Linkage and association between distinct variants of the APOA1/C3/A4/A5 gene cluster and familial combined hyperlipidemia

Published in:

Arteriosