TY - JOUR T1 - Candidate gene association resource (CARe): design, methods, and proof of concept. JF - Circ Cardiovasc Genet Y1 - 2010 A1 - Musunuru, Kiran A1 - Lettre, Guillaume A1 - Young, Taylor A1 - Farlow, Deborah N A1 - Pirruccello, James P A1 - Ejebe, Kenechi G A1 - Keating, Brendan J A1 - Yang, Qiong A1 - Chen, Ming-Huei A1 - Lapchyk, Nina A1 - Crenshaw, Andrew A1 - Ziaugra, Liuda A1 - Rachupka, Anthony A1 - Benjamin, Emelia J A1 - Cupples, L Adrienne A1 - Fornage, Myriam A1 - Fox, Ervin R A1 - Heckbert, Susan R A1 - Hirschhorn, Joel N A1 - Newton-Cheh, Christopher A1 - Nizzari, Marcia M A1 - Paltoo, Dina N A1 - Papanicolaou, George J A1 - Patel, Sanjay R A1 - Psaty, Bruce M A1 - Rader, Daniel J A1 - Redline, Susan A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Taylor, Herman A A1 - Tracy, Russell P A1 - Vasan, Ramachandran S A1 - Wilson, James G A1 - Kathiresan, Sekar A1 - Fabsitz, Richard R A1 - Boerwinkle, Eric A1 - Gabriel, Stacey B KW - African Americans KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Cohort Studies KW - Databases, Genetic KW - European Continental Ancestry Group KW - Genetic Association Studies KW - Genotype KW - Humans KW - Phenotype KW - Pilot Projects KW - Polymorphism, Single Nucleotide KW - Research Design KW - Triglycerides AB -

BACKGROUND: The National Heart, Lung, and Blood Institute's Candidate Gene Association Resource (CARe), a planned cross-cohort analysis of genetic variation in cardiovascular, pulmonary, hematologic, and sleep-related traits, comprises >40,000 participants representing 4 ethnic groups in 9 community-based cohorts. The goals of CARe include the discovery of new variants associated with traits using a candidate gene approach and the discovery of new variants using the genome-wide association mapping approach specifically in African Americans.

METHODS AND RESULTS: CARe has assembled DNA samples for >40,000 individuals self-identified as European American, African American, Hispanic, or Chinese American, with accompanying data on hundreds of phenotypes that have been standardized and deposited in the CARe Phenotype Database. All participants were genotyped for 7 single-nucleotide polymorphisms (SNPs) selected based on prior association evidence. We performed association analyses relating each of these SNPs to lipid traits, stratified by sex and ethnicity, and adjusted for age and age squared. In at least 2 of the ethnic groups, SNPs near CETP, LIPC, and LPL strongly replicated for association with high-density lipoprotein cholesterol concentrations, PCSK9 with low-density lipoprotein cholesterol levels, and LPL and APOA5 with serum triglycerides. Notably, some SNPs showed varying effect sizes and significance of association in different ethnic groups.

CONCLUSIONS: The CARe Pilot Study validates the operational framework for phenotype collection, SNP genotyping, and analytic pipeline of the CARe project and validates the planned candidate gene study of approximately 2000 biological candidate loci in all participants and genome-wide association study in approximately 8000 African American participants. CARe will serve as a valuable resource for the scientific community.

VL - 3 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20400780?dopt=Abstract ER - TY - JOUR T1 - Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study. JF - Hum Mol Genet Y1 - 2011 A1 - Fox, Ervin R A1 - Young, J Hunter A1 - Li, Yali A1 - Dreisbach, Albert W A1 - Keating, Brendan J A1 - Musani, Solomon K A1 - Liu, Kiang A1 - Morrison, Alanna C A1 - Ganesh, Santhi A1 - Kutlar, Abdullah A1 - Ramachandran, Vasan S A1 - Polak, Josef F A1 - Fabsitz, Richard R A1 - Dries, Daniel L A1 - Farlow, Deborah N A1 - Redline, Susan A1 - Adeyemo, Adebowale A1 - Hirschorn, Joel N A1 - Sun, Yan V A1 - Wyatt, Sharon B A1 - Penman, Alan D A1 - Palmas, Walter A1 - Rotter, Jerome I A1 - Townsend, Raymond R A1 - Doumatey, Ayo P A1 - Tayo, Bamidele O A1 - Mosley, Thomas H A1 - Lyon, Helen N A1 - Kang, Sun J A1 - Rotimi, Charles N A1 - Cooper, Richard S A1 - Franceschini, Nora A1 - Curb, J David A1 - Martin, Lisa W A1 - Eaton, Charles B A1 - Kardia, Sharon L R A1 - Taylor, Herman A A1 - Caulfield, Mark J A1 - Ehret, Georg B A1 - Johnson, Toby A1 - Chakravarti, Aravinda A1 - Zhu, Xiaofeng A1 - Levy, Daniel KW - Adult KW - African Americans KW - Aged KW - Blood Pressure KW - Cohort Studies KW - Diastole KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Hypertension KW - Male KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Systole AB -

The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10(-8)) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10(-8)). The top IBC association for SBP was rs2012318 (P= 6.4 × 10(-6)) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10(-6)) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity.

VL - 20 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21378095?dopt=Abstract ER - TY - JOUR T1 - Association of genomic loci from a cardiovascular gene SNP array with fibrinogen levels in European Americans and African-Americans from six cohort studies: the Candidate Gene Association Resource (CARe). JF - Blood Y1 - 2011 A1 - Wassel, Christina L A1 - Lange, Leslie A A1 - Keating, Brendan J A1 - Taylor, Kira C A1 - Johnson, Andrew D A1 - Palmer, Cameron A1 - Ho, Lindsey A A1 - Smith, Nicholas L A1 - Lange, Ethan M A1 - Li, Yun A1 - Yang, Qiong A1 - Delaney, Joseph A A1 - Tang, Weihong A1 - Tofler, Geoffrey A1 - Redline, Susan A1 - Taylor, Herman A A1 - Wilson, James G A1 - Tracy, Russell P A1 - Jacobs, David R A1 - Folsom, Aaron R A1 - Green, David A1 - O'Donnell, Christopher J A1 - Reiner, Alexander P KW - Adult KW - African Americans KW - Aged KW - Cardiovascular Diseases KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Fibrinogen KW - Genetic Predisposition to Disease KW - Haplotypes KW - Humans KW - Male KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

Several common genomic loci, involving various immunity- and metabolism-related genes, have been associated with plasma fibrinogen in European Americans (EAs). The genetic determinants of fibrinogen in African Americans (AAs) are poorly characterized. Using a vascular gene-centric array in 23,634 EA and 6657 AA participants from 6 studies comprising the Candidate Gene Association Resource project, we examined the association of 47,539 common and lower frequency variants with fibrinogen concentration. We identified a rare Pro265Leu variant in FGB (rs6054) associated with lower fibrinogen. Common fibrinogen gene single nucleotide polymorphisms (FGB rs1800787 and FGG rs2066861) significantly associated with fibrinogen in EAs were prevalent in AAs and showed consistent associations. Several fibrinogen locus single nucleotide polymorphism associated with lower fibrinogen were exclusive to AAs; these include a newly reported association with FGA rs10050257. For IL6R, IL1RN, and NLRP3 inflammatory gene loci, associations with fibrinogen were concordant between EAs and AAs, but not at other loci (CPS1, PCCB, and SCL22A5-IRF1). The association of FGG rs2066861 with fibrinogen differed according to assay type used to measure fibrinogen. Further characterization of common and lower-frequency genetic variants that contribute to interpopulation differences in fibrinogen phenotype may help refine our understanding of the contribution of hemostasis and inflammation to atherothrombotic risk.

