Chromosome 9p21 haplotypes and prognosis in white and black patients with coronary artery disease

Yan Gong, Amber L Beitelshees, Rhonda M Cooper-DeHoff, Maximilian T Lobmeyer, Taimour Y Langaee, Jun Wu, Sharon Cresci, Michael A Province, John A Spertus, Carl J Pepine, Julie A Johnson, Yan Gong, Amber L Beitelshees, Rhonda M Cooper-DeHoff, Maximilian T Lobmeyer, Taimour Y Langaee, Jun Wu, Sharon Cresci, Michael A Province, John A Spertus, Carl J Pepine, Julie A Johnson

Abstract

Background: Although numerous single-nucleotide polymorphisms (SNPs) in chromosome 9p21 have been associated with coronary artery disease (CAD) and incident myocardial infarction (MI) in whites, there are limited and conflicting reports on the association of this locus with prognosis in whites with existing CAD and no reports in blacks or Hispanics. We investigated the hypothesis that 9p21 polymorphisms are associated with increased risk for adverse cardiovascular outcomes in patients with documented CAD.

Methods and results: We studied the association of 155 chromosome 9p21 SNPs with adverse outcomes among hypertension patients with CAD of multiple races/ethnicities in INVEST-GENES (the International Verapamil SR Trandolapril Study Genetic Substudy) (n=1460 and n=5979 for 2 SNPs) with replication testing of 4 SNPs in the INFORM (Investigation of Outcomes From Acute Coronary Syndrome) study (n=714) of patients with acute coronary syndromes. In INVEST, the haplotype comprising the risk allele for the widely reported 9p21 SNPs was associated with better prognosis in whites (odds ratio [OR], 0.72; 95% CI, 0.57 to 0.92; P=0.0085) but not in blacks (OR, 1.21; 95% CI, 0.68 to 1.24; P=0.52) or Hispanics (OR, 0.96; 95% CI, 0.65 to 1.44; P=0.86). A less commonly reported linkage disequilibrium block was associated with worse prognosis in INVEST in both whites (OR, 1.52; 95% CI, 1.20 to 1.93; P=0.0006) and blacks (OR, 4.11; 95% CI, 1.55 to 10.88; P=0.004).

Conclusions: Our findings suggest that previously reported chromosome 9p21 SNPs, which predict incident CAD, are not associated with higher risk for adverse outcomes in patients with established CAD. The less commonly reported linkage disequilibrium block warrants further investigation. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00133692.

Figures

Figure 1
Figure 1
LD (r2) of significant chromosome 9p21 SNPs on the Illumina CVD SNP array in Caucasian (A), African Americans (B) and Hispanics (C).
Figure 1
Figure 1
LD (r2) of significant chromosome 9p21 SNPs on the Illumina CVD SNP array in Caucasian (A), African Americans (B) and Hispanics (C).
Figure 1
Figure 1
LD (r2) of significant chromosome 9p21 SNPs on the Illumina CVD SNP array in Caucasian (A), African Americans (B) and Hispanics (C).
Figure 2
Figure 2
Haplotype analyses of the 2 LD blocks in 9p21 region in Caucasians, African Americans and Hispanics. (highlighted in gray are the major alleles in each population). A. Block 1: less commonly reported haplotype block B. Block 2: the haplotype block containing the 6 most widely reported SNPs
Figure 2
Figure 2
Haplotype analyses of the 2 LD blocks in 9p21 region in Caucasians, African Americans and Hispanics. (highlighted in gray are the major alleles in each population). A. Block 1: less commonly reported haplotype block B. Block 2: the haplotype block containing the 6 most widely reported SNPs

Source: PubMed

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