Association of the APOLIPOPROTEIN A1/C3/A4/A5 Gene Cluster With Triglyceride Levels and LDL Particle Size in Familial Combined Hyperlipidemia

Abstract

The APOLIPOPROTEIN ( APO ) A1/C3/A4/A5 gene cluster on chromosome 11 has been hypothesized to be a modifier of plasma triglycerides in FCH. In the present study, we extended previous association analyses of the gene cluster to include APOA5 , a newly discovered member of the cluster. Eight SNPs across the APOA1/C3/A4/A5 gene region were analyzed in 78 FCH probands and their normolipidemic spouses as well as in 27 Dutch FCH families. Of the individual SNPs tested in the case-control panel, the strongest evidence of association was obtained with SNPs in APOA1 ( P =0.001) and APOA5 ( P =0.001). A single haplotype defined by a missense mutation in APOA5 was enriched 3-fold in FCH probands when compared with the normolipidemic spouses ( P =0.001) and a second haplotype was significantly enriched in the spouses ( P =0.001). Family-based tests also indicated significant association of triglyceride levels and LDL particle size with the investigated SNPs of APOC3 and APOA5 . These findings suggest that genetic variation in the APOA1/C3/A4/A5 gene cluster acts as a modifier of plasma triglyceride levels and LDL particle size within FCH families and furthermore indicate that a number of haplotypes may contribute to FCH.