VL - 117 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20978265?dopt=Abstract ER - TY - JOUR T1 - A gene-centric association scan for Coagulation Factor VII levels in European and African Americans: the Candidate Gene Association Resource (CARe) Consortium. JF - Hum Mol Genet Y1 - 2011 A1 - Taylor, Kira C A1 - Lange, Leslie A A1 - Zabaneh, Delilah A1 - Lange, Ethan A1 - Keating, Brendan J A1 - Tang, Weihong A1 - Smith, Nicholas L A1 - Delaney, Joseph A A1 - Kumari, Meena A1 - Hingorani, Aroon A1 - North, Kari E A1 - Kivimaki, Mika A1 - Tracy, Russell P A1 - O'Donnell, Christopher J A1 - Folsom, Aaron R A1 - Green, David A1 - Humphries, Steve E A1 - Reiner, Alexander P KW - Adult KW - African Americans KW - Aged KW - Cardiovascular Diseases KW - European Continental Ancestry Group KW - Factor VII KW - Female KW - Genetic Predisposition to Disease KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide AB -

Polymorphisms in several distinct genomic regions, including the F7 gene, were recently associated with factor VII (FVII) levels in European Americans (EAs). The genetic determinants of FVII in African Americans (AAs) are unknown. We used a 50,000 single nucleotide polymorphism (SNP) gene-centric array having dense coverage of over 2,000 candidate genes for cardiovascular disease (CVD) pathways in a community-based sample of 16,324 EA and 3898 AA participants from the Candidate Gene Association Resource (CARe) consortium. Our aim was the discovery of new genomic loci and more detailed characterization of existing loci associated with FVII levels. In EAs, we identified three new loci associated with FVII, of which APOA5 on chromosome 11q23 and HNF4A on chromosome 20q12-13 were replicated in a sample of 4289 participants from the Whitehall II study. We confirmed four previously reported FVII-associated loci (GCKR, MS4A6A, F7 and PROCR) in CARe EA samples. In AAs, the F7 and PROCR regions were significantly associated with FVII. Several of the FVII-associated regions are known to be associated with lipids and other cardiovascular-related traits. At the F7 locus, there was evidence of at least five independently associated SNPs in EAs and three independent signals in AAs. Though the variance in FVII explained by the existing loci is substantial (20% in EA and 10% in AA), larger sample sizes and investigation of lower frequency variants may be required to identify additional FVII-associated loci in EAs and AAs and further clarify the relationship between FVII and other CVD risk factors.

VL - 20 IS - 17 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21676895?dopt=Abstract ER - TY - JOUR T1 - Novel loci associated with PR interval in a genome-wide association study of 10 African American cohorts. JF - Circ Cardiovasc Genet Y1 - 2012 A1 - Butler, Anne M A1 - Yin, Xiaoyan A1 - Evans, Daniel S A1 - Nalls, Michael A A1 - Smith, Erin N A1 - Tanaka, Toshiko A1 - Li, Guo A1 - Buxbaum, Sarah G A1 - Whitsel, Eric A A1 - Alonso, Alvaro A1 - Arking, Dan E A1 - Benjamin, Emelia J A1 - Berenson, Gerald S A1 - Bis, Josh C A1 - Chen, Wei A1 - Deo, Rajat A1 - Ellinor, Patrick T A1 - Heckbert, Susan R A1 - Heiss, Gerardo A1 - Hsueh, Wen-Chi A1 - Keating, Brendan J A1 - Kerr, Kathleen F A1 - Li, Yun A1 - Limacher, Marian C A1 - Liu, Yongmei A1 - Lubitz, Steven A A1 - Marciante, Kristin D A1 - Mehra, Reena A1 - Meng, Yan A A1 - Newman, Anne B A1 - Newton-Cheh, Christopher A1 - North, Kari E A1 - Palmer, Cameron D A1 - Psaty, Bruce M A1 - Quibrera, P Miguel A1 - Redline, Susan A1 - Reiner, Alex P A1 - Rotter, Jerome I A1 - Schnabel, Renate B A1 - Schork, Nicholas J A1 - Singleton, Andrew B A1 - Smith, J Gustav A1 - Soliman, Elsayed Z A1 - Srinivasan, Sathanur R A1 - Zhang, Zhu-Ming A1 - Zonderman, Alan B A1 - Ferrucci, Luigi A1 - Murray, Sarah S A1 - Evans, Michele K A1 - Sotoodehnia, Nona A1 - Magnani, Jared W A1 - Avery, Christy L KW - Adult KW - African Americans KW - Cohort Studies KW - Electrocardiography KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Male KW - Meta-Analysis as Topic KW - Middle Aged KW - Polymorphism, Single Nucleotide AB -

BACKGROUND: The PR interval, as measured by the resting, standard 12-lead ECG, reflects the duration of atrial/atrioventricular nodal depolarization. Substantial evidence exists for a genetic contribution to PR, including genome-wide association studies that have identified common genetic variants at 9 loci influencing PR in populations of European and Asian descent. However, few studies have examined loci associated with PR in African Americans.

METHODS AND RESULTS: We present results from the largest genome-wide association study to date of PR in 13 415 adults of African descent from 10 cohorts. We tested for association between PR (ms) and ≈2.8 million genotyped and imputed single-nucleotide polymorphisms. Imputation was performed using HapMap 2 YRI and CEU panels. Study-specific results, adjusted for global ancestry and clinical correlates of PR, were meta-analyzed using the inverse variance method. Variation in genome-wide test statistic distributions was noted within studies (λ range: 0.9-1.1), although not after genomic control correction was applied to the overall meta-analysis (λ: 1.008). In addition to generalizing previously reported associations with MEIS1, SCN5A, ARHGAP24, CAV1, and TBX5 to African American populations at the genome-wide significance level (P<5.0 × 10(-8)), we also identified a novel locus: ITGA9, located in a region previously implicated in SCN5A expression. The 3p21 region harboring SCN5A also contained 2 additional independent secondary signals influencing PR (P<5.0 × 10(-8)).

CONCLUSIONS: This study demonstrates the ability to map novel loci in African Americans as well as the generalizability of loci associated with PR across populations of African, European, and Asian descent.

VL - 5 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23139255?dopt=Abstract ER - TY - JOUR T1 - Ultraconserved elements in the human genome: association and transmission analyses of highly constrained single-nucleotide polymorphisms. JF - Genetics Y1 - 2012 A1 - Chiang, Charleston W K A1 - Liu, Ching-Ti A1 - Lettre, Guillaume A1 - Lange, Leslie A A1 - Jorgensen, Neal W A1 - Keating, Brendan J A1 - Vedantam, Sailaja A1 - Nock, Nora L A1 - Franceschini, Nora A1 - Reiner, Alex P A1 - Demerath, Ellen W A1 - Boerwinkle, Eric A1 - Rotter, Jerome I A1 - Wilson, James G A1 - North, Kari E A1 - Papanicolaou, George J A1 - Cupples, L Adrienne A1 - Murabito, Joanne M A1 - Hirschhorn, Joel N KW - Alleles KW - Animals KW - Body Height KW - Body Mass Index KW - Child KW - Conserved Sequence KW - Dogs KW - Evolution, Molecular KW - Female KW - Genetic Fitness KW - Genetic Variation KW - Genome, Human KW - Genotype KW - Humans KW - Inheritance Patterns KW - Male KW - Mice KW - Pedigree KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Rats KW - Reproduction KW - Young Adult AB -

