%0 Journal Article %J Nat Genet %D 2017 %T Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms. %A Howson, Joanna M M %A Zhao, Wei %A Barnes, Daniel R %A Ho, Weang-Kee %A Young, Robin %A Paul, Dirk S %A Waite, Lindsay L %A Freitag, Daniel F %A Fauman, Eric B %A Salfati, Elias L %A Sun, Benjamin B %A Eicher, John D %A Johnson, Andrew D %A Sheu, Wayne H H %A Nielsen, Sune F %A Lin, Wei-Yu %A Surendran, Praveen %A Mälarstig, Anders %A Wilk, Jemma B %A Tybjærg-Hansen, Anne %A Rasmussen, Katrine L %A Kamstrup, Pia R %A Deloukas, Panos %A Erdmann, Jeanette %A Kathiresan, Sekar %A Samani, Nilesh J %A Schunkert, Heribert %A Watkins, Hugh %A Do, Ron %A Rader, Daniel J %A Johnson, Julie A %A Hazen, Stanley L %A Quyyumi, Arshed A %A Spertus, John A %A Pepine, Carl J %A Franceschini, Nora %A Justice, Anne %A Reiner, Alex P %A Buyske, Steven %A Hindorff, Lucia A %A Carty, Cara L %A North, Kari E %A Kooperberg, Charles %A Boerwinkle, Eric %A Young, Kristin %A Graff, Mariaelisa %A Peters, Ulrike %A Absher, Devin %A Hsiung, Chao A %A Lee, Wen-Jane %A Taylor, Kent D %A Chen, Ying-Hsiang %A Lee, I-Te %A Guo, Xiuqing %A Chung, Ren-Hua %A Hung, Yi-Jen %A Rotter, Jerome I %A Juang, Jyh-Ming J %A Quertermous, Thomas %A Wang, Tzung-Dau %A Rasheed, Asif %A Frossard, Philippe %A Alam, Dewan S %A Majumder, Abdulla Al Shafi %A Di Angelantonio, Emanuele %A Chowdhury, Rajiv %A Chen, Yii-Der Ida %A Nordestgaard, Børge G %A Assimes, Themistocles L %A Danesh, John %A Butterworth, Adam S %A Saleheen, Danish %K Arteries %K Atherosclerosis %K Cell Adhesion %K Chemotaxis, Leukocyte %K Coronary Artery Disease %K Energy Metabolism %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Histone Code %K Humans %K Male %K Muscle, Smooth, Vascular %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Risk Factors %X

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10, in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms.

%B Nat Genet %V 49 %P 1113-1119 %8 2017 Jul %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/28530674?dopt=Abstract %R 10.1038/ng.3874 %0 Journal Article %J PLoS One %D 2014 %T Prospective associations of coronary heart disease loci in African Americans using the MetaboChip: the PAGE study. %A Franceschini, Nora %A Hu, Yijuan %A Reiner, Alex P %A Buyske, Steven %A Nalls, Mike %A Yanek, Lisa R %A Li, Yun %A Hindorff, Lucia A %A Cole, Shelley A %A Howard, Barbara V %A Stafford, Jeanette M %A Carty, Cara L %A Sethupathy, Praveen %A Martin, Lisa W %A Lin, Dan-Yu %A Johnson, Karen C %A Becker, Lewis C %A North, Kari E %A Dehghan, Abbas %A Bis, Joshua C %A Liu, Yongmei %A Greenland, Philip %A Manson, JoAnn E %A Maeda, Nobuyo %A Garcia, Melissa %A Harris, Tamara B %A Becker, Diane M %A O'Donnell, Christopher %A Heiss, Gerardo %A Kooperberg, Charles %A Boerwinkle, Eric %K Adaptor Proteins, Vesicular Transport %K Black or African American %K Coronary Disease %K Female %K Genetic Association Studies %K Genetic Predisposition to Disease %K Humans %K Male %K Oligonucleotide Array Sequence Analysis %K Polymorphism, Single Nucleotide %K Prospective Studies %K Proto-Oncogene Proteins c-myc %X

BACKGROUND: Coronary heart disease (CHD) is a leading cause of morbidity and mortality in African Americans. However, there is a paucity of studies assessing genetic determinants of CHD in African Americans. We examined the association of published variants in CHD loci with incident CHD, attempted to fine map these loci, and characterize novel variants influencing CHD risk in African Americans.

METHODS AND RESULTS: Up to 8,201 African Americans (including 546 first CHD events) were genotyped using the MetaboChip array in the Atherosclerosis Risk in Communities (ARIC) study and Women's Health Initiative (WHI). We tested associations using Cox proportional hazard models in sex- and study-stratified analyses and combined results using meta-analysis. Among 44 validated CHD loci available in the array, we replicated and fine-mapped the SORT1 locus, and showed same direction of effects as reported in studies of individuals of European ancestry for SNPs in 22 additional published loci. We also identified a SNP achieving array wide significance (MYC: rs2070583, allele frequency 0.02, P = 8.1 × 10(-8)), but the association did not replicate in an additional 8,059 African Americans (577 events) from the WHI, HealthABC and GeneSTAR studies, and in a meta-analysis of 5 cohort studies of European ancestry (24,024 individuals including 1,570 cases of MI and 2,406 cases of CHD) from the CHARGE Consortium.

CONCLUSIONS: Our findings suggest that some CHD loci previously identified in individuals of European ancestry may be relevant to incident CHD in African Americans.

%B PLoS One %V 9 %P e113203 %8 2014 %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/25542012?dopt=Abstract %R 10.1371/journal.pone.0113203