Association of the 9p21.3 Locus With Risk of First-Ever Myocardial Infarction in Pakistanis

Abstract

Objective-To examine variants at the 9p21 locus in a case-control study of acute myocardial infarction (MI) in Pakistanis and to perform an updated meta-analysis of published studies in people of European ancestry. Methods and Results-A total of 1851 patients with first-ever confirmed MI and 1903 controls were genotyped for 89 tagging single-nucleotide polymorphisms at locus 9p21, including the lead variant (rs1333049) identified by the Wellcome Trust Case Control Consortium. Minor allele frequencies and extent of linkage disequilibrium observed in Pakistanis were broadly similar to those seen in Europeans. In the Pakistani study, 6 variants were associated with MI (PϽ10 Ϫ2) in the initial sample set, and in an additional 741 cases and 674 controls in whom further genotyping was performed for these variants. For Pakistanis, the odds ratio for MI was 1.13 (95% CI, 1.05 to 1.22; Pϭ2ϫ10 Ϫ3) for each copy of the C allele at rs1333049. In comparison, a meta-analysis of studies in Europeans yielded an odds ratio of 1.31 (95% CI, 1.26 to 1.37) for the same variant (Pϭ1ϫ10 Key Words: myocardial infarction Ⅲ 9p21 Ⅲ Pakistanis Ⅲ risk factor Ⅲ South Asia Ⅲ meta-analysis V ariants at the 9p21.3 locus have been established as among the strongest common genetic factors associated with the risk of coronary artery disease (CAD) in people of European continental ancestry. [1][2][3][4][5] These variants are in highlinkage disequilibrium (LD) and span a 58-kb region that has multiple neighboring genes (CDKN2A, CDNK2B, and MTAP), without annotating to any single protein sequence. 5 An RNA coding gene, ANRIL, that overlaps with the risk To our knowledge, we report the first large-scale study of variants at the 9p21 locus in relation to risk of acute myocardial infarction (MI) in Pakistanis. This study involved 1851 patients with confirmed diagnoses of first-ever MI and 1903 control subjects from the Pakistan Risk of Myocardial Infarction Study 8 (PROMIS). Genotyping was conducted on 89 tagging single-nucleotide polymorphisms (SNPs) at the 9p21.3 locus, including the lead variant (rs1333049) identified by the Wellcome Trust Case Control Consortium in association with CAD. 1,2 To place our findings in context, we also report a literaturebased meta-analysis of relevant studies, encompassing information on 23 variants at the 9p21 locus in up to 38 250 CAD cases and 84 820 controls. The current meta-analysis substantially updates a previous relevant review, 5 involving data from an additional 82 117 participants and 20 additional variants. Methods Study DesignThis article follows the reporting recommendations of STrengthening the REporting of Genetic Association studies. 9 PROMIS is a casecontrol study of acute first-ever MI in urban Pakistan. 8 Patients with MI experienced the following: (1) symptoms within 24 hours of hospital presentation, (2) typical ECG characteristics (eg, Ն1-mm ST elevation in any Ն2 contiguous limb leads or new-onset left bundle branch block), and (3) a positive troponin test result (Ͼ1 ng/mL). Controls were indi...

Genome-wide association study of coronary artery disease in the Japanese

“…6,9 In addition, the present genome-wide exploration identified significant association near CDKN2A/B in East Asians, as previously reported in European-descent populations. 1,2,5,7,8 Of the three loci, which we claim to be associated with CAD in the Japanese GWA study (Table 2), the disease association at two loci -12q24 and 9p21 -have been reported in several Asian populations 10,11,26 and could be regarded confirmatory. Nevertheless, two novel findings are noted in our study: (1) the other locus within an HLA gene, HLA-DQB1, which is considered to explain the previous descriptions of CAD (in particular, MI) association signals on 6p21 in the Japanese 21 and (2) a pronounced association with MI, as compared with CAD, for the variants on 12q24.…”

The rs10757278 Polymorphism of the 9p21.3 Locus Is Associated with Premature Coronary Artery Disease in Polish Patients

“…Three meta-analyses of the associations of the 9p21.3 locus with CAD and/or MI have been published to date (Lemmens et al, 2009;Palomaki et al, 2010;Saleheen et al, 2010). In two cases, the authors included different SNPs of the 9p21.3 locus tested in the context of CAD/MI, justifying their decision by a high linkage disequilibrium between the individual polymorphisms.…”

“…This fact may slightly underestimate the observed effect. Third, meta-analysis by Saleheen et al (2010), in terms of ethnicity (separate effect for the populations High-risk subgroups (subjects exposed to 5-9 risk factors) of European and Asian origin), was carried out properly and showed results for each of the SNPs individually. The total effect of the rs10757278 G allele on CAD risk for populations of European origin is OR = 1.30 and 95% CI: 1.22-1.39.…”

Recent Studies of the Human Chromosome 9p21 Locus, Which Is Associated With Atherosclerosis in Human Populations

“…[3][4][5][6] The locus has now been replicated in many ethnicities, such as Korean, 14 Japanese, 15 Chinese, 16 Pakistani, 17 and US Hispanic 18 populations. Although the association of 9p21 with CAD risk is consistent among these populations, the haplotype structure of this region and relationship to CAD differs for African blacks.…”