@article {690, title = {No association of plasma prothrombin concentration or the G20210A mutation with incident cardiovascular disease: results from the Cardiovascular Health Study.}, journal = {Thromb Haemost}, volume = {87}, year = {2002}, month = {2002 Apr}, pages = {614-21}, abstract = {

Prothrombin is a key factor in blood clotting, a process intimately involved in thrombotic disease. We assessed prothrombin levels and G20210A genotype in a case-control study within the Cardiovascular Health Study. Cases included angina, myocardial infarction, stroke, and the presence of MRI-detectable infarcts (n approximately 250 each). Population-based controls free of clinical cardiovascular disease (CVD) (n approximately 500) and a subset free of clinical and subclinical CVD (n approximately 250) were used for comparison. The 20210 A allele, frequency 2.9\%, was associated with higher mean prothrombin levels: 166.3 vs. 139.5 microg/ml (P <0.001). Significant correlates of prothrombin included gender, plasma lipids, other vitamin K-dependent proteins, and inflammatory markers, but not race, smoking, hypertension, diabetes, measures of subclinical CVD, or markers of procoagulant activity. Compared to controls, neither genotype nor prothrombin level was associated with any CVD case group. We conclude that, in the elderly, neither prothrombin level nor 20210 genotype were associated with either CVD risk factors or events. This is consistent with the lack of association of prothrombin levels with measures of underlying CVD or procoagulant markers.

}, keywords = {3{\textquoteright} Untranslated Regions, Aged, Aged, 80 and over, Alleles, Angina Pectoris, Blood Proteins, Cardiovascular Diseases, Case-Control Studies, Comorbidity, Diabetes Mellitus, Female, Genetic Predisposition to Disease, Humans, Hyperlipidemias, Hypertension, Male, Mutation, Myocardial Infarction, Obesity, Promoter Regions, Genetic, Prothrombin, Risk Factors, Smoking, Stroke, Vermont}, issn = {0340-6245}, author = {Smiles, Adam M and Jenny, Nancy S and Tang, Zhonghua and Arnold, Alice and Cushman, Mary and Tracy, Russell P} } @article {772, title = {Traditional and novel risk factors in older adults: cardiovascular risk assessment late in life.}, journal = {Am J Geriatr Cardiol}, volume = {13}, year = {2004}, month = {2004 Mar-Apr}, pages = {69-80}, abstract = {

As a population-based, longitudinal study of nearly 6000 older American adults, the Cardiovascular Health Study provides an excellent opportunity to assess the roles of traditional and novel cardiovascular risk factors in the development of coronary heart disease. Cardiovascular Health Study investigators have analyzed both traditional risk factors, such as diabetes, hypertension, and smoking, and new risk factors, such as hemostatic factors, inflammatory markers, exposure to infectious agents, and genetic determinants. These analyses have led to several important conclusions. First, older adults without previous cardiovascular events have a tremendous burden of subclinical vascular disease, which may change how physicians view risk factor modification in this age group. Second, some traditional cardiovascular risk factors lose importance as predictors of cardiovascular disease among older adults. Third, even modest elevations in fasting blood glucose or systolic blood pressure-below the levels used to define diabetes or hypertension-may have prognostic implications. Fourth, novel cardiovascular risk factors may add further information about cardiovascular disease risk in older adults. Promising potential candidates identified in the Cardiovascular Health Study include markers of hemostatic activation, fibrinogen, factor VIII coagulant activity, C-reactive protein, and exposure to herpes simplex virus-1 and possibly chlamydia. Future Cardiovascular Health Study investigations will help to clarify which combination of traditional and newer risk factors provides the best estimate of cardiovascular risk for older adults.

}, keywords = {Aged, Blood Coagulation Factors, Cardiovascular Diseases, Cohort Studies, Diabetes Complications, Female, Genetic Predisposition to Disease, Humans, Hypertension, Infections, Inflammation, Lipids, Longitudinal Studies, Male, Obesity, Predictive Value of Tests, Risk Factors, Smoking, United States}, issn = {1076-7460}, doi = {10.1111/j.1076-7460.2004.02123.x}, author = {Mukamal, Kenneth J and Kronmal, Richard A and Tracy, Russell P and Cushman, Mary and Siscovick, David S} } @article {850, title = {Alcohol use and risk of ischemic stroke among older adults: the cardiovascular health study.}, journal = {Stroke}, volume = {36}, year = {2005}, month = {2005 Sep}, pages = {1830-4}, abstract = {

BACKGROUND AND PURPOSE: The association of light to moderate alcohol consumption with risk of ischemic stroke remains uncertain, as are the roles of potentially mediating factors and modification by apolipoprotein E (apoE) genotype.

METHODS: We studied the prospective association of alcohol consumption and risk of ischemic stroke among 4410 participants free of cardiovascular disease at baseline in the Cardiovascular Health Study, a population-based cohort study of older adults from 4 US communities. Participants reported their consumption of alcoholic beverages yearly.

RESULTS: During an average follow-up period of 9.2 years, 434 cases of incident ischemic stroke occurred. Compared with long-term abstainers, the multivariate relative risks of ischemic stroke were 0.85 (95\% CI, 0.63 to 1.13), 0.75 (95\% CI, 0.53 to 1.06), 0.82 (95\% CI, 0.51 to 1.30), and 1.03 (95\% CI, 0.68 to 1.57) among consumers of <1, 1 to 6, 7 to 13, and > or =14 drinks per week (P quadratic trend 0.06). ApoE genotype appeared to modify the alcohol-ischemic stroke relationship (P interaction 0.08), with generally lower risks among drinkers than abstainers in apoE4-negative participants but higher risks among drinkers than abstainers among apoE4-positive participants. We could not identify candidate mediators among lipid, inflammatory, and prothrombotic factors.

CONCLUSIONS: In this study of older adults, the association of alcohol use and risk of ischemic stroke was U-shaped, with modestly lower risk among consumers of 1 to 6 drinks per week. However, apoE genotype may modify this association, and even moderate alcohol intake may be associated with an increased risk of ischemic stroke among apoE4-positive older adults.

