%0 Journal Article %J Circ Cardiovasc Genet %D 2011 %T Association of genetic variants and incident coronary heart disease in multiethnic cohorts: the PAGE study. %A Franceschini, Nora %A Carty, Cara %A Bůzková, Petra %A Reiner, Alex P %A Garrett, Tiana %A Lin, Yi %A Vöckler, Jens-S %A Hindorff, Lucia A %A Cole, Shelley A %A Boerwinkle, Eric %A Lin, Dan-Yu %A Bookman, Ebony %A Best, Lyle G %A Bella, Jonathan N %A Eaton, Charles %A Greenland, Philip %A Jenny, Nancy %A North, Kari E %A Taverna, Darin %A Young, Alicia M %A Deelman, Ewa %A Kooperberg, Charles %A Psaty, Bruce %A Heiss, Gerardo %K Aged %K Aged, 80 and over %K Continental Population Groups %K Coronary Disease %K Female %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Prospective Studies %X

BACKGROUND: Genome-wide association studies identified several single nucleotide polymorphisms (SNP) associated with prevalent coronary heart disease (CHD), but less is known of associations with incident CHD. The association of 13 published CHD SNPs was examined in 5 ancestry groups of 4 large US prospective cohorts.

METHODS AND RESULTS: The analyses included incident coronary events over an average 9.1 to 15.7 follow-up person-years in up to 26 617 white individuals (6626 events), 8018 black individuals (914 events), 1903 Hispanic individuals (113 events), 3669 American Indian individuals (595 events), and 885 Asian/Pacific Islander individuals (66 events). We used Cox proportional hazards models (with additive mode of inheritance) adjusted for age, sex, and ancestry (as needed). Nine loci were statistically associated with incident CHD events in white participants: 9p21 (rs10757278; P=4.7 × 10(-41)), 16q23.1 (rs2549513; P=0.0004), 6p24.1 (rs499818; P=0.0002), 2q36.3 (rs2943634; P=6.7 × 10(-6)), MTHFD1L (rs6922269, P=5.1 × 10(-10)), APOE (rs429358; P=2.7×10(-18)), ZNF627 (rs4804611; P=5.0 × 10(-8)), CXCL12 (rs501120; P=1.4 × 10(-6)) and LPL (rs268; P=2.7 × 10(-17)). The 9p21 region showed significant between-study heterogeneity, with larger effects in individuals age 55 years or younger and in women. Inclusion of coronary revascularization procedures among the incident CHD events introduced heterogeneity. The SNPs were not associated with CHD in black participants, and associations varied in other US minorities.

CONCLUSIONS: Prospective analyses of white participants replicated several reported cross-sectional CHD-SNP associations.

%B Circ Cardiovasc Genet %V 4 %P 661-72 %8 2011 Dec %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/22042884?dopt=Abstract %R 10.1161/CIRCGENETICS.111.960096 %0 Journal Article %J Am J Epidemiol %D 2013 %T Association of functional polymorphism rs2231142 (Q141K) in the ABCG2 gene with serum uric acid and gout in 4 US populations: the PAGE Study. %A Zhang, Lili %A Spencer, Kylee L %A Voruganti, V Saroja %A Jorgensen, Neal W %A Fornage, Myriam %A Best, Lyle G %A Brown-Gentry, Kristin D %A Cole, Shelley A %A Crawford, Dana C %A Deelman, Ewa %A Franceschini, Nora %A Gaffo, Angelo L %A Glenn, Kimberly R %A Heiss, Gerardo %A Jenny, Nancy S %A Köttgen, Anna %A Li, Qiong %A Liu, Kiang %A Matise, Tara C %A North, Kari E %A Umans, Jason G %A Kao, W H Linda %K Adult %K African Americans %K Age Distribution %K ATP-Binding Cassette Transporters %K Comorbidity %K European Continental Ancestry Group %K Female %K Genetic Predisposition to Disease %K Genetics, Population %K Genome-Wide Association Study %K Gout %K Hormone Replacement Therapy %K Humans %K Indians, North American %K Male %K Mexican Americans %K Middle Aged %K Neoplasm Proteins %K Polymorphism, Genetic %K Postmenopause %K Sex Distribution %K United States %K Uric Acid %X

A loss-of-function mutation (Q141K, rs2231142) in the ATP-binding cassette, subfamily G, member 2 gene (ABCG2) has been shown to be associated with serum uric acid levels and gout in Asians, Europeans, and European and African Americans; however, less is known about these associations in other populations. Rs2231142 was genotyped in 22,734 European Americans, 9,720 African Americans, 3,849 Mexican Americans, and 3,550 American Indians in the Population Architecture using Genomics and Epidemiology (PAGE) Study (2008-2012). Rs2231142 was significantly associated with serum uric acid levels (P = 2.37 × 10(-67), P = 3.98 × 10(-5), P = 6.97 × 10(-9), and P = 5.33 × 10(-4) in European Americans, African Americans, Mexican Americans, and American Indians, respectively) and gout (P = 2.83 × 10(-10), P = 0.01, and P = 0.01 in European Americans, African Americans, and Mexican Americans, respectively). Overall, the T allele was associated with a 0.24-mg/dL increase in serum uric acid level (P = 1.37 × 10(-80)) and a 1.75-fold increase in the odds of gout (P = 1.09 × 10(-12)). The association between rs2231142 and serum uric acid was significantly stronger in men, postmenopausal women, and hormone therapy users compared with their counterparts. The association with gout was also significantly stronger in men than in women. These results highlight a possible role of sex hormones in the regulation of ABCG2 urate transporter and its potential implications for the prevention, diagnosis, and treatment of hyperuricemia and gout.

