Association between the chromosome 9p21 locus and angiographic coronary artery disease burden: a collaborative meta-analysis.
Chan K., Patel RS., Newcombe P., Nelson CP., Qasim A., Epstein SE., Burnett S., Vaccarino VL., Zafari AM., Shah SH., Anderson JL., Carlquist JF., Hartiala J., Allayee H., Hinohara K., Lee B-S., Erl A., Ellis KL., Goel A., Schaefer AS., El Mokhtari NE., Goldstein BA., Hlatky MA., Go AS., Shen G-Q., Gong Y., Pepine C., Laxton RC., Whittaker JC., Tang WHW., Johnson JA., Wang QK., Assimes TL., Nöthlings U., Farrall M., Watkins H., Richards AM., Cameron VA., Muendlein A., Drexel H., Koch W., Park JE., Kimura A., Shen W-F., Simpson IA., Hazen SL., Horne BD., Hauser ER., Quyyumi AA., Reilly MP., Samani NJ., Ye S.
OBJECTIVES: This study sought to ascertain the relationship of 9p21 locus with: 1) angiographic coronary artery disease (CAD) burden; and 2) myocardial infarction (MI) in individuals with underlying CAD. BACKGROUND: Chromosome 9p21 variants have been robustly associated with coronary heart disease, but questions remain on the mechanism of risk, specifically whether the locus contributes to coronary atheroma burden or plaque instability. METHODS: We established a collaboration of 21 studies consisting of 33,673 subjects with information on both CAD (clinical or angiographic) and MI status along with 9p21 genotype. Tabular data are provided for each cohort on the presence and burden of angiographic CAD, MI cases with underlying CAD, and the diabetic status of all subjects. RESULTS: We first confirmed an association between 9p21 and CAD with angiographically defined cases and control subjects (pooled odds ratio [OR]: 1.31, 95% confidence interval [CI]: 1.20 to 1.43). Among subjects with angiographic CAD (n = 20,987), random-effects model identified an association with multivessel CAD, compared with those with single-vessel disease (OR: 1.10, 95% CI: 1.04 to 1.17)/copy of risk allele). Genotypic models showed an OR of 1.15, 95% CI: 1.04 to 1.26 for heterozygous carrier and OR: 1.23, 95% CI: 1.08 to 1.39 for homozygous carrier. Finally, there was no significant association between 9p21 and prevalent MI when both cases (n = 17,791) and control subjects (n = 15,882) had underlying CAD (OR: 0.99, 95% CI: 0.95 to 1.03)/risk allele. CONCLUSIONS: The 9p21 locus shows convincing association with greater burden of CAD but not with MI in the presence of underlying CAD. This adds further weight to the hypothesis that 9p21 locus primarily mediates an atherosclerotic phenotype.