APOE/C1/C4/C2 Gene Cluster Genotypes, Haplotypes and Lipid Levels in Prospective Coronary Heart Disease Risk Among UK Healthy Men
The role of common APOE variants on plasma lipids, particularly low density lipoprotein (LDL) levels, and coronary heart disease (CHD) risk is well known; the influence of variation in the other nearby apolipoprotein genes APOC1, APOC4 and APOC2 is unclear. This study examines the association between APOE/C1/C4/C2gene cluster variation using tagging SNPs and plasma lipid concentration along with risk of CHD in a prospective cohort. Genotypes for 11 common APOE/C1/C4/C2SNPs were determined in 2,767 middle-aged (49 to 64 years) men from the Second Northwick Park Heart Study, with 275 CHD events over a 15-year follow-up period. Seven SNPs showed significant associations with one or more lipid trait in univariate analysis. Multivariate and haplotype analysis showed that the APOE genotypes are most strongly associated with effects on LDL-C and apoB concentration (explaining 3.4% of the LDL-C variance) while the other SNPs in this gene cluster explained an additional 1.2%. Haplotypes in APOC2 and APOC4 were associated with modest effects on HDL-C and apoAI (explaining respectively 1.4% and 1.2%). Carriers of the APOE ε2 SNP had a significantly lower risk of CHD hazard ratio (HR) of 0.63 (95% confidence interval (CI): 0.42–0.95), as did carriers of the APOC2 SNP rs5127 (HR = 0.72, 95% CI: 0.56–0.93), while carriers of APOC1 SNP rs4803770 had higher risk of CHD (HR = 1.36, 95% CI: 1.04–1.78) compared with noncarriers. While the common APOE polymorphism explains the majority of the locus genetic determinants of plasma lipid levels, additional SNPs in the APOC1/C2 region may contribute to CHD risk, but these effects require confirmation.
We acknowledge the contribution of the late Professor George Miller (1939-2006) who was the PI on the NPHSII study. We thank Sarah Leigh for providing bioinformatics support. The British Heart Foundation support FD and SEH (RG2008/008). The NPHSII study was supported by the Medical Research Council, the US National Institutes of Health (NHLBI 33014) and DuPont Pharma. We also thank all the medical staff and patients who contributed to the NPHSII study and the Office for National Statistics (NHS) Central Registry for provision of mortality data.
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