%B Am J Epidemiol %V 177 %P 923-32 %8 2013 May 1 %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/23552988?dopt=Abstract %R 10.1093/aje/kws330 %0 Journal Article %J Atherosclerosis %D 2013 %T Lack of associations of ten candidate coronary heart disease risk genetic variants and subclinical atherosclerosis in four US populations: the Population Architecture using Genomics and Epidemiology (PAGE) study. %A Zhang, Lili %A Bůzková, Petra %A Wassel, Christina L %A Roman, Mary J %A North, Kari E %A Crawford, Dana C %A Boston, Jonathan %A Brown-Gentry, Kristin D %A Cole, Shelley A %A Deelman, Ewa %A Goodloe, Robert %A Wilson, Sarah %A Heiss, Gerardo %A Jenny, Nancy S %A Jorgensen, Neal W %A Matise, Tara C %A McClellan, Bob E %A Nato, Alejandro Q %A Ritchie, Marylyn D %A Franceschini, Nora %A Kao, W H Linda %K African Americans %K Aged %K Ankle Brachial Index %K Asymptomatic Diseases %K Carotid Artery Diseases %K Carotid Intima-Media Thickness %K Coronary Disease %K European Continental Ancestry Group %K Female %K Gene Frequency %K Genetic Association Studies %K Genetic Predisposition to Disease %K Humans %K Indians, North American %K Linear Models %K Logistic Models %K Male %K Mexican Americans %K Middle Aged %K Odds Ratio %K Phenotype %K Polymorphism, Single Nucleotide %K Predictive Value of Tests %K Risk Assessment %K Risk Factors %K United States %X

BACKGROUND: A number of genetic variants have been discovered by recent genome-wide association studies for their associations with clinical coronary heart disease (CHD). However, it is unclear whether these variants are also associated with the development of CHD as measured by subclinical atherosclerosis phenotypes, ankle brachial index (ABI), carotid artery intima-media thickness (cIMT) and carotid plaque.

METHODS: Ten CHD risk single nucleotide polymorphisms (SNPs) were genotyped in individuals of European American (EA), African American (AA), American Indian (AI), and Mexican American (MA) ancestry in the Population Architecture using Genomics and Epidemiology (PAGE) study. In each individual study, we performed linear or logistic regression to examine population-specific associations between SNPs and ABI, common and internal cIMT, and plaque. The results from individual studies were meta-analyzed using a fixed effect inverse variance weighted model.

RESULTS: None of the ten SNPs was significantly associated with ABI and common or internal cIMT, after Bonferroni correction. In the sample of 13,337 EA, 3809 AA, and 5353 AI individuals with carotid plaque measurement, the GCKR SNP rs780094 was significantly associated with the presence of plaque in AI only (OR = 1.32, 95% confidence interval: 1.17, 1.49, P = 1.08 × 10(-5)), but not in the other populations (P = 0.90 in EA and P = 0.99 in AA). A 9p21 region SNP, rs1333049, was nominally associated with plaque in EA (OR = 1.07, P = 0.02) and in AI (OR = 1.10, P = 0.05).

CONCLUSIONS: We identified a significant association between rs780094 and plaque in AI populations, which needs to be replicated in future studies. There was little evidence that the index CHD risk variants identified through genome-wide association studies in EA influence the development of CHD through subclinical atherosclerosis as assessed by cIMT and ABI across ancestries.

%B Atherosclerosis %V 228 %P 390-9 %8 2013 Jun %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/23587283?dopt=Abstract %R 10.1016/j.atherosclerosis.2013.02.038 %0 Journal Article %J Epidemiology %D 2014 %T Evidence of heterogeneity by race/ethnicity in genetic determinants of QT interval. %A Seyerle, Amanda A %A Young, Alicia M %A Jeff, Janina M %A Melton, Phillip E %A Jorgensen, Neal W %A Lin, Yi %A Carty, Cara L %A Deelman, Ewa %A Heckbert, Susan R %A Hindorff, Lucia A %A Jackson, Rebecca D %A Martin, Lisa W %A Okin, Peter M %A Perez, Marco V %A Psaty, Bruce M %A Soliman, Elsayed Z %A Whitsel, Eric A %A North, Kari E %A Laston, Sandra %A Kooperberg, Charles %A Avery, Christy L %K Aged %K Continental Population Groups %K Electrocardiography %K Female %K Genetic Predisposition to Disease %K Haplotypes %K Humans %K Long QT Syndrome %K Male %K Middle Aged %K Phenotype %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Quantitative Trait, Heritable %K Risk Factors %X

BACKGROUND: QT interval (QT) prolongation is an established risk factor for ventricular tachyarrhythmia and sudden cardiac death. Previous genome-wide association studies in populations of the European descent have identified multiple genetic loci that influence QT, but few have examined these loci in ethnically diverse populations.

METHODS: Here, we examine the direction, magnitude, and precision of effect sizes for 21 previously reported SNPs from 12 QT loci, in populations of European (n = 16,398), African (n = 5,437), American Indian (n = 5,032), Hispanic (n = 1,143), and Asian (n = 932) descent as part of the Population Architecture using Genomics and Epidemiology (PAGE) study. Estimates obtained from linear regression models stratified by race/ethnicity were combined using inverse-variance weighted meta-analysis. Heterogeneity was evaluated using Cochran's Q test.

RESULTS: Of 21 SNPs, 7 showed consistent direction of effect across all 5 populations, and an additional 9 had estimated effects that were consistent across 4 populations. Despite consistent direction of effect, 9 of 16 SNPs had evidence (P < 0.05) of heterogeneity by race/ethnicity. For these 9 SNPs, linkage disequilibrium plots often indicated substantial variation in linkage disequilibrium patterns among the various racial/ethnic groups, as well as possible allelic heterogeneity.

CONCLUSIONS: These results emphasize the importance of analyzing racial/ethnic groups separately in genetic studies. Furthermore, they underscore the possible utility of trans-ethnic studies to pinpoint underlying casual variants influencing heritable traits such as QT.

%B Epidemiology %V 25 %P 790-8 %8 2014 Nov %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/25166880?dopt=Abstract %R 10.1097/EDE.0000000000000168 %0 Journal Article %J Circ Cardiovasc Genet %D 2014 %T Multiancestral analysis of inflammation-related genetic variants and C-reactive protein in the population architecture using genomics and epidemiology study. %A Kocarnik, Jonathan M %A Pendergrass, Sarah A %A Carty, Cara L %A Pankow, James S %A Schumacher, Fredrick R %A Cheng, Iona %A Durda, Peter %A Ambite, Jose Luis %A Deelman, Ewa %A Cook, Nancy R %A Liu, Simin %A Wactawski-Wende, Jean %A Hutter, Carolyn %A Brown-Gentry, Kristin %A Wilson, Sarah %A Best, Lyle G %A Pankratz, Nathan %A Hong, Ching-Ping %A Cole, Shelley A %A Voruganti, V Saroja %A Bůzková, Petra %A Jorgensen, Neal W %A Jenny, Nancy S %A Wilkens, Lynne R %A Haiman, Christopher A %A Kolonel, Laurence N %A LaCroix, Andrea %A North, Kari %A Jackson, Rebecca %A Le Marchand, Loïc %A Hindorff, Lucia A %A Crawford, Dana C %A Gross, Myron %A Peters, Ulrike %K Adult %K African Continental Ancestry Group %K Aged %K Asian Continental Ancestry Group %K C-Reactive Protein %K Female %K Genetic Variation %K Genome-Wide Association Study %K Hispanic Americans %K Humans %K Indians, North American %K Inflammation %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K United States %K Young Adult %X

BACKGROUND: C-reactive protein (CRP) is a biomarker of inflammation. Genome-wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) associated with CRP concentrations and inflammation-related traits such as cardiovascular disease, type 2 diabetes mellitus, and obesity. We aimed to replicate previous CRP-SNP associations, assess whether these associations generalize to additional race/ethnicity groups, and evaluate inflammation-related SNPs for a potentially pleiotropic association with CRP.

METHODS AND RESULTS: We selected and analyzed 16 CRP-associated and 250 inflammation-related GWAS SNPs among 40 473 African American, American Indian, Asian/Pacific Islander, European American, and Hispanic participants from 7 studies collaborating in the Population Architecture using Genomics and Epidemiology (PAGE) study. Fixed-effect meta-analyses combined study-specific race/ethnicity-stratified linear regression estimates to evaluate the association between each SNP and high-sensitivity CRP. Overall, 18 SNPs in 8 loci were significantly associated with CRP (Bonferroni-corrected P<3.1×10(-3) for replication, P<2.0×10(-4) for pleiotropy): Seven of these were specific to European Americans, while 9 additionally generalized to African Americans (1), Hispanics (5), or both (3); 1 SNP was seen only in African Americans and Hispanics. Two SNPs in the CELSR2/PSRC1/SORT1 locus showed a potentially novel association with CRP: rs599839 (P=2.0×10(-6)) and rs646776 (P=3.1×10(-5)).

CONCLUSIONS: We replicated 16 SNP-CRP associations, 10 of which generalized to African Americans and/or Hispanics. We also identified potentially novel pleiotropic associations with CRP for two SNPs previously associated with coronary artery disease and/or low-density lipoprotein-cholesterol. These findings demonstrate the benefit of evaluating genotype-phenotype associations in multiple race/ethnicity groups and looking for pleiotropic relationships among SNPs previously associated with related phenotypes.

%B Circ Cardiovasc Genet %V 7 %P 178-88 %8 2014 Apr %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24622110?dopt=Abstract %R 10.1161/CIRCGENETICS.113.000173