Linkage and Association Between Distinct Variants of the APOA1/C3/A4/A5 Gene Cluster and Familial Combined Hyperlipidemia

Abstract

Objective— Combined hyperlipidemia is a common disorder, characterized by a highly atherogenic lipoprotein profile and a substantially increased risk of coronary heart disease. The purpose of this study was to establish whether variations of apolipoprotein A5 ( APOA5 ), a newly discovered gene of lipid metabolism located 30 kbp downstream of the APOA1/C3/A4 gene cluster, contributes to the transmission of familial combined hyperlipidemia (FCHL). Methods and Results— We performed linkage and association tests on 128 families. Two independent alleles, APOA5 c.56G and APOC3 c.386G , of the APOA1/C3/A4/A5 gene cluster were overtransmitted in FCHL ( P =0.004 and 0.007, respectively). This was paired with reduced transmission of the common APOA1/C3/A4/A5 haplotype (frequency 0.4461) to affected subjects ( P =0.012). The APOA5 c.56G genotype accounted for 7.3% to 13.8% of the variance in plasma triglyceride levels in probands ( P <0.004). The APOC3 c.386G genotypes accounted for 4.4% to 5.1% of the variance in triglyceride levels in FCHL spouses ( P <0.007), suggesting that this allele marks a FCHL quantitative trait as well as representing a susceptibility locus for the condition. Conclusions— A combined linkage and association analysis establishes that variation at the APOA1/C3/A4/A5 gene cluster contributes to FCHL transmission in a substantial proportion of northern European families.