Ultraconserved elements in the human genome likely harbor important biological functions as they are dosage sensitive and are able to direct tissue-specific expression. Because they are under purifying selection, variants in these elements may have a lower frequency in the population but a higher likelihood of association with complex traits. We tested a set of highly constrained SNPs (hcSNPs) distributed genome-wide among ultraconserved and nearly ultraconserved elements for association with seven traits related to reproductive (age at natural menopause, number of children, age at first child, and age at last child) and overall [longevity, body mass index (BMI), and height] fitness. Using up to 24,047 European-American samples from the National Heart, Lung, and Blood Institute Candidate Gene Association Resource (CARe), we observed an excess of associations with BMI and height. In an independent replication panel the most strongly associated SNPs showed an 8.4-fold enrichment of associations at the nominal level, including three variants in previously identified loci and one in a locus (DENND1A) previously shown to be associated with polycystic ovary syndrome. Finally, using 1430 family trios, we showed that the transmissions from heterozygous parents to offspring of the derived alleles of rare (frequency ≤ 0.5%) hcSNPs are not biased, particularly after adjusting for the rates of genotype missingness and error in the data. The lack of transmission bias ruled out an immediately and strongly deleterious effect due to the rare derived alleles, consistent with the observation that mice homozygous for the deletion of ultraconserved elements showed no overt phenotype. Our study also illustrated the importance of carefully modeling potential technical confounders when analyzing genotype data of rare variants.

VL - 192 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22714408?dopt=Abstract ER - TY - JOUR T1 - Gene-centric meta-analyses of 108 912 individuals confirm known body mass index loci and reveal three novel signals. JF - Hum Mol Genet Y1 - 2013 A1 - Guo, Yiran A1 - Lanktree, Matthew B A1 - Taylor, Kira C A1 - Hakonarson, Hakon A1 - Lange, Leslie A A1 - Keating, Brendan J KW - Body Mass Index KW - Cohort Studies KW - Ethnic Groups KW - Humans KW - Polymorphism, Single Nucleotide AB -

Recent genetic association studies have made progress in uncovering components of the genetic architecture of the body mass index (BMI). We used the ITMAT-Broad-Candidate Gene Association Resource (CARe) (IBC) array comprising up to 49 320 single nucleotide polymorphisms (SNPs) across ~2100 metabolic and cardiovascular-related loci to genotype up to 108 912 individuals of European ancestry (EA), African-Americans, Hispanics and East Asians, from 46 studies, to provide additional insight into SNPs underpinning BMI. We used a five-phase study design: Phase I focused on meta-analysis of EA studies providing individual level genotype data; Phase II performed a replication of cohorts providing summary level EA data; Phase III meta-analyzed results from the first two phases; associated SNPs from Phase III were used for replication in Phase IV; finally in Phase V, a multi-ethnic meta-analysis of all samples from four ethnicities was performed. At an array-wide significance (P < 2.40E-06), we identify novel BMI associations in loci translocase of outer mitochondrial membrane 40 homolog (yeast) - apolipoprotein E - apolipoprotein C-I (TOMM40-APOE-APOC1) (rs2075650, P = 2.95E-10), sterol regulatory element binding transcription factor 2 (SREBF2, rs5996074, P = 9.43E-07) and neurotrophic tyrosine kinase, receptor, type 2 [NTRK2, a brain-derived neurotrophic factor (BDNF) receptor gene, rs1211166, P = 1.04E-06] in the Phase IV meta-analysis. Of 10 loci with previous evidence for BMI association represented on the IBC array, eight were replicated, with the remaining two showing nominal significance. Conditional analyses revealed two independent BMI-associated signals in BDNF and melanocortin 4 receptor (MC4R) regions. Of the 11 array-wide significant SNPs, three are associated with gene expression levels in both primary B-cells and monocytes; with rs4788099 in SH2B adaptor protein 1 (SH2B1) notably being associated with the expression of multiple genes in cis. These multi-ethnic meta-analyses expand our knowledge of BMI genetics.

VL - 22 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23001569?dopt=Abstract ER - TY - JOUR T1 - Genome-wide and gene-centric analyses of circulating myeloperoxidase levels in the charge and care consortia. JF - Hum Mol Genet Y1 - 2013 A1 - Reiner, Alexander P A1 - Hartiala, Jaana A1 - Zeller, Tanja A1 - Bis, Joshua C A1 - Dupuis, Josée A1 - Fornage, Myriam A1 - Baumert, Jens A1 - Kleber, Marcus E A1 - Wild, Philipp S A1 - Baldus, Stephan A1 - Bielinski, Suzette J A1 - Fontes, João D A1 - Illig, Thomas A1 - Keating, Brendan J A1 - Lange, Leslie A A1 - Ojeda, Francisco A1 - Müller-Nurasyid, Martina A1 - Munzel, Thomas F A1 - Psaty, Bruce M A1 - Rice, Kenneth A1 - Rotter, Jerome I A1 - Schnabel, Renate B A1 - Tang, W H Wilson A1 - Thorand, Barbara A1 - Erdmann, Jeanette A1 - Jacobs, David R A1 - Wilson, James G A1 - Koenig, Wolfgang A1 - Tracy, Russell P A1 - Blankenberg, Stefan A1 - März, Winfried A1 - Gross, Myron D A1 - Benjamin, Emelia J A1 - Hazen, Stanley L A1 - Allayee, Hooman KW - Adult KW - African Americans KW - Aged KW - Case-Control Studies KW - Complement Factor H KW - Coronary Artery Disease KW - European Continental Ancestry Group KW - Female KW - Gene Expression Regulation, Enzymologic KW - Genetic Association Studies KW - Genetic Variation KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Male KW - Middle Aged KW - Peroxidase KW - Polymorphism, Single Nucleotide KW - Young Adult AB -

Increased systemic levels of myeloperoxidase (MPO) are associated with the risk of coronary artery disease (CAD). To identify the genetic factors that are associated with circulating MPO levels, we carried out a genome-wide association study (GWAS) and a gene-centric analysis in subjects of European ancestry and African Americans (AAs). A locus on chromosome 1q31.1 containing the complement factor H (CFH) gene was strongly associated with serum MPO levels in 9305 subjects of European ancestry (lead SNP rs800292; P = 4.89 × 10(-41)) and in 1690 AA subjects (rs505102; P = 1.05 × 10(-8)). Gene-centric analyses in 8335 subjects of European ancestry additionally identified two rare MPO coding sequence variants that were associated with serum MPO levels (rs28730837, P = 5.21 × 10(-12); rs35897051, P = 3.32 × 10(-8)). A GWAS for plasma MPO levels in 9260 European ancestry subjects identified a chromosome 17q22 region near MPO that was significantly associated (lead SNP rs6503905; P = 2.94 × 10(-12)), but the CFH locus did not exhibit evidence of association with plasma MPO levels. Functional analyses revealed that rs800292 was associated with levels of complement proteins in serum. Variants at chromosome 17q22 also had pleiotropic cis effects on gene expression. In a case-control analysis of ∼80 000 subjects from CARDIoGRAM, none of the identified single-nucleotide polymorphisms (SNPs) were associated with CAD. These results suggest that distinct genetic factors regulate serum and plasma MPO levels, which may have relevance for various acute and chronic inflammatory disorders. The clinical implications for CAD and a better understanding of the functional basis for the association of CFH and MPO variants with circulating MPO levels require further study.

