. | Melzer, David | Ouwehand, Willem H. | Levy, Daniel | Boerwinkle, Eric | Singleton, Andrew B. | Hernandez, Dena G. | Longo, Dan L. | Soranzo, Nicole | Witteman, Jacqueline C. M. | Psaty, Bruce M. | Ferrucci, Luigi | Harris, Tamara B. | O'Donnell, Christopher J. | Ganesh, Santhi K.
PLoS Genetics  2011;7(6):e1002113.
White blood cell (WBC) count is a common clinical measure from complete blood count assays, and it varies widely among healthy individuals. Total WBC count and its constituent subtypes have been shown to be moderately heritable, with the heritability estimates varying across cell types. We studied 19,509 subjects from seven cohorts in a discovery analysis, and 11,823 subjects from ten cohorts for replication analyses, to determine genetic factors influencing variability within the normal hematological range for total WBC count and five WBC subtype measures. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We identified and replicated ten associations with total WBC count and five WBC subtypes at seven different genomic loci (total WBC count—6p21 in the HLA region, 17q21 near ORMDL3, and CSF3; neutrophil count—17q21; basophil count- 3p21 near RPN1 and C3orf27; lymphocyte count—6p21, 19p13 at EPS15L1; monocyte count—2q31 at ITGA4, 3q21, 8q24 an intergenic region, 9q31 near EDG2), including three previously reported associations and seven novel associations. To investigate functional relationships among variants contributing to variability in the six WBC traits, we utilized gene expression- and pathways-based analyses. We implemented gene-clustering algorithms to evaluate functional connectivity among implicated loci and showed functional relationships across cell types. Gene expression data from whole blood was utilized to show that significant biological consequences can be extracted from our genome-wide analyses, with effect estimates for significant loci from the meta-analyses being highly corellated with the proximal gene expression. In addition, collaborative efforts between the groups contributing to this study and related studies conducted by the COGENT and RIKEN groups allowed for the examination of effect homogeneity for genome-wide significant associations across populations of diverse ancestral backgrounds.
Author Summary
WBC traits are highly variable, moderately heritable, and commonly assayed as part of clinical complete blood count (CBC) examinations. The counts of constituent cell subtypes comprising the WBC count measure are assayed as part of a standard clinical WBC differential test. In this study we employed meta-analytic techniques and identified ten associations with WBC measures at seven genomic loci in a large sample set of over 31,000 participants. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We confirm previous associations of WBC traits with three loci and identified seven novel loci. We also utilize a number of additional analytic methods to infer the functional relatedness of independently implicated loci across WBC phenotypes, as well as investigate direct functional consequences of these loci through analyses of genomic variation affecting the expression of proximal genes in samples of whole blood. In addition, subsequent collaborative efforts with studies of WBC traits in African-American and Japanese cohorts allowed for the investigation of the effects of these genomic variants across populations of diverse continental ancestries.
doi:10.1371/journal.pgen.1002113
PMCID: PMC3128114  PMID: 21738480
Human Molecular Genetics  2014;23(25):6944-6960.
White blood cell (WBC) count is a common clinical measure used as a predictor of certain aspects of human health, including immunity and infection status. WBC count is also a complex trait that varies among individuals and ancestry groups. Differences in linkage disequilibrium structure and heterogeneity in allelic effects are expected to play a role in the associations observed between populations. Prior genome-wide association study (GWAS) meta-analyses have identified genomic loci associated with WBC and its subtypes, but much of the heritability of these phenotypes remains unexplained. Using GWAS summary statistics for over 50 000 individuals from three diverse populations (Japanese, African-American and European ancestry), a Bayesian model methodology was employed to account for heterogeneity between ancestry groups. This approach was used to perform a trans-ethnic meta-analysis of total WBC, neutrophil and monocyte counts. Ten previously known associations were replicated and six new loci were identified, including several regions harboring genes related to inflammation and immune cell function. Ninety-five percent credible interval regions were calculated to narrow the association signals and fine-map the putatively causal variants within loci. Finally, a conditional analysis was performed on the most significant SNPs identified by the trans-ethnic meta-analysis (MA), and nine secondary signals within loci previously associated with WBC or its subtypes were identified. This work illustrates the potential of trans-ethnic analysis and ascribes a critical role to multi-ethnic cohorts and consortia in exploring complex phenotypes with respect to variants that lie outside the European-biased GWAS pool.
doi:10.1093/hmg/ddu401
PMCID: PMC4245044  PMID: 25096241

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