}, keywords = {Aged, Alcohol Drinking, Apolipoproteins E, Brain Infarction, Brain Ischemia, Cohort Studies, Female, Follow-Up Studies, Genetic Predisposition to Disease, Genotype, Humans, Hypertension, Inflammation, Ischemia, Lipids, Male, Middle Aged, Multivariate Analysis, Myocardial Infarction, Prospective Studies, Risk, Risk Factors, Stroke, Substance-Related Disorders, Thrombosis, Time Factors, Vascular Diseases}, issn = {1524-4628}, doi = {10.1161/01.STR.0000177587.76846.89}, author = {Mukamal, Kenneth J and Chung, Hyoju and Jenny, Nancy S and Kuller, Lewis H and Longstreth, W T and Mittleman, Murray A and Burke, Gregory L and Cushman, Mary and Beauchamp, Norman J and Siscovick, David S} } @article {982, title = {IL-6 gene variation is associated with IL-6 and C-reactive protein levels but not cardiovascular outcomes in the Cardiovascular Health Study.}, journal = {Hum Genet}, volume = {122}, year = {2007}, month = {2007 Dec}, pages = {485-94}, abstract = {

Interleukin-6 (IL-6) and C-reactive protein (CRP) levels increase with age and likely play a role in adverse health outcomes in older adults. The relationship between IL-6 gene tag single nucleotide polymorphisms (SNPs) and circulating IL-6 and CRP levels, cardiovascular disease (CVD) outcomes, and mortality in Caucasian (CA) and African American (AA) participants of the Cardiovascular Health Study (CHS) was evaluated using ANCOVA and Cox proportional hazards models. The minor allele of the promoter SNP 1510 and intronic SNP 3572 associates with significantly higher serum IL-6 and CRP levels in CA but not AA. The CRP association persisted after CA and AA populations were combined and after accounting for multiple comparisons. These associations did not carry through to cardiovascular disease outcomes. Decreased risk of stroke was identified in CA, with the minor allele of SNP 1111 (HRR 0.71, 95\% CI 0.52, 0.95), P = 0.02, and increased risk of CVD and all-cause mortality (HRR 1.31, 95\% CI 1.05-1.64) in AAs heterozygote for SNP 2989. While genetic variation in the IL-6 gene was associated with circulating IL-6 and especially with CRP concentrations in this study, there is little evidence for association between common IL-6 gene variation and adverse health outcomes in this population of older adults.

}, keywords = {African Americans, Aged, Alleles, C-Reactive Protein, Cardiovascular Diseases, Cohort Studies, European Continental Ancestry Group, Female, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Humans, Interleukin-6, Introns, Longitudinal Studies, Male, Polymorphism, Single Nucleotide, Promoter Regions, Genetic}, issn = {1432-1203}, doi = {10.1007/s00439-007-0428-x}, author = {Walston, Jeremy D and Fallin, M Daniele and Cushman, Mary and Lange, Leslie and Psaty, Bruce and Jenny, Nancy and Browner, Warren and Tracy, Russell and Durda, Peter and Reiner, Alex} } @article {1019, title = {Associations between common fibrinogen gene polymorphisms and cardiovascular disease in older adults. The Cardiovascular Health Study.}, journal = {Thromb Haemost}, volume = {99}, year = {2008}, month = {2008 Feb}, pages = {388-95}, abstract = {

Elevated plasma fibrinogen is a risk factor for cardiovascular disease (CVD), but associations between fibrinogen single nucleotide polymorphisms (SNPs) and disease risk are inconsistent. We investigated whether common (> or = 5\% minor allele frequency) variation in the fibrinogen genes (FGA, FGB, FGG) is associated with fibrinogen concentration, carotid artery intima-medial thickness (IMT) and risk of incident myocardial infarction (MI), ischemic stroke and CVD mortality in European- (EA) and African-descent (AA) adults (> or = 65 years) from the Cardiovascular Health Study. TagSNPs were genotyped in 3,969 EA and 719 AA free of MI or stroke at baseline. Race-specific models included multiple testing correction and adjustment for sex, age and site. Among EA, minor alleles of FGA3807, FGB1437 and FGG902 were associated with higher fibrinogen levels; whereas FGA251, FGA2224, FGA6534 and FGG10034 were associated with lower levels, p<0.004 for each. Strongest associations were seen for FGB1437; each additional copy of the minor allele was associated with 13 mg/dl (95\%CI: 9-16) higher fibrinogen level. Similar trends in AA were not significant. Fibrinogen haplotypes were not significantly associated with internal or common carotid IMT. No associations with MI or CVD mortality were seen in EA, though FGB1038 and FGG902 were significantly associated with increased and decreased risk of stroke in men, respectively, as were related haplotypes. FGB1038 was also associated with CVD mortality in AA, HR = 1.9 (95\%CI: 1.3-2.7). In conclusion, while fibrinogen genetic variation was strongly associated with fibrinogen levels, there was less evidence of association with the more complex outcomes of IMT and CVD events.

}, keywords = {African Americans, Age Factors, Aged, Brain Ischemia, Cardiovascular Diseases, Carotid Artery Diseases, European Continental Ancestry Group, Female, Fibrinogen, Gene Frequency, Genetic Predisposition to Disease, Haplotypes, Humans, Male, Myocardial Infarction, Polymorphism, Single Nucleotide, Population Surveillance, Proportional Hazards Models, Prospective Studies, Reproducibility of Results, Risk Assessment, Risk Factors, Sex Factors, Stroke, United States}, issn = {0340-6245}, doi = {10.1160/TH07-08-0523}, author = {Carty, Cara L and Cushman, Mary and Jones, Daniel and Lange, Leslie A and Hindorff, Lucia A and Rice, Kenneth and Jenny, Nancy S and Durda, J Peter and Walston, Jeremy and Carlson, Christopher S and Nickerson, Debbie and Tracy, Russell P and Reiner, Alex P} } @article {1092, title = {Genomewide association studies of stroke.}, journal = {N Engl J Med}, volume = {360}, year = {2009}, month = {2009 Apr 23}, pages = {1718-28}, abstract = {

BACKGROUND: The genes underlying the risk of stroke in the general population remain undetermined.

METHODS: We carried out an analysis of genomewide association data generated from four large cohorts composing the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 white persons (mean [+/-SD] age, 63+/-8 years) in whom 1544 incident strokes (1164 ischemic strokes) developed over an average follow-up of 11 years. We tested the markers most strongly associated with stroke in a replication cohort of 2430 black persons with 215 incident strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke and 3613 unaffected persons.

RESULTS: Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P<5x10(-8)). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95\% confidence interval [CI], 1.19 to 1.42) and 1.33 (95\% CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11\% and 12\% in the discovery cohorts. Corresponding hazard ratios were 1.35 (95\% CI, 1.01 to 1.79; P=0.04) and 1.42 (95\% CI, 1.06 to 1.91; P=0.02) in the large cohort of black persons and 1.17 (95\% CI, 1.01 to 1.37; P=0.03) and 1.19 (95\% CI, 1.01 to 1.41; P=0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant.

CONCLUSIONS: A genetic locus on chromosome 12p13 is associated with an increased risk of stroke.