VL - 22 IS - 16 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23620142?dopt=Abstract ER - TY - JOUR T1 - A meta-analysis identifies new loci associated with body mass index in individuals of African ancestry. JF - Nat Genet Y1 - 2013 A1 - Monda, Keri L A1 - Chen, Gary K A1 - Taylor, Kira C A1 - Palmer, Cameron A1 - Edwards, Todd L A1 - Lange, Leslie A A1 - Ng, Maggie C Y A1 - Adeyemo, Adebowale A A1 - Allison, Matthew A A1 - Bielak, Lawrence F A1 - Chen, Guanjie A1 - Graff, Mariaelisa A1 - Irvin, Marguerite R A1 - Rhie, Suhn K A1 - Li, Guo A1 - Liu, Yongmei A1 - Liu, Youfang A1 - Lu, Yingchang A1 - Nalls, Michael A A1 - Sun, Yan V A1 - Wojczynski, Mary K A1 - Yanek, Lisa R A1 - Aldrich, Melinda C A1 - Ademola, Adeyinka A1 - Amos, Christopher I A1 - Bandera, Elisa V A1 - Bock, Cathryn H A1 - Britton, Angela A1 - Broeckel, Ulrich A1 - Cai, Quiyin A1 - Caporaso, Neil E A1 - Carlson, Chris S A1 - Carpten, John A1 - Casey, Graham A1 - Chen, Wei-Min A1 - Chen, Fang A1 - Chen, Yii-der I A1 - Chiang, Charleston W K A1 - Coetzee, Gerhard A A1 - Demerath, Ellen A1 - Deming-Halverson, Sandra L A1 - Driver, Ryan W A1 - Dubbert, Patricia A1 - Feitosa, Mary F A1 - Feng, Ye A1 - Freedman, Barry I A1 - Gillanders, Elizabeth M A1 - Gottesman, Omri A1 - Guo, Xiuqing A1 - Haritunians, Talin A1 - Harris, Tamara A1 - Harris, Curtis C A1 - Hennis, Anselm J M A1 - Hernandez, Dena G A1 - McNeill, Lorna H A1 - Howard, Timothy D A1 - Howard, Barbara V A1 - Howard, Virginia J A1 - Johnson, Karen C A1 - Kang, Sun J A1 - Keating, Brendan J A1 - Kolb, Suzanne A1 - Kuller, Lewis H A1 - Kutlar, Abdullah A1 - Langefeld, Carl D A1 - Lettre, Guillaume A1 - Lohman, Kurt A1 - Lotay, Vaneet A1 - Lyon, Helen A1 - Manson, JoAnn E A1 - Maixner, William A1 - Meng, Yan A A1 - Monroe, Kristine R A1 - Morhason-Bello, Imran A1 - Murphy, Adam B A1 - Mychaleckyj, Josyf C A1 - Nadukuru, Rajiv A1 - Nathanson, Katherine L A1 - Nayak, Uma A1 - N'diaye, Amidou A1 - Nemesure, Barbara A1 - Wu, Suh-Yuh A1 - Leske, M Cristina A1 - Neslund-Dudas, Christine A1 - Neuhouser, Marian A1 - Nyante, Sarah A1 - Ochs-Balcom, Heather A1 - Ogunniyi, Adesola A1 - Ogundiran, Temidayo O A1 - Ojengbede, Oladosu A1 - Olopade, Olufunmilayo I A1 - Palmer, Julie R A1 - Ruiz-Narvaez, Edward A A1 - Palmer, Nicholette D A1 - Press, Michael F A1 - Rampersaud, Evandine A1 - Rasmussen-Torvik, Laura J A1 - Rodriguez-Gil, Jorge L A1 - Salako, Babatunde A1 - Schadt, Eric E A1 - Schwartz, Ann G A1 - Shriner, Daniel A A1 - Siscovick, David A1 - Smith, Shad B A1 - Wassertheil-Smoller, Sylvia A1 - Speliotes, Elizabeth K A1 - Spitz, Margaret R A1 - Sucheston, Lara A1 - Taylor, Herman A1 - Tayo, Bamidele O A1 - Tucker, Margaret A A1 - Van Den Berg, David J A1 - Edwards, Digna R Velez A1 - Wang, Zhaoming A1 - Wiencke, John K A1 - Winkler, Thomas W A1 - Witte, John S A1 - Wrensch, Margaret A1 - Wu, Xifeng A1 - Yang, James J A1 - Levin, Albert M A1 - Young, Taylor R A1 - Zakai, Neil A A1 - Cushman, Mary A1 - Zanetti, Krista A A1 - Zhao, Jing Hua A1 - Zhao, Wei A1 - Zheng, Yonglan A1 - Zhou, Jie A1 - Ziegler, Regina G A1 - Zmuda, Joseph M A1 - Fernandes, Jyotika K A1 - Gilkeson, Gary S A1 - Kamen, Diane L A1 - Hunt, Kelly J A1 - Spruill, Ida J A1 - Ambrosone, Christine B A1 - Ambs, Stefan A1 - Arnett, Donna K A1 - Atwood, Larry A1 - Becker, Diane M A1 - Berndt, Sonja I A1 - Bernstein, Leslie A1 - Blot, William J A1 - Borecki, Ingrid B A1 - Bottinger, Erwin P A1 - Bowden, Donald W A1 - Burke, Gregory A1 - Chanock, Stephen J A1 - Cooper, Richard S A1 - Ding, Jingzhong A1 - Duggan, David A1 - Evans, Michele K A1 - Fox, Caroline A1 - Garvey, W Timothy A1 - Bradfield, Jonathan P A1 - Hakonarson, Hakon A1 - Grant, Struan F A A1 - Hsing, Ann A1 - Chu, Lisa A1 - Hu, Jennifer J A1 - Huo, Dezheng A1 - Ingles, Sue A A1 - John, Esther M A1 - Jordan, Joanne M A1 - Kabagambe, Edmond K A1 - Kardia, Sharon L R A1 - Kittles, Rick A A1 - Goodman, Phyllis J A1 - Klein, Eric A A1 - Kolonel, Laurence N A1 - Le Marchand, Loïc A1 - Liu, Simin A1 - McKnight, Barbara A1 - Millikan, Robert C A1 - Mosley, Thomas H A1 - Padhukasahasram, Badri A1 - Williams, L Keoki A1 - Patel, Sanjay R A1 - Peters, Ulrike A1 - Pettaway, Curtis A A1 - Peyser, Patricia A A1 - Psaty, Bruce M A1 - Redline, Susan A1 - Rotimi, Charles N A1 - Rybicki, Benjamin A A1 - Sale, Michèle M A1 - Schreiner, Pamela J A1 - Signorello, Lisa B A1 - Singleton, Andrew B A1 - Stanford, Janet L A1 - Strom, Sara S A1 - Thun, Michael J A1 - Vitolins, Mara A1 - Zheng, Wei A1 - Moore, Jason H A1 - Williams, Scott M A1 - Ketkar, Shamika A1 - Zhu, Xiaofeng A1 - Zonderman, Alan B A1 - Kooperberg, Charles A1 - Papanicolaou, George J A1 - Henderson, Brian E A1 - Reiner, Alex P A1 - Hirschhorn, Joel N A1 - Loos, Ruth J F A1 - North, Kari E A1 - Haiman, Christopher A KW - African Americans KW - Body Mass Index KW - Case-Control Studies KW - Gene Frequency KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Linkage Disequilibrium KW - Obesity KW - Polymorphism, Single Nucleotide AB -

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 × 10(-11)) and another at 7p15 when we included data from the GIANT consortium (MIR148A-NFE2L3, rs10261878, P = 1.2 × 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 × 10(-8)). Thirty-two of the 36 previously established BMI variants showed directionally consistent effect estimates in our GWAS (binomial P = 9.7 × 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.

