Coronary Heart Disease, Susceptibility To, 1
Coronary heart disease is a complex multifactorial disorder for which several loci have been identified. CHDS1 represents a locus on chromosome 16pter-p13; CHDS2 (608316), on 2q21.1-q22; CHDS3 (300464), on Xq23-q26; CHDS4 (608318), on 14q32, and CHDS9 (612030) on 8p22. CHDS5 (608901) represents susceptibility associated with single-nucleotide polymorphism (SNP) in the KALRN gene (604605), on 3q13. CHDS6 (614466) is associated with a polymorphism in the promoter region of the MMP3 gene (185250), and CHDS7 (610938) represents susceptibility correlated with a common haplotype in the CD36 gene (173510) and high free fatty acid levels. CHDS8 (611139) is associated with SNP variation on 9p21.
MappingThe prevalences of coronary heart disease (CHD), type II diabetes (NIDDM; 125853), and the metabolic syndrome (605552) in Mauritius are among the highest in the world. Francke et al. (2001) conducted a genomewide scan in 99 independent families of northeastern Indian origin, each containing a proband with onset of CHD before 52 years of age and additional sibs with myocardial infarction or NIDDM. Multipoint linkage analysis revealed a locus for CHD on chromosome 16pter-p13 (lod = 3.06, P = 0.00017), which partially overlapped a high pressure peak.
Associations Pending Confirmation
In a metaanalysis of 7 prospective studies involving a polymorphism (W719R; rs20455) in the KIF6 gene (613919) on chromosome 6p21.2, including 3 prospective studies of individuals without CHD events at baseline and the placebo groups of 4 statin trials, Li et al. (2010) found that the risk ratio was 1.22 (combined p = 1.02 x 10(-6)). The risk estimate for 719R carriers in individual cohorts was not appreciably altered after adjustment for traditional risk factors, suggesting that the W719R polymorphism in KIF6 is a new independent risk factor for CHD. Li et al. (2010) noted that an association between the KIF6 W719R polymorphism and CHD was not observed in the Wellcome Trust Case Control Consortium (2007), but that the negative results might have been due to the fact that the association was not analyzed according to statin use in that study, thus reducing the power of the case-control design if individuals receiving statin therapy were included.
Assimes et al. (2010) genotyped the KIF6 W719R polymorphism in 19 case-control studies of nonfatal coronary artery disease (CAD), involving a total of 17,000 cases and 39,369 controls of European descent as well as a modest number of South Asians, African Americans, Hispanics, East Asians, and admixed cases and controls. None of the 19 studies demonstrated an increased risk of CAD in carriers of the 719R allele compared to noncarriers, and there was also no increase in the risk of CAD among 719R carriers in the subset of Europeans with early onset disease compared to similarly aged controls. Assimes et al. (2010) noted that their study did not explore whether statin use modifies the effect of the 719R allele on risk, but stated that it was unlikely that the null results were due to high prevalence of statin use at the time of event in cases.
Li et al. (2011) analyzed 170 SNPs in the KIF6 region in participants in 3 prospective, double-blind randomized clinical trials evaluating the effect of statin therapy on coronary events and identified 2 intronic SNPs, rs9462535 and rs9471077, that were associated with event reduction from statin therapy (interaction p less than 0.1 in each of the 3 studies). Li et al. (2011) noted that all 3 KIF6 SNPs were in high linkage disequilibrium with each other, and that functional studies were needed to understand the role of KIF6 in the pathogenesis of CHD and differential response to statin therapy.