}, keywords = {African Continental Ancestry Group, Aged, Chromosomes, Human, Pair 12, Cohort Studies, European Continental Ancestry Group, Female, Genetic Markers, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Proportional Hazards Models, Risk Factors, Stroke}, issn = {1533-4406}, doi = {10.1056/NEJMoa0900094}, author = {Ikram, M Arfan and Seshadri, Sudha and Bis, Joshua C and Fornage, Myriam and DeStefano, Anita L and Aulchenko, Yurii S and Debette, Stephanie and Lumley, Thomas and Folsom, Aaron R and van den Herik, Evita G and Bos, Michiel J and Beiser, Alexa and Cushman, Mary and Launer, Lenore J and Shahar, Eyal and Struchalin, Maksim and Du, Yangchun and Glazer, Nicole L and Rosamond, Wayne D and Rivadeneira, Fernando and Kelly-Hayes, Margaret and Lopez, Oscar L and Coresh, Josef and Hofman, Albert and DeCarli, Charles and Heckbert, Susan R and Koudstaal, Peter J and Yang, Qiong and Smith, Nicholas L and Kase, Carlos S and Rice, Kenneth and Haritunians, Talin and Roks, Gerwin and de Kort, Paul L M and Taylor, Kent D and de Lau, Lonneke M and Oostra, Ben A and Uitterlinden, Andr{\'e} G and Rotter, Jerome I and Boerwinkle, Eric and Psaty, Bruce M and Mosley, Thomas H and van Duijn, Cornelia M and Breteler, Monique M B and Longstreth, W T and Wolf, Philip A} } @article {1156, title = {Genome-wide association studies of MRI-defined brain infarcts: meta-analysis from the CHARGE Consortium.}, journal = {Stroke}, volume = {41}, year = {2010}, month = {2010 Feb}, pages = {210-7}, abstract = {

BACKGROUND AND PURPOSE: Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI infarct in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.

METHODS: Using 2.2 million genotyped and imputed single nucleotide polymorphisms, each study performed cross-sectional genome-wide association analysis of MRI infarct using age- and sex-adjusted logistic regression models. Study-specific findings were combined in an inverse-variance-weighted meta-analysis, including 9401 participants with mean age 69.7 (19.4\% of whom had >or=1 MRI infarct).

RESULTS: The most significant association was found with rs2208454 (minor allele frequency, 20\%), located in intron 3 of MACRO domain containing 2 gene and in the downstream region of fibronectin leucine-rich transmembrane protein 3 gene. Each copy of the minor allele was associated with lower risk of MRI infarcts (odds ratio, 0.76; 95\% confidence interval, 0.68-0.84; P=4.64x10(-7)). Highly suggestive associations (P<1.0x10(-5)) were also found for 22 other single nucleotide polymorphisms in linkage disequilibrium (r(2)>0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 black participants, although 4 single nucleotide polymorphisms within 200 kb from rs2208454 were associated with MRI infarcts in the black population sample.

CONCLUSIONS: This first community-based, genome-wide association study on covert MRI infarcts uncovered novel associations. Although replication of the association with top single nucleotide polymorphisms failed, possibly because of insufficient power, results in the black population sample are encouraging, and further efforts at replication are needed.

}, keywords = {African Americans, Aged, Brain, Brain Infarction, Cohort Studies, DNA Mutational Analysis, Female, Gene Frequency, Genetic Markers, Genetic Predisposition to Disease, Genetic Testing, Genetic Variation, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Magnetic Resonance Imaging, Male, Middle Aged, Polymorphism, Single Nucleotide, Prospective Studies}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.109.569194}, author = {Debette, Stephanie and Bis, Joshua C and Fornage, Myriam and Schmidt, Helena and Ikram, M Arfan and Sigurdsson, Sigurdur and Heiss, Gerardo and Struchalin, Maksim and Smith, Albert V and van der Lugt, Aad and DeCarli, Charles and Lumley, Thomas and Knopman, David S and Enzinger, Christian and Eiriksdottir, Gudny and Koudstaal, Peter J and DeStefano, Anita L and Psaty, Bruce M and Dufouil, Carole and Catellier, Diane J and Fazekas, Franz and Aspelund, Thor and Aulchenko, Yurii S and Beiser, Alexa and Rotter, Jerome I and Tzourio, Christophe and Shibata, Dean K and Tscherner, Maria and Harris, Tamara B and Rivadeneira, Fernando and Atwood, Larry D and Rice, Kenneth and Gottesman, Rebecca F and van Buchem, Mark A and Uitterlinden, Andr{\'e} G and Kelly-Hayes, Margaret and Cushman, Mary and Zhu, Yicheng and Boerwinkle, Eric and Gudnason, Vilmundur and Hofman, Albert and Romero, Jose R and Lopez, Oscar and van Duijn, Cornelia M and Au, Rhoda and Heckbert, Susan R and Wolf, Philip A and Mosley, Thomas H and Seshadri, Sudha and Breteler, Monique M B and Schmidt, Reinhold and Launer, Lenore J and Longstreth, W T} } @article {1158, title = {Interaction between fibrinogen and IL-6 genetic variants and associations with cardiovascular disease risk in the Cardiovascular Health Study.}, journal = {Ann Hum Genet}, volume = {74}, year = {2010}, month = {2010 Jan}, pages = {1-10}, abstract = {

The inflammatory cytokine interleukin-6 (IL-6) is a main regulator of fibrinogen synthesis, though its interaction with fibrinogen genes (FGA, FGB, FGG) and subsequent impact on cardiovascular disease (CVD) risk is not well-studied. We investigated joint associations of fibrinogen and IL6 tagSNPs with fibrinogen concentrations, carotid intima-media thickness, and myocardial infarction or ischemic stroke in 3900 European-American Cardiovascular Health Study participants. To identify combinations of genetic main effects and interactions associated with outcomes, we used logic regression. We also evaluated whether the relationship between fibrinogen SNPs and fibrinogen level varied by IL-6 level using linear regression models with multiplicative interaction terms. Combinations of fibrinogen and IL6 SNPs were significantly associated with fibrinogen level (p < 0.005), but not with other outcomes. Fibrinogen levels were higher in individuals having FGB1437 (rs1800790) and lacking FGA6534 (rs6050) minor alleles; these SNPs interacted with IL6 rs1800796 to influence fibrinogen level. Marginally significant (p= 0.03) interactions between IL-6 level and FGA and FGG promoter SNPs associated with fibrinogen levels were detected. We identified potential gene-gene interactions influencing fibrinogen levels. Although IL-6 responsive binding sites are present in fibrinogen gene promoter regions, we did not find strong evidence of interaction between fibrinogen SNPs and IL6 SNPs or levels influencing CVD.

}, keywords = {Aged, Cardiovascular Diseases, Carotid Arteries, Female, Fibrinogen, Genetic Predisposition to Disease, Genetic Variation, Humans, Interleukin-6, Male, Models, Biological, Myocardial Infarction, Polymorphism, Single Nucleotide, Risk, Stroke}, issn = {1469-1809}, doi = {10.1111/j.1469-1809.2009.00551.x}, author = {Carty, Cara L and Heagerty, Patrick and Heckbert, Susan R and Jarvik, Gail P and Lange, Leslie A and Cushman, Mary and Tracy, Russell P and Reiner, Alexander P} } @article {1298, title = {Genome-wide association studies of cerebral white matter lesion burden: the CHARGE consortium.}, journal = {Ann Neurol}, volume = {69}, year = {2011}, month = {2011 Jun}, pages = {928-39}, abstract = {

OBJECTIVE: White matter hyperintensities (WMHs) detectable by magnetic resonance imaging are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMHs are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified.