VL - 45 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23583978?dopt=Abstract ER - TY - JOUR T1 - Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data. JF - BMJ Y1 - 2014 A1 - Holmes, Michael V A1 - Dale, Caroline E A1 - Zuccolo, Luisa A1 - Silverwood, Richard J A1 - Guo, Yiran A1 - Ye, Zheng A1 - Prieto-Merino, David A1 - Dehghan, Abbas A1 - Trompet, Stella A1 - Wong, Andrew A1 - Cavadino, Alana A1 - Drogan, Dagmar A1 - Padmanabhan, Sandosh A1 - Li, Shanshan A1 - Yesupriya, Ajay A1 - Leusink, Maarten A1 - Sundström, Johan A1 - Hubacek, Jaroslav A A1 - Pikhart, Hynek A1 - Swerdlow, Daniel I A1 - Panayiotou, Andrie G A1 - Borinskaya, Svetlana A A1 - Finan, Chris A1 - Shah, Sonia A1 - Kuchenbaecker, Karoline B A1 - Shah, Tina A1 - Engmann, Jorgen A1 - Folkersen, Lasse A1 - Eriksson, Per A1 - Ricceri, Fulvio A1 - Melander, Olle A1 - Sacerdote, Carlotta A1 - Gamble, Dale M A1 - Rayaprolu, Sruti A1 - Ross, Owen A A1 - McLachlan, Stela A1 - Vikhireva, Olga A1 - Sluijs, Ivonne A1 - Scott, Robert A A1 - Adamkova, Vera A1 - Flicker, Leon A1 - Bockxmeer, Frank M van A1 - Power, Christine A1 - Marques-Vidal, Pedro A1 - Meade, Tom A1 - Marmot, Michael G A1 - Ferro, Jose M A1 - Paulos-Pinheiro, Sofia A1 - Humphries, Steve E A1 - Talmud, Philippa J A1 - Mateo Leach, Irene A1 - Verweij, Niek A1 - Linneberg, Allan A1 - Skaaby, Tea A1 - Doevendans, Pieter A A1 - Cramer, Maarten J A1 - van der Harst, Pim A1 - Klungel, Olaf H A1 - Dowling, Nicole F A1 - Dominiczak, Anna F A1 - Kumari, Meena A1 - Nicolaides, Andrew N A1 - Weikert, Cornelia A1 - Boeing, Heiner A1 - Ebrahim, Shah A1 - Gaunt, Tom R A1 - Price, Jackie F A1 - Lannfelt, Lars A1 - Peasey, Anne A1 - Kubinova, Ruzena A1 - Pajak, Andrzej A1 - Malyutina, Sofia A1 - Voevoda, Mikhail I A1 - Tamosiunas, Abdonas A1 - Maitland-van der Zee, Anke H A1 - Norman, Paul E A1 - Hankey, Graeme J A1 - Bergmann, Manuela M A1 - Hofman, Albert A1 - Franco, Oscar H A1 - Cooper, Jackie A1 - Palmen, Jutta A1 - Spiering, Wilko A1 - de Jong, Pim A A1 - Kuh, Diana A1 - Hardy, Rebecca A1 - Uitterlinden, André G A1 - Ikram, M Arfan A1 - Ford, Ian A1 - Hyppönen, Elina A1 - Almeida, Osvaldo P A1 - Wareham, Nicholas J A1 - Khaw, Kay-Tee A1 - Hamsten, Anders A1 - Husemoen, Lise Lotte N A1 - Tjønneland, Anne A1 - Tolstrup, Janne S A1 - Rimm, Eric A1 - Beulens, Joline W J A1 - Verschuren, W M Monique A1 - Onland-Moret, N Charlotte A1 - Hofker, Marten H A1 - Wannamethee, S Goya A1 - Whincup, Peter H A1 - Morris, Richard A1 - Vicente, Astrid M A1 - Watkins, Hugh A1 - Farrall, Martin A1 - Jukema, J Wouter A1 - Meschia, James A1 - Cupples, L Adrienne A1 - Sharp, Stephen J A1 - Fornage, Myriam A1 - Kooperberg, Charles A1 - LaCroix, Andrea Z A1 - Dai, James Y A1 - Lanktree, Matthew B A1 - Siscovick, David S A1 - Jorgenson, Eric A1 - Spring, Bonnie A1 - Coresh, Josef A1 - Li, Yun R A1 - Buxbaum, Sarah G A1 - Schreiner, Pamela J A1 - Ellison, R Curtis A1 - Tsai, Michael Y A1 - Patel, Sanjay R A1 - Redline, Susan A1 - Johnson, Andrew D A1 - Hoogeveen, Ron C A1 - Hakonarson, Hakon A1 - Rotter, Jerome I A1 - Boerwinkle, Eric A1 - de Bakker, Paul I W A1 - Kivimaki, Mika A1 - Asselbergs, Folkert W A1 - Sattar, Naveed A1 - Lawlor, Debbie A A1 - Whittaker, John A1 - Davey Smith, George A1 - Mukamal, Kenneth A1 - Psaty, Bruce M A1 - Wilson, James G A1 - Lange, Leslie A A1 - Hamidovic, Ajna A1 - Hingorani, Aroon D A1 - Nordestgaard, Børge G A1 - Bobak, Martin A1 - Leon, David A A1 - Langenberg, Claudia A1 - Palmer, Tom M A1 - Reiner, Alex P A1 - Keating, Brendan J A1 - Dudbridge, Frank A1 - Casas, Juan P KW - Adult KW - Aged KW - Alcohol Dehydrogenase KW - Alcohol Drinking KW - Biomarkers KW - Coronary Disease KW - Female KW - Genetic Markers KW - Genotype KW - Humans KW - Male KW - Mendelian Randomization Analysis KW - Middle Aged KW - Models, Statistical KW - Polymorphism, Single Nucleotide KW - Stroke AB -

OBJECTIVE: To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease.

DESIGN: Mendelian randomisation meta-analysis of 56 epidemiological studies.

PARTICIPANTS: 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers.

MAIN OUTCOME MEASURES: Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption.

RESULTS: Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2% (-7.8 to -2.4%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to -0.10) kg/m(2)). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)).

CONCLUSIONS: Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health.

VL - 349 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25011450?dopt=Abstract ER - TY - JOUR T1 - Large multiethnic Candidate Gene Study for C-reactive protein levels: identification of a novel association at CD36 in African Americans. JF - Hum Genet Y1 - 2014 A1 - Ellis, Jaclyn A1 - Lange, Ethan M A1 - Li, Jin A1 - Dupuis, Josée A1 - Baumert, Jens A1 - Walston, Jeremy D A1 - Keating, Brendan J A1 - Durda, Peter A1 - Fox, Ervin R A1 - Palmer, Cameron D A1 - Meng, Yan A A1 - Young, Taylor A1 - Farlow, Deborah N A1 - Schnabel, Renate B A1 - Marzi, Carola S A1 - Larkin, Emma A1 - Martin, Lisa W A1 - Bis, Joshua C A1 - Auer, Paul A1 - Ramachandran, Vasan S A1 - Gabriel, Stacey B A1 - Willis, Monte S A1 - Pankow, James S A1 - Papanicolaou, George J A1 - Rotter, Jerome I A1 - Ballantyne, Christie M A1 - Gross, Myron D A1 - Lettre, Guillaume A1 - Wilson, James G A1 - Peters, Ulrike A1 - Koenig, Wolfgang A1 - Tracy, Russell P A1 - Redline, Susan A1 - Reiner, Alex P A1 - Benjamin, Emelia J A1 - Lange, Leslie A KW - Adult KW - African Americans KW - Aged KW - Biomarkers KW - C-Reactive Protein KW - Cardiovascular Diseases KW - CD36 Antigens KW - Female KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genetics, Population KW - Genome-Wide Association Study KW - Humans KW - Meta-Analysis as Topic KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

