Abstract 20876: Genomewide Analysis Finds a Variant in the KCNC2 Gene Associated With Sex-Dependent Differences in HDL Cholesterol Levels
Background: HDL-cholesterol (HDL-C) levels differ between men and women suggesting sex-specific differences in lipoprotein metabolism. We tested for sex-specific effects of genetic variants with HDL-C in a genomewide association approach.
Methods: We studied 1780 healthy European American individuals (18-84 years, 52% women) from 466 families ascertained from a proband with premature coronary artery disease (<60 years), all genotyped using the Illumina Human 1M chip. Sex-SNP interactions for HDL-C associations were estimated using family-based mixed model analysis adjusting for age, smoking and statin use. Genome-wide significance of the interaction was determined in two stages: (1) a 2-df screening test, testing jointly for the SNP and interaction (significance threshold: p<10−6); (2) a second stage testing for heterogeneity by sex correcting for the significance of the screening test (Bonferroni threshold: 0.05/n where n = number of SNPs passing the screening test).
Results: 12 SNPs passed the screening threshold, of which one passed the second stage (p<0.004): rs7304239 (conditional heterogeneity p = 3.2×10−4, original interaction p = 9.2×10−8) in the KCNC2 gene, which is involved in the reactivity of islet cells in the pancreas. Table 1 presents genotypic distributions for HDL-C by sex for rs7304239.
Conclusion: The minor allele [A] of rs7304239 in intron 2 the KCNC2 gene is associated with low HDL-C in women, but the opposite trend in men. This finding strongly suggests sex specific regulation of lipoprotein pathways involving pancreatic beta cell function.
- © 2010 by American Heart Association, Inc.