METHODS: We performed a meta-analysis of genome-wide association studies (GWASs) for WMH burden in 9,361 stroke-free individuals of European descent from 7 community-based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts.

RESULTS: We identified 6 novel risk-associated single nucleotide polymorphisms (SNPs) in 1 locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (p(discovery) = 4.0 {\texttimes} 10(-9) ; p(replication) = 1.3 {\texttimes} 10(-7) ; p(combined) = 4.0 {\texttimes} 10(-15) ). Other SNPs in this region also reaching genome-wide significance were rs9894383 (p = 5.3 {\texttimes} 10(-9) ), rs11869977 (p = 5.7 {\texttimes} 10(-9) ), rs936393 (p = 6.8 {\texttimes} 10(-9) ), rs3744017 (p = 7.3 {\texttimes} 10(-9) ), and rs1055129 (p = 4.1 {\texttimes} 10(-8) ). Variant alleles at these loci conferred a small increase in WMH burden (4-8\% of the overall mean WMH burden in the sample).

INTERPRETATION: This large GWAS of WMH burden in community-based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH.

}, keywords = {Aged, Aged, 80 and over, Cerebral Cortex, Chromosomes, Human, Pair 17, Cognition Disorders, Cohort Studies, European Continental Ancestry Group, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Leukoencephalopathies, Magnetic Resonance Imaging, Male, Middle Aged, Movement Disorders, Nerve Fibers, Myelinated, Polymorphism, Single Nucleotide, Residence Characteristics, RNA, Messenger}, issn = {1531-8249}, doi = {10.1002/ana.22403}, author = {Fornage, Myriam and Debette, Stephanie and Bis, Joshua C and Schmidt, Helena and Ikram, M Arfan and Dufouil, Carole and Sigurdsson, Sigurdur and Lumley, Thomas and DeStefano, Anita L and Fazekas, Franz and Vrooman, Henri A and Shibata, Dean K and Maillard, Pauline and Zijdenbos, Alex and Smith, Albert V and Gudnason, Haukur and de Boer, Renske and Cushman, Mary and Mazoyer, Bernard and Heiss, Gerardo and Vernooij, Meike W and Enzinger, Christian and Glazer, Nicole L and Beiser, Alexa and Knopman, David S and Cavalieri, Margherita and Niessen, Wiro J and Harris, Tamara B and Petrovic, Katja and Lopez, Oscar L and Au, Rhoda and Lambert, Jean-Charles and Hofman, Albert and Gottesman, Rebecca F and Garcia, Melissa and Heckbert, Susan R and Atwood, Larry D and Catellier, Diane J and Uitterlinden, Andr{\'e} G and Yang, Qiong and Smith, Nicholas L and Aspelund, Thor and Romero, Jose R and Rice, Kenneth and Taylor, Kent D and Nalls, Michael A and Rotter, Jerome I and Sharrett, Richey and van Duijn, Cornelia M and Amouyel, Philippe and Wolf, Philip A and Gudnason, Vilmundur and van der Lugt, Aad and Boerwinkle, Eric and Psaty, Bruce M and Seshadri, Sudha and Tzourio, Christophe and Breteler, Monique M B and Mosley, Thomas H and Schmidt, Reinhold and Longstreth, W T and DeCarli, Charles and Launer, Lenore J} } @article {6078, title = {A meta-analysis identifies new loci associated with body mass index in individuals of African ancestry.}, journal = {Nat Genet}, volume = {45}, year = {2013}, month = {2013 Jun}, pages = {690-6}, abstract = {

Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one new locus at 5q33 (GALNT10, rs7708584, P = 3.4 {\texttimes} 10(-11)) and another at 7p15 when we included data from the GIANT consortium (MIR148A-NFE2L3, rs10261878, P = 1.2 {\texttimes} 10(-10)). We also found suggestive evidence of an association at a third locus at 6q16 in the African-ancestry sample (KLHL32, rs974417, P = 6.9 {\texttimes} 10(-8)). Thirty-two of the 36 previously established BMI variants showed directionally consistent effect estimates in our GWAS (binomial P = 9.7 {\texttimes} 10(-7)), five of which reached genome-wide significance. These findings provide strong support for shared BMI loci across populations, as well as for the utility of studying ancestrally diverse populations.