C-reactive protein (CRP) is a heritable biomarker of systemic inflammation and a predictor of cardiovascular disease (CVD). Large-scale genetic association studies for CRP have largely focused on individuals of European descent. We sought to uncover novel genetic variants for CRP in a multiethnic sample using the ITMAT Broad-CARe (IBC) array, a custom 50,000 SNP gene-centric array having dense coverage of over 2,000 candidate CVD genes. We performed analyses on 7,570 African Americans (AA) from the Candidate gene Association Resource (CARe) study and race-combined meta-analyses that included 29,939 additional individuals of European descent from CARe, the Women's Health Initiative (WHI) and KORA studies. We observed array-wide significance (p < 2.2 × 10(-6)) for four loci in AA, three of which have been reported previously in individuals of European descent (IL6R, p = 2.0 × 10(-6); CRP, p = 4.2 × 10(-71); APOE, p = 1.6 × 10(-6)). The fourth significant locus, CD36 (p = 1.6 × 10(-6)), was observed at a functional variant (rs3211938) that is extremely rare in individuals of European descent. We replicated the CD36 finding (p = 1.8 × 10(-5)) in an independent sample of 8,041 AA women from WHI; a meta-analysis combining the CARe and WHI AA results at rs3211938 reached genome-wide significance (p = 1.5 × 10(-10)). In the race-combined meta-analyses, 13 loci reached significance, including ten (CRP, TOMM40/APOE/APOC1, HNF1A, LEPR, GCKR, IL6R, IL1RN, NLRP3, HNF4A and BAZ1B/BCL7B) previously associated with CRP, and one (ARNTL) previously reported to be nominally associated with CRP. Two novel loci were also detected (RPS6KB1, p = 2.0 × 10(-6); CD36, p = 1.4 × 10(-6)). These results highlight both shared and unique genetic risk factors for CRP in AA compared to populations of European descent.

VL - 133 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24643644?dopt=Abstract ER - TY - JOUR T1 - Gene-centric approach identifies new and known loci for FVIII activity and VWF antigen levels in European Americans and African Americans. JF - Am J Hematol Y1 - 2015 A1 - Tang, Weihong A1 - Cushman, Mary A1 - Green, David A1 - Rich, Stephen S A1 - Lange, Leslie A A1 - Yang, Qiong A1 - Tracy, Russell P A1 - Tofler, Geoffrey H A1 - Basu, Saonli A1 - Wilson, James G A1 - Keating, Brendan J A1 - Weng, Lu-Chen A1 - Taylor, Herman A A1 - Jacobs, David R A1 - Delaney, Joseph A A1 - Palmer, Cameron D A1 - Young, Taylor A1 - Pankow, James S A1 - O'Donnell, Christopher J A1 - Smith, Nicholas L A1 - Reiner, Alexander P A1 - Folsom, Aaron R KW - Adult KW - African Americans KW - Aged KW - European Continental Ancestry Group KW - Factor VIII KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Male KW - Methionine Adenosyltransferase KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Venous Thromboembolism KW - von Willebrand Factor AB -

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, 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 (P51.69 × 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.

VL - 90 IS - 6 ER - TY - JOUR T1 - HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. JF - Lancet Y1 - 2015 A1 - Swerdlow, Daniel I A1 - Preiss, David A1 - Kuchenbaecker, Karoline B A1 - Holmes, Michael V A1 - Engmann, Jorgen E L A1 - Shah, Tina A1 - Sofat, Reecha A1 - Stender, Stefan A1 - Johnson, Paul C D A1 - Scott, Robert A A1 - Leusink, Maarten A1 - Verweij, Niek A1 - Sharp, Stephen J A1 - Guo, Yiran A1 - Giambartolomei, Claudia A1 - Chung, Christina A1 - Peasey, Anne A1 - Amuzu, Antoinette A1 - Li, KaWah A1 - Palmen, Jutta A1 - Howard, Philip A1 - Cooper, Jackie A A1 - Drenos, Fotios A1 - Li, Yun R A1 - Lowe, Gordon A1 - Gallacher, John A1 - Stewart, Marlene C W A1 - Tzoulaki, Ioanna A1 - Buxbaum, Sarah G A1 - van der A, Daphne L A1 - Forouhi, Nita G A1 - Onland-Moret, N Charlotte A1 - van der Schouw, Yvonne T A1 - Schnabel, Renate B A1 - Hubacek, Jaroslav A A1 - Kubinova, Ruzena A1 - Baceviciene, Migle A1 - Tamosiunas, Abdonas A1 - Pajak, Andrzej A1 - Topor-Madry, Roman A1 - Stepaniak, Urszula A1 - Malyutina, Sofia A1 - Baldassarre, Damiano A1 - Sennblad, Bengt A1 - Tremoli, Elena A1 - de Faire, Ulf A1 - Veglia, Fabrizio A1 - Ford, Ian A1 - Jukema, J Wouter A1 - Westendorp, Rudi G J A1 - de Borst, Gert Jan A1 - de Jong, Pim A A1 - Algra, Ale A1 - Spiering, Wilko A1 - Maitland-van der Zee, Anke H A1 - Klungel, Olaf H A1 - de Boer, Anthonius A1 - Doevendans, Pieter A A1 - Eaton, Charles B A1 - Robinson, Jennifer G A1 - Duggan, David A1 - Kjekshus, John A1 - Downs, John R A1 - Gotto, Antonio M A1 - Keech, Anthony C A1 - Marchioli, Roberto A1 - Tognoni, Gianni A1 - Sever, Peter S A1 - Poulter, Neil R A1 - Waters, David D A1 - Pedersen, Terje R A1 - Amarenco, Pierre A1 - Nakamura, Haruo A1 - McMurray, John J V A1 - Lewsey, James D A1 - Chasman, Daniel I A1 - Ridker, Paul M A1 - Maggioni, Aldo P A1 - Tavazzi, Luigi A1 - Ray, Kausik K A1 - Seshasai, Sreenivasa Rao Kondapally A1 - Manson, JoAnn E A1 - Price, Jackie F A1 - Whincup, Peter H A1 - Morris, Richard W A1 - Lawlor, Debbie A A1 - Smith, George Davey A1 - Ben-Shlomo, Yoav A1 - Schreiner, Pamela J A1 - Fornage, Myriam A1 - Siscovick, David S A1 - Cushman, Mary A1 - Kumari, Meena A1 - Wareham, Nick J A1 - Verschuren, W M Monique A1 - Redline, Susan A1 - Patel, Sanjay R A1 - Whittaker, John C A1 - Hamsten, Anders A1 - Delaney, Joseph A A1 - Dale, Caroline A1 - Gaunt, Tom R A1 - Wong, Andrew A1 - Kuh, Diana A1 - Hardy, Rebecca A1 - Kathiresan, Sekar A1 - Castillo, Berta A A1 - van der Harst, Pim A1 - Brunner, Eric J A1 - Tybjaerg-Hansen, Anne A1 - Marmot, Michael G A1 - Krauss, Ronald M A1 - Tsai, Michael A1 - Coresh, Josef A1 - Hoogeveen, Ronald C A1 - Psaty, Bruce M A1 - Lange, Leslie A A1 - Hakonarson, Hakon A1 - Dudbridge, Frank A1 - Humphries, Steve E A1 - Talmud, Philippa J A1 - Kivimaki, Mika A1 - Timpson, Nicholas J A1 - Langenberg, Claudia A1 - Asselbergs, Folkert W A1 - Voevoda, Mikhail A1 - Bobak, Martin A1 - Pikhart, Hynek A1 - Wilson, James G A1 - Reiner, Alex P A1 - Keating, Brendan J A1 - Hingorani, Aroon D A1 - Sattar, Naveed KW - Aged KW - Body Mass Index KW - Body Weight KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Diabetes Mellitus, Type 2 KW - Female KW - Genetic Testing KW - Humans KW - Hydroxymethylglutaryl CoA Reductases KW - Hydroxymethylglutaryl-CoA Reductase Inhibitors KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Randomized Controlled Trials as Topic KW - Risk Factors AB -

BACKGROUND: Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target.