}, keywords = {African Americans, Body Mass Index, Case-Control Studies, Gene Frequency, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Obesity, Polymorphism, Single Nucleotide}, issn = {1546-1718}, doi = {10.1038/ng.2608}, author = {Monda, Keri L and Chen, Gary K and Taylor, Kira C and Palmer, Cameron and Edwards, Todd L and Lange, Leslie A and Ng, Maggie C Y and Adeyemo, Adebowale A and Allison, Matthew A and Bielak, Lawrence F and Chen, Guanjie and Graff, Mariaelisa and Irvin, Marguerite R and Rhie, Suhn K and Li, Guo and Liu, Yongmei and Liu, Youfang and Lu, Yingchang and Nalls, Michael A and Sun, Yan V and Wojczynski, Mary K and Yanek, Lisa R and Aldrich, Melinda C and Ademola, Adeyinka and Amos, Christopher I and Bandera, Elisa V and Bock, Cathryn H and Britton, Angela and Broeckel, Ulrich and Cai, Quiyin and Caporaso, Neil E and Carlson, Chris S and Carpten, John and Casey, Graham and Chen, Wei-Min and Chen, Fang and Chen, Yii-der I and Chiang, Charleston W K and Coetzee, Gerhard A and Demerath, Ellen and Deming-Halverson, Sandra L and Driver, Ryan W and Dubbert, Patricia and Feitosa, Mary F and Feng, Ye and Freedman, Barry I and Gillanders, Elizabeth M and Gottesman, Omri and Guo, Xiuqing and Haritunians, Talin and Harris, Tamara and Harris, Curtis C and Hennis, Anselm J M and Hernandez, Dena G and McNeill, Lorna H and Howard, Timothy D and Howard, Barbara V and Howard, Virginia J and Johnson, Karen C and Kang, Sun J and Keating, Brendan J and Kolb, Suzanne and Kuller, Lewis H and Kutlar, Abdullah and Langefeld, Carl D and Lettre, Guillaume and Lohman, Kurt and Lotay, Vaneet and Lyon, Helen and Manson, JoAnn E and Maixner, William and Meng, Yan A and Monroe, Kristine R and Morhason-Bello, Imran and Murphy, Adam B and Mychaleckyj, Josyf C and Nadukuru, Rajiv and Nathanson, Katherine L and Nayak, Uma and N{\textquoteright}diaye, Amidou and Nemesure, Barbara and Wu, Suh-Yuh and Leske, M Cristina and Neslund-Dudas, Christine and Neuhouser, Marian and Nyante, Sarah and Ochs-Balcom, Heather and Ogunniyi, Adesola and Ogundiran, Temidayo O and Ojengbede, Oladosu and Olopade, Olufunmilayo I and Palmer, Julie R and Ruiz-Narvaez, Edward A and Palmer, Nicholette D and Press, Michael F and Rampersaud, Evandine and Rasmussen-Torvik, Laura J and Rodriguez-Gil, Jorge L and Salako, Babatunde and Schadt, Eric E and Schwartz, Ann G and Shriner, Daniel A and Siscovick, David and Smith, Shad B and Wassertheil-Smoller, Sylvia and Speliotes, Elizabeth K and Spitz, Margaret R and Sucheston, Lara and Taylor, Herman and Tayo, Bamidele O and Tucker, Margaret A and Van Den Berg, David J and Edwards, Digna R Velez and Wang, Zhaoming and Wiencke, John K and Winkler, Thomas W and Witte, John S and Wrensch, Margaret and Wu, Xifeng and Yang, James J and Levin, Albert M and Young, Taylor R and Zakai, Neil A and Cushman, Mary and Zanetti, Krista A and Zhao, Jing Hua and Zhao, Wei and Zheng, Yonglan and Zhou, Jie and Ziegler, Regina G and Zmuda, Joseph M and Fernandes, Jyotika K and Gilkeson, Gary S and Kamen, Diane L and Hunt, Kelly J and Spruill, Ida J and Ambrosone, Christine B and Ambs, Stefan and Arnett, Donna K and Atwood, Larry and Becker, Diane M and Berndt, Sonja I and Bernstein, Leslie and Blot, William J and Borecki, Ingrid B and Bottinger, Erwin P and Bowden, Donald W and Burke, Gregory and Chanock, Stephen J and Cooper, Richard S and Ding, Jingzhong and Duggan, David and Evans, Michele K and Fox, Caroline and Garvey, W Timothy and Bradfield, Jonathan P and Hakonarson, Hakon and Grant, Struan F A and Hsing, Ann and Chu, Lisa and Hu, Jennifer J and Huo, Dezheng and Ingles, Sue A and John, Esther M and Jordan, Joanne M and Kabagambe, Edmond K and Kardia, Sharon L R and Kittles, Rick A and Goodman, Phyllis J and Klein, Eric A and Kolonel, Laurence N and Le Marchand, Lo{\"\i}c and Liu, Simin and McKnight, Barbara and Millikan, Robert C and Mosley, Thomas H and Padhukasahasram, Badri and Williams, L Keoki and Patel, Sanjay R and Peters, Ulrike and Pettaway, Curtis A and Peyser, Patricia A and Psaty, Bruce M and Redline, Susan and Rotimi, Charles N and Rybicki, Benjamin A and Sale, Mich{\`e}le M and Schreiner, Pamela J and Signorello, Lisa B and Singleton, Andrew B and Stanford, Janet L and Strom, Sara S and Thun, Michael J and Vitolins, Mara and Zheng, Wei and Moore, Jason H and Williams, Scott M and Ketkar, Shamika and Zhu, Xiaofeng and Zonderman, Alan B and Kooperberg, Charles and Papanicolaou, George J and Henderson, Brian E and Reiner, Alex P and Hirschhorn, Joel N and Loos, Ruth J F and North, Kari E and Haiman, Christopher A} } @article {6007, title = {Risk of venous thromboembolism associated with single and combined effects of Factor V Leiden, Prothrombin 20210A and Methylenetethraydrofolate reductase C677T: a meta-analysis involving over 11,000 cases and 21,000 controls.}, journal = {Eur J Epidemiol}, volume = {28}, year = {2013}, month = {2013 Aug}, pages = {621-47}, abstract = {

Genetic and environmental factors interact in determining the risk of venous thromboembolism (VTE). The risk associated with the polymorphic variants G1691A of factor V (Factor V Leiden, FVL), G20210A of prothrombin (PT20210A) and C677T of methylentetrahydrofolate reductase (C677T MTHFR) genes has been investigated in many studies. We performed a pooled analysis of case-control and cohort studies investigating in adults the association between each variant and VTE, published on Pubmed, Embase or Google through January 2010. Authors of eligible papers, were invited to provide all available individual data for the pooling. The Odds Ratio (OR) for first VTE associated with each variant, individually and combined with the others, were calculated with a random effect model, in heterozygotes and homozygotes (dominant model for FVL and PT20210A; recessive for C677T MTHFR). We analysed 31 databases, including 11,239 cases and 21,521 controls. No significant association with VTE was found for homozygous C677T MTHFR (OR: 1.38; 95~\% confidence intervals [CI]: 0.98-1.93), whereas the risk was increased in carriers of either heterozygous FVL or PT20210 (OR~=~4.22; 95~\% CI: 3.35-5.32; and OR~=~2.79;95~\% CI: 2.25-3.46, respectively), in double heterozygotes (OR~=~3.42; 95~\%CI 1.64-7.13), and in homozygous FVL or PT20210A (OR~=~11.45; 95~\%CI: 6.79-19.29; and OR: 6.74 (CI 95~\% 2.19-20.72), respectively). The stratified analyses showed a stronger effect of FVL on individuals~<=~45~years (p value for interaction~=~0.036) and of PT20210A in women using oral contraceptives (p-value for interaction~=~0.045). In this large pooled analysis, inclusive of large studies like MEGA, no effect was found for C677T MTHFR on VTE; FVL and PT20210A were confirmed to be moderate risk factors. Notably, double carriers of the two genetic variants produced an impact on VTE risk significantly increased but weaker than previously thought.

}, keywords = {Case-Control Studies, Factor V, Genetic Predisposition to Disease, Humans, Methylenetetrahydrofolate Reductase (NADPH2), Prothrombin, Risk Factors, Venous Thromboembolism}, issn = {1573-7284}, doi = {10.1007/s10654-013-9825-8}, author = {Simone, Benedetto and De Stefano, Valerio and Leoncini, Emanuele and Zacho, Jeppe and Martinelli, Ida and Emmerich, Joseph and Rossi, Elena and Folsom, Aaron R and Almawi, Wassim Y and Scarabin, Pierre Y and den Heijer, Martin and Cushman, Mary and Penco, Silvana and Vaya, Amparo and Angchaisuksiri, Pantep and Okumus, Gulfer and Gemmati, Donato and Cima, Simona and Akar, Nejat and Oguzulgen, Kivilcim I and Ducros, V{\'e}ronique and Lichy, Christoph and Fernandez-Miranda, Consuelo and Szczeklik, Andrzej and Nieto, Jos{\'e} A and Torres, Jose Domingo and Le Cam-Duchez, V{\'e}ronique and Ivanov, Petar and Cantu-Brito, Carlos and Shmeleva, Veronika M and Stegnar, Mojka and Ogunyemi, Dotun and Eid, Suhair S and Nicolotti, Nicola and De Feo, Emma and Ricciardi, Walter and Boccia, Stefania} } @article {1564, title = {Soluble CD14: genomewide association analysis and relationship to cardiovascular risk and mortality in older adults.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {33}, year = {2013}, month = {2013 Jan}, pages = {158-64}, abstract = {

OBJECTIVE: CD14 is a glycosylphosphotidylinositol-anchored membrane glycoprotein expressed on neutrophils and monocytes/macrophages that also circulates as a soluble form (sCD14). Despite the well-recognized role of CD14 in inflammation, relatively little is known about the genetic determinants of sCD14 or the relationship of sCD14 to vascular- and aging-related phenotypes.