METHODS: We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis.

FINDINGS: Data were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05-0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18-0·43), waist circumference (0·32 cm, 0·16-0·47), plasma insulin concentration (1·62%, 0·53-2·72), and plasma glucose concentration (0·23%, 0·02-0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00-1·05); the rs12916-T allele association was consistent (1·06, 1·03-1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18-1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10-0·38 in all trials; 0·33 kg, 95% CI 0·24-0·42 in placebo or standard care controlled trials and -0·15 kg, 95% CI -0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9-6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06-1·18 in all trials; 1·11, 95% CI 1·03-1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04-1·22 in intensive-dose vs moderate dose trials).

INTERPRETATION: The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition.

FUNDING: The funding sources are cited at the end of the paper.

VL - 385 IS - 9965 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25262344?dopt=Abstract ER - TY - JOUR T1 - Mendelian randomization of blood lipids for coronary heart disease. JF - Eur Heart J Y1 - 2015 A1 - Holmes, Michael V A1 - Asselbergs, Folkert W A1 - Palmer, Tom M A1 - Drenos, Fotios A1 - Lanktree, Matthew B A1 - Nelson, Christopher P A1 - Dale, Caroline E A1 - Padmanabhan, Sandosh A1 - Finan, Chris A1 - Swerdlow, Daniel I A1 - Tragante, Vinicius A1 - van Iperen, Erik P A A1 - Sivapalaratnam, Suthesh A1 - Shah, Sonia A1 - Elbers, Clara C A1 - Shah, Tina A1 - Engmann, Jorgen A1 - Giambartolomei, Claudia A1 - White, Jon A1 - Zabaneh, Delilah A1 - Sofat, Reecha A1 - McLachlan, Stela A1 - Doevendans, Pieter A A1 - Balmforth, Anthony J A1 - Hall, Alistair S A1 - North, Kari E A1 - Almoguera, Berta A1 - Hoogeveen, Ron C A1 - Cushman, Mary A1 - Fornage, Myriam A1 - Patel, Sanjay R A1 - Redline, Susan A1 - Siscovick, David S A1 - Tsai, Michael Y A1 - Karczewski, Konrad J A1 - Hofker, Marten H A1 - Verschuren, W Monique A1 - Bots, Michiel L A1 - van der Schouw, Yvonne T A1 - Melander, Olle A1 - Dominiczak, Anna F A1 - Morris, Richard A1 - Ben-Shlomo, Yoav A1 - Price, Jackie A1 - Kumari, Meena A1 - Baumert, Jens A1 - Peters, Annette A1 - Thorand, Barbara A1 - Koenig, Wolfgang A1 - Gaunt, Tom R A1 - Humphries, Steve E A1 - Clarke, Robert A1 - Watkins, Hugh A1 - Farrall, Martin A1 - Wilson, James G A1 - Rich, Stephen S A1 - de Bakker, Paul I W A1 - Lange, Leslie A A1 - Davey Smith, George A1 - Reiner, Alex P A1 - Talmud, Philippa J A1 - Kivimaki, Mika A1 - Lawlor, Debbie A A1 - Dudbridge, Frank A1 - Samani, Nilesh J A1 - Keating, Brendan J A1 - Hingorani, Aroon D A1 - Casas, Juan P KW - Case-Control Studies KW - Cholesterol, HDL KW - Coronary Artery Disease KW - Female KW - Gene Frequency KW - Genotype KW - Genotyping Techniques KW - Humans KW - Male KW - Mendelian Randomization Analysis KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Risk Assessment KW - Triglycerides AB -

AIMS: To investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization.

METHODS AND RESULTS: We developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a prior meta-analysis (threshold P < 2 × 10(-6)); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P ≤ 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestricted allele score (48 SNPs) was associated with CHD (OR: 0.53; 95% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95% CI: 1.24, 2.11 and 1.61; 95% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95% CI: 0.59, 1.75).

CONCLUSION: The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.

VL - 36 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24474739?dopt=Abstract ER - TY - JOUR T1 - Discovery and replication of SNP-SNP interactions for quantitative lipid traits in over 60,000 individuals. JF - BioData Min Y1 - 2017 A1 - Holzinger, Emily R A1 - Verma, Shefali S A1 - Moore, Carrie B A1 - Hall, Molly A1 - De, Rishika A1 - Gilbert-Diamond, Diane A1 - Lanktree, Matthew B A1 - Pankratz, Nathan A1 - Amuzu, Antoinette A1 - Burt, Amber A1 - Dale, Caroline A1 - Dudek, Scott A1 - Furlong, Clement E A1 - Gaunt, Tom R A1 - Kim, Daniel Seung A1 - Riess, Helene A1 - Sivapalaratnam, Suthesh A1 - Tragante, Vinicius A1 - van Iperen, Erik P A A1 - Brautbar, Ariel A1 - Carrell, David S A1 - Crosslin, David R A1 - Jarvik, Gail P A1 - Kuivaniemi, Helena A1 - Kullo, Iftikhar J A1 - Larson, Eric B A1 - Rasmussen-Torvik, Laura J A1 - Tromp, Gerard A1 - Baumert, Jens A1 - Cruickshanks, Karen J A1 - Farrall, Martin A1 - Hingorani, Aroon D A1 - Hovingh, G K A1 - Kleber, Marcus E A1 - Klein, Barbara E A1 - Klein, Ronald A1 - Koenig, Wolfgang A1 - Lange, Leslie A A1 - Mӓrz, Winfried A1 - North, Kari E A1 - Charlotte Onland-Moret, N A1 - Reiner, Alex P A1 - Talmud, Philippa J A1 - van der Schouw, Yvonne T A1 - Wilson, James G A1 - Kivimaki, Mika A1 - Kumari, Meena A1 - Moore, Jason H A1 - Drenos, Fotios A1 - Asselbergs, Folkert W A1 - Keating, Brendan J A1 - Ritchie, Marylyn D AB -

BACKGROUND: The genetic etiology of human lipid quantitative traits is not fully elucidated, and interactions between variants may play a role. We performed a gene-centric interaction study for four different lipid traits: low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG).

RESULTS: Our analysis consisted of a discovery phase using a merged dataset of five different cohorts (n = 12,853 to n = 16,849 depending on lipid phenotype) and a replication phase with ten independent cohorts totaling up to 36,938 additional samples. Filters are often applied before interaction testing to correct for the burden of testing all pairwise interactions. We used two different filters: 1. A filter that tested only single nucleotide polymorphisms (SNPs) with a main effect of p < 0.001 in a previous association study. 2. A filter that only tested interactions identified by Biofilter 2.0. Pairwise models that reached an interaction significance level of p < 0.001 in the discovery dataset were tested for replication. We identified thirteen SNP-SNP models that were significant in more than one replication cohort after accounting for multiple testing.

CONCLUSIONS: These results may reveal novel insights into the genetic etiology of lipid levels. Furthermore, we developed a pipeline to perform a computationally efficient interaction analysis with multi-cohort replication.