METHODS AND RESULTS: We measured baseline levels of sCD14 in >5000 European-American and black adults aged 65 years and older from the Cardiovascular Health Study, who were well characterized at baseline for atherosclerotic risk factors and subclinical cardiovascular disease, and who have been followed for clinical cardiovascular disease and mortality outcomes up to 20 years. At baseline, sCD14 generally showed strong positive correlations with traditional cardio-metabolic risk factors and with subclinical measures of vascular disease such as carotid wall thickness and ankle-brachial index (independently of traditional cardiovascular disease risk factors), and was also inversely correlated with body mass index. In genomewide association analyses of sCD14, we (1) confirmed the importance of the CD14 locus on chromosome 5q21 in European-American; (2) identified a novel African ancestry-specific allele of CD14 associated with lower sCD14 in blacks; and (3) identified a putative novel association in European-American of a nonsynonymous variant of PIGC, which encodes an enzyme required for the first step in glycosylphosphotidylinositol anchor biosynthesis. Finally, we show that, like other acute phase inflammatory biomarkers, sCD14 predicts incident cardiovascular disease, and strongly and independently predicts all-cause mortality in older adults.

CONCLUSIONS: CD14 independently predicts risk mortality in older adults.

}, keywords = {African Americans, Age Factors, Aged, Biomarkers, Cardiovascular Diseases, Chromosomes, Human, Pair 5, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Haplotypes, Hexosyltransferases, Humans, Incidence, Inflammation Mediators, Linear Models, Lipopolysaccharide Receptors, Logistic Models, Male, Membrane Proteins, Multivariate Analysis, Phenotype, Polymorphism, Single Nucleotide, Principal Component Analysis, Prognosis, Proportional Hazards Models, Prospective Studies, Risk Assessment, Risk Factors, Time Factors, United States}, issn = {1524-4636}, doi = {10.1161/ATVBAHA.112.300421}, author = {Reiner, Alex P and Lange, Ethan M and Jenny, Nancy S and Chaves, Paulo H M and Ellis, Jaclyn and Li, Jin and Walston, Jeremy and Lange, Leslie A and Cushman, Mary and Tracy, Russell P} } @article {6367, title = {Genome-wide association study for circulating tissue plasminogen activator levels and functional follow-up implicates endothelial STXBP5 and STX2.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {34}, year = {2014}, month = {2014 May}, pages = {1093-101}, abstract = {

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. We conducted a meta-analysis of genome-wide association studies 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{\texttimes}10(-8)). The first locus is on 6q24.3, with the lead single nucleotide polymorphism (SNP; rs9399599; P=2.9{\texttimes}10(-14)) within STXBP5. The second locus is on 8p11.21. The lead SNP (rs3136739; P=1.3{\texttimes}10(-9)) is intronic to POLB and <200 kb away from the tPA encoding the gene PLAT. We identified a nonsynonymous SNP (rs2020921) in modest linkage disequilibrium with rs3136739 (r(2)=0.50) within exon 5 of PLAT (P=2.0{\texttimes}10(-8)). The third locus is on 12q24.33, with the lead SNP (rs7301826; P=1.0{\texttimes}10(-9)) within intron 7 of STX2. We further found evidence for the association of lead SNPs in STXBP5 and STX2 with expression levels of the respective transcripts. In in vitro cell studies, silencing STXBP5 decreased the release of tPA from vascular endothelial cells, whereas silencing STX2 increased the tPA release. Through an in silico lookup, we found no associations of the 3 lead SNPs with coronary artery disease or stroke.

CONCLUSIONS: We identified 3 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.

}, keywords = {Aged, Cells, Cultured, Coronary Artery Disease, Endothelial Cells, Europe, Female, Gene Expression Regulation, Gene Silencing, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Nerve Tissue Proteins, Phenotype, Polymorphism, Single Nucleotide, R-SNARE Proteins, Risk Factors, Stroke, Syntaxin 1, Tissue Plasminogen Activator, Transfection, United States, Up-Regulation}, issn = {1524-4636}, doi = {10.1161/ATVBAHA.113.302088}, author = {Huang, Jie and Huffman, Jennifer E and Yamakuchi, Munekazu and Yamkauchi, Munekazu and Trompet, Stella and Asselbergs, Folkert W and Sabater-Lleal, Maria and Tr{\'e}gou{\"e}t, David-Alexandre and Chen, Wei-Min and Smith, Nicholas L and Kleber, Marcus E and Shin, So-Youn and Becker, Diane M and Tang, Weihong and Dehghan, Abbas and Johnson, Andrew D and Truong, Vinh and Folkersen, Lasse and Yang, Qiong and Oudot-Mellkah, Tiphaine and Buckley, Brendan M and Moore, Jason H and Williams, Frances M K and Campbell, Harry and Silbernagel, G{\"u}nther and Vitart, Veronique and Rudan, Igor and Tofler, Geoffrey H and Navis, Gerjan J and DeStefano, Anita and Wright, Alan F and Chen, Ming-Huei and de Craen, Anton J M and Worrall, Bradford B and Rudnicka, Alicja R and Rumley, Ann and Bookman, Ebony B and Psaty, Bruce M and Chen, Fang and Keene, Keith L and Franco, Oscar H and B{\"o}hm, Bernhard O and Uitterlinden, Andr{\'e} G and Carter, Angela M and Jukema, J Wouter and Sattar, Naveed and Bis, Joshua C and Ikram, Mohammad A and Sale, Mich{\`e}le M and McKnight, Barbara and Fornage, Myriam and Ford, Ian and Taylor, Kent and Slagboom, P Eline and McArdle, Wendy L and Hsu, Fang-Chi and Franco-Cereceda, Anders and Goodall, Alison H and Yanek, Lisa R and Furie, Karen L and Cushman, Mary and Hofman, Albert and Witteman, Jacqueline C M and Folsom, Aaron R and Basu, Saonli and Matijevic, Nena and van Gilst, Wiek H and Wilson, James F and Westendorp, Rudi G J and Kathiresan, Sekar and Reilly, Muredach P and Tracy, Russell P and Polasek, Ozren and Winkelmann, Bernhard R and Grant, Peter J and Hillege, Hans L and Cambien, Francois and Stott, David J and Lowe, Gordon D and Spector, Timothy D and Meigs, James B and M{\"a}rz, Winfried and Eriksson, Per and Becker, Lewis C and Morange, Pierre-Emmanuel and Soranzo, Nicole and Williams, Scott M and Hayward, Caroline and van der Harst, Pim and Hamsten, Anders and Lowenstein, Charles J and Strachan, David P and O{\textquoteright}Donnell, Christopher J} } @article {6809, title = {Plasma Levels of Soluble Interleukin-2 Receptor α: Associations With Clinical Cardiovascular Events and Genome-Wide Association Scan.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {35}, year = {2015}, month = {2015 Oct}, pages = {2246-53}, abstract = {

OBJECTIVE: Interleukin (IL) -2 receptor subunit α regulates lymphocyte activation, which plays an important role in atherosclerosis. Associations between soluble IL-2Rα (sIL-2Rα) and cardiovascular disease (CVD) have not been widely studied and little is known about the genetic determinants of sIL-2Rα levels.

APPROACH AND RESULTS: We measured baseline levels of sIL-2Rα in 4408 European American (EA) and 766 African American (AA) adults from the Cardiovascular Health Study (CHS) and examined associations with baseline CVD risk factors, subclinical CVD, and incident CVD events. We also performed a genome-wide association study for sIL-2Rα in CHS (2964 EAs and 683 AAs) and further combined CHS EA results with those from two other EA cohorts in a meta-analysis (n=4464 EAs). In age, sex- and race- adjusted models, sIL-2Rα was positively associated with current smoking, type 2 diabetes mellitus, hypertension, insulin, waist circumference, C-reactive protein, IL-6, fibrinogen, internal carotid wall thickness, all-cause mortality, CVD mortality, and incident CVD, stroke, and heart failure. When adjusted for baseline CVD risk factors and subclinical CVD, associations with all-cause mortality, CVD mortality, and heart failure remained significant in both EAs and AAs. In the EA genome-wide association study analysis, we observed 52 single-nucleotide polymorphisms in the chromosome 10p15-14 region, which contains IL2RA, IL15RA, and RMB17, that reached genome-wide significance (P<5{\texttimes}10(-8)). The most significant single-nucleotide polymorphism was rs7911500 (P=1.31{\texttimes}10(-75)). The EA meta-analysis results were highly consistent with CHS-only results. No single-nucleotide polymorphisms reached statistical significance in the AAs.

CONCLUSIONS: These results support a role for sIL-2Rα in atherosclerosis and provide evidence for multiple-associated single-nucleotide polymorphisms at chromosome 10p15-14.

}, keywords = {Adult, African Americans, Age Distribution, Aged, Cardiovascular Diseases, Cohort Studies, Coronary Artery Disease, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Incidence, Interleukin-2 Receptor alpha Subunit, Kaplan-Meier Estimate, Male, Middle Aged, Polymorphism, Single Nucleotide, Proportional Hazards Models, Prospective Studies, Risk Assessment, Sex Distribution, Survival Analysis}, issn = {1524-4636}, doi = {10.1161/ATVBAHA.115.305289}, author = {Durda, Peter and Sabourin, Jeremy and Lange, Ethan M and Nalls, Mike A and Mychaleckyj, Josyf C and Jenny, Nancy Swords and Li, Jin and Walston, Jeremy and Harris, Tamara B and Psaty, Bruce M and Valdar, William and Liu, Yongmei and Cushman, Mary and Reiner, Alex P and Tracy, Russell P and Lange, Leslie A} } @article {9104, title = {Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation.}, journal = {Nat Genet}, volume = {54}, year = {2022}, month = {2022 May}, pages = {560-572}, abstract = {

We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9\% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 {\texttimes} 10), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4\% of T2D associations to a single variant with >50\% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background.

}, keywords = {Diabetes Mellitus, Type 2, Ethnicity, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Risk Factors}, issn = {1546-1718}, doi = {10.1038/s41588-022-01058-3}, author = {Mahajan, Anubha and Spracklen, Cassandra N and Zhang, Weihua and Ng, Maggie C Y and Petty, Lauren E and Kitajima, Hidetoshi and Yu, Grace Z and R{\"u}eger, Sina and Speidel, Leo and Kim, Young Jin and Horikoshi, Momoko and Mercader, Josep M and Taliun, Daniel and Moon, Sanghoon and Kwak, Soo-Heon and Robertson, Neil R and Rayner, Nigel W and Loh, Marie and Kim, Bong-Jo and Chiou, Joshua and Miguel-Escalada, Irene and Della Briotta Parolo, Pietro and Lin, Kuang and Bragg, Fiona and Preuss, Michael H and Takeuchi, Fumihiko and Nano, Jana and Guo, Xiuqing and Lamri, Amel and Nakatochi, Masahiro and Scott, Robert A and Lee, Jung-Jin and Huerta-Chagoya, Alicia and Graff, Mariaelisa and Chai, Jin-Fang and Parra, Esteban J and Yao, Jie and Bielak, Lawrence F and Tabara, Yasuharu and Hai, Yang and Steinthorsdottir, Valgerdur and Cook, James P and Kals, Mart and Grarup, Niels and Schmidt, Ellen M and Pan, Ian and Sofer, Tamar and Wuttke, Matthias and Sarnowski, Chloe and Gieger, Christian and Nousome, Darryl and Trompet, Stella and Long, Jirong and Sun, Meng and Tong, Lin and Chen, Wei-Min and Ahmad, Meraj and Noordam, Raymond and Lim, Victor J Y and Tam, Claudia H T and Joo, Yoonjung Yoonie and Chen, Chien-Hsiun and Raffield, Laura M and Lecoeur, C{\'e}cile and Prins, Bram Peter and Nicolas, Aude and Yanek, Lisa R and Chen, Guanjie and Jensen, Richard A and Tajuddin, Salman and Kabagambe, Edmond K and An, Ping and Xiang, Anny H and Choi, Hyeok Sun and Cade, Brian E and Tan, Jingyi and Flanagan, Jack and Abaitua, Fernando and Adair, Linda S and Adeyemo, Adebowale and Aguilar-Salinas, Carlos A and Akiyama, Masato and Anand, Sonia S and Bertoni, Alain and Bian, Zheng and Bork-Jensen, Jette and Brandslund, Ivan and Brody, Jennifer A and Brummett, Chad M and Buchanan, Thomas A and Canouil, Micka{\"e}l and Chan, Juliana C N and Chang, Li-Ching and Chee, Miao-Li and Chen, Ji and Chen, Shyh-Huei and Chen, Yuan-Tsong and Chen, Zhengming and Chuang, Lee-Ming and Cushman, Mary and Das, Swapan K and de Silva, H Janaka and Dedoussis, George and Dimitrov, Latchezar and Doumatey, Ayo P and Du, Shufa and Duan, Qing and Eckardt, Kai-Uwe and Emery, Leslie S and Evans, Daniel S and Evans, Michele K and Fischer, Krista and Floyd, James S and Ford, Ian and Fornage, Myriam and Franco, Oscar H and Frayling, Timothy M and Freedman, Barry I and Fuchsberger, Christian and Genter, Pauline and Gerstein, Hertzel C and Giedraitis, Vilmantas and Gonz{\'a}lez-Villalpando, Clicerio and Gonzalez-Villalpando, Maria Elena and Goodarzi, Mark O and Gordon-Larsen, Penny and Gorkin, David and Gross, Myron and Guo, Yu and Hackinger, Sophie and Han, Sohee and Hattersley, Andrew T and Herder, Christian and Howard, Annie-Green and Hsueh, Willa and Huang, Mengna and Huang, Wei and Hung, Yi-Jen and Hwang, Mi Yeong and Hwu, Chii-Min and Ichihara, Sahoko and Ikram, Mohammad Arfan and Ingelsson, Martin and Islam, Md Tariqul and Isono, Masato and Jang, Hye-Mi and Jasmine, Farzana and Jiang, Guozhi and Jonas, Jost B and J{\o}rgensen, Marit E and J{\o}rgensen, Torben and Kamatani, Yoichiro and Kandeel, Fouad R and Kasturiratne, Anuradhani and Katsuya, Tomohiro and Kaur, Varinderpal and Kawaguchi, Takahisa and Keaton, Jacob M and Kho, Abel N and Khor, Chiea-Chuen and Kibriya, Muhammad G and Kim, Duk-Hwan and Kohara, Katsuhiko and Kriebel, Jennifer and Kronenberg, Florian and Kuusisto, Johanna and L{\"a}ll, Kristi and Lange, Leslie A and Lee, Myung-Shik and Lee, Nanette R and Leong, Aaron and Li, Liming and Li, Yun and Li-Gao, Ruifang and Ligthart, Symen and Lindgren, Cecilia M and Linneberg, Allan and Liu, Ching-Ti and Liu, Jianjun and Locke, Adam E and Louie, Tin and Luan, Jian{\textquoteright}an and Luk, Andrea O and Luo, Xi and Lv, Jun and Lyssenko, Valeriya and Mamakou, Vasiliki and Mani, K Radha and Meitinger, Thomas and Metspalu, Andres and Morris, Andrew D and Nadkarni, Girish N and Nadler, Jerry L and Nalls, Michael A and Nayak, Uma and Nongmaithem, Suraj S and Ntalla, Ioanna and Okada, Yukinori and Orozco, Lorena and Patel, Sanjay R and Pereira, Mark A and Peters, Annette and Pirie, Fraser J and Porneala, Bianca and Prasad, Gauri and Preissl, Sebastian and Rasmussen-Torvik, Laura J and Reiner, Alexander P and Roden, Michael and Rohde, Rebecca and Roll, Kathryn and Sabanayagam, Charumathi and Sander, Maike and Sandow, Kevin and Sattar, Naveed and Sch{\"o}nherr, Sebastian and Schurmann, Claudia and Shahriar, Mohammad and Shi, Jinxiu and Shin, Dong Mun and Shriner, Daniel and Smith, Jennifer A and So, Wing Yee and Stan{\v c}{\'a}kov{\'a}, Alena and Stilp, Adrienne M and Strauch, Konstantin and Suzuki, Ken and Takahashi, Atsushi and Taylor, Kent D and Thorand, Barbara and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Tomlinson, Brian and Torres, Jason M and Tsai, Fuu-Jen and Tuomilehto, Jaakko and Tusi{\'e}-Luna, Teresa and Udler, Miriam S and Valladares-Salgado, Adan and van Dam, Rob M and van Klinken, Jan B and Varma, Rohit and Vujkovic, Marijana and Wacher-Rodarte, Niels and Wheeler, Eleanor and Whitsel, Eric A and Wickremasinghe, Ananda R and van Dijk, Ko Willems and Witte, Daniel R and Yajnik, Chittaranjan S and Yamamoto, Ken and Yamauchi, Toshimasa and Yengo, Loic and Yoon, Kyungheon and Yu, Canqing and Yuan, Jian-Min and Yusuf, Salim and Zhang, Liang and Zheng, Wei and Raffel, Leslie J and Igase, Michiya and Ipp, Eli and Redline, Susan and Cho, Yoon Shin and Lind, Lars and Province, Michael A and Hanis, Craig L and Peyser, Patricia A and Ingelsson, Erik and Zonderman, Alan B and Psaty, Bruce M and Wang, Ya-Xing and Rotimi, Charles N and Becker, Diane M and Matsuda, Fumihiko and Liu, Yongmei and Zeggini, Eleftheria and Yokota, Mitsuhiro and Rich, Stephen S and Kooperberg, Charles and Pankow, James S and Engert, James C and Chen, Yii-Der Ida and Froguel, Philippe and Wilson, James G and Sheu, Wayne H H and Kardia, Sharon L R and Wu, Jer-Yuarn and Hayes, M Geoffrey and Ma, Ronald C W and Wong, Tien-Yin and Groop, Leif and Mook-Kanamori, Dennis O and Chandak, Giriraj R and Collins, Francis S and Bharadwaj, Dwaipayan and Par{\'e}, Guillaume and Sale, Mich{\`e}le M and Ahsan, Habibul and Motala, Ayesha A and Shu, Xiao-Ou and Park, Kyong-Soo and Jukema, J Wouter and Cruz, Miguel and McKean-Cowdin, Roberta and Grallert, Harald and Cheng, Ching-Yu and Bottinger, Erwin P and Dehghan, Abbas and Tai, E-Shyong and Dupuis, Jos{\'e}e and Kato, Norihiro and Laakso, Markku and K{\"o}ttgen, Anna and Koh, Woon-Puay and Palmer, Colin N A and Liu, Simin and Abecasis, Goncalo and Kooner, Jaspal S and Loos, Ruth J F and North, Kari E and Haiman, Christopher A and Florez, Jose C and Saleheen, Danish and Hansen, Torben and Pedersen, Oluf and M{\"a}gi, Reedik and Langenberg, Claudia and Wareham, Nicholas J and Maeda, Shiro and Kadowaki, Takashi and Lee, Juyoung and Millwood, Iona Y and Walters, Robin G and Stefansson, Kari and Myers, Simon R and Ferrer, Jorge and Gaulton, Kyle J and Meigs, James B and Mohlke, Karen L and Gloyn, Anna L and Bowden, Donald W and Below, Jennifer E and Chambers, John C and Sim, Xueling and Boehnke, Michael and Rotter, Jerome I and McCarthy, Mark I and Morris, Andrew P} }