VL - 10 ER - TY - JOUR T1 - Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry. JF - Am J Hum Genet Y1 - 2021 A1 - Graff, Mariaelisa A1 - Justice, Anne E A1 - Young, Kristin L A1 - Marouli, Eirini A1 - Zhang, Xinruo A1 - Fine, Rebecca S A1 - Lim, Elise A1 - Buchanan, Victoria A1 - Rand, Kristin A1 - Feitosa, Mary F A1 - Wojczynski, Mary K A1 - Yanek, Lisa R A1 - Shao, Yaming A1 - Rohde, Rebecca A1 - Adeyemo, Adebowale A A1 - Aldrich, Melinda C A1 - Allison, Matthew A A1 - Ambrosone, Christine B A1 - Ambs, Stefan A1 - Amos, Christopher A1 - Arnett, Donna K A1 - Atwood, Larry A1 - Bandera, Elisa V A1 - Bartz, Traci A1 - Becker, Diane M A1 - Berndt, Sonja I A1 - Bernstein, Leslie A1 - Bielak, Lawrence F A1 - Blot, William J A1 - Bottinger, Erwin P A1 - Bowden, Donald W A1 - Bradfield, Jonathan P A1 - Brody, Jennifer A A1 - Broeckel, Ulrich A1 - Burke, Gregory A1 - Cade, Brian E A1 - Cai, Qiuyin A1 - Caporaso, Neil A1 - Carlson, Chris A1 - Carpten, John A1 - Casey, Graham A1 - Chanock, Stephen J A1 - Chen, Guanjie A1 - Chen, Minhui A1 - Chen, Yii-der I A1 - Chen, Wei-Min A1 - Chesi, Alessandra A1 - Chiang, Charleston W K A1 - Chu, Lisa A1 - Coetzee, Gerry A A1 - Conti, David V A1 - Cooper, Richard S A1 - Cushman, Mary A1 - Demerath, Ellen A1 - Deming, Sandra L A1 - Dimitrov, Latchezar A1 - Ding, Jingzhong A1 - Diver, W Ryan A1 - Duan, Qing A1 - Evans, Michele K A1 - Falusi, Adeyinka G A1 - Faul, Jessica D A1 - Fornage, Myriam A1 - Fox, Caroline A1 - Freedman, Barry I A1 - Garcia, Melissa A1 - Gillanders, Elizabeth M A1 - Goodman, Phyllis A1 - Gottesman, Omri A1 - Grant, Struan F A A1 - Guo, Xiuqing A1 - Hakonarson, Hakon A1 - Haritunians, Talin A1 - Harris, Tamara B A1 - Harris, Curtis C A1 - Henderson, Brian E A1 - Hennis, Anselm A1 - Hernandez, Dena G A1 - Hirschhorn, Joel N A1 - McNeill, Lorna Haughton A1 - Howard, Timothy D A1 - Howard, Barbara A1 - Hsing, Ann W A1 - Hsu, Yu-Han H A1 - Hu, Jennifer J A1 - Huff, Chad D A1 - Huo, Dezheng A1 - Ingles, Sue A A1 - Irvin, Marguerite R A1 - John, Esther M A1 - Johnson, Karen C A1 - Jordan, Joanne M A1 - Kabagambe, Edmond K A1 - Kang, Sun J A1 - Kardia, Sharon L A1 - Keating, Brendan J A1 - Kittles, Rick A A1 - Klein, Eric A A1 - Kolb, Suzanne A1 - Kolonel, Laurence N A1 - Kooperberg, Charles A1 - Kuller, Lewis A1 - Kutlar, Abdullah A1 - Lange, Leslie A1 - Langefeld, Carl D A1 - Le Marchand, Loïc A1 - Leonard, Hampton A1 - Lettre, Guillaume A1 - Levin, Albert M A1 - Li, Yun A1 - Li, Jin A1 - Liu, Yongmei A1 - Liu, Youfang A1 - Liu, Simin A1 - Lohman, Kurt A1 - Lotay, Vaneet A1 - Lu, Yingchang A1 - Maixner, William A1 - Manson, JoAnn E A1 - McKnight, Barbara A1 - Meng, Yan A1 - Monda, Keri L A1 - Monroe, Kris A1 - Moore, Jason H A1 - Mosley, Thomas H A1 - Mudgal, Poorva A1 - Murphy, Adam B A1 - Nadukuru, Rajiv A1 - Nalls, Mike A A1 - Nathanson, Katherine L A1 - Nayak, Uma A1 - N'diaye, Amidou A1 - Nemesure, Barbara A1 - Neslund-Dudas, Christine A1 - Neuhouser, Marian L A1 - Nyante, Sarah A1 - Ochs-Balcom, Heather A1 - Ogundiran, Temidayo O A1 - Ogunniyi, Adesola A1 - Ojengbede, Oladosu A1 - Okut, Hayrettin A1 - Olopade, Olufunmilayo I A1 - Olshan, Andrew A1 - Padhukasahasram, Badri A1 - Palmer, Julie A1 - Palmer, Cameron D A1 - Palmer, Nicholette D A1 - Papanicolaou, George A1 - Patel, Sanjay R A1 - Pettaway, Curtis A A1 - Peyser, Patricia A A1 - Press, Michael F A1 - Rao, D C A1 - Rasmussen-Torvik, Laura J A1 - Redline, Susan A1 - Reiner, Alex P A1 - Rhie, Suhn K A1 - Rodriguez-Gil, Jorge L A1 - Rotimi, Charles N A1 - Rotter, Jerome I A1 - Ruiz-Narvaez, Edward A A1 - Rybicki, Benjamin A A1 - Salako, Babatunde A1 - Sale, Michèle M A1 - Sanderson, Maureen A1 - Schadt, Eric A1 - Schreiner, Pamela J A1 - Schurmann, Claudia A1 - Schwartz, Ann G A1 - Shriner, Daniel A A1 - Signorello, Lisa B A1 - Singleton, Andrew B A1 - Siscovick, David S A1 - Smith, Jennifer A A1 - Smith, Shad A1 - Speliotes, Elizabeth A1 - Spitz, Margaret A1 - Stanford, Janet L A1 - Stevens, Victoria L A1 - Stram, Alex A1 - Strom, Sara S A1 - Sucheston, Lara A1 - Sun, Yan V A1 - Tajuddin, Salman M A1 - Taylor, Herman A1 - Taylor, Kira A1 - Tayo, Bamidele O A1 - Thun, Michael J A1 - Tucker, Margaret A A1 - Vaidya, Dhananjay A1 - Van Den Berg, David J A1 - Vedantam, Sailaja A1 - Vitolins, Mara A1 - Wang, Zhaoming A1 - Ware, Erin B A1 - Wassertheil-Smoller, Sylvia A1 - Weir, David R A1 - Wiencke, John K A1 - Williams, Scott M A1 - Williams, L Keoki A1 - Wilson, James G A1 - Witte, John S A1 - Wrensch, Margaret A1 - Wu, Xifeng A1 - Yao, Jie A1 - Zakai, Neil A1 - Zanetti, Krista A1 - Zemel, Babette S A1 - Zhao, Wei A1 - Zhao, Jing Hua A1 - Zheng, Wei A1 - Zhi, Degui A1 - Zhou, Jie A1 - Zhu, Xiaofeng A1 - Ziegler, Regina G A1 - Zmuda, Joe A1 - Zonderman, Alan B A1 - Psaty, Bruce M A1 - Borecki, Ingrid B A1 - Cupples, L Adrienne A1 - Liu, Ching-Ti A1 - Haiman, Christopher A A1 - Loos, Ruth A1 - Ng, Maggie C Y A1 - North, Kari E AB -

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.

VL - 108 IS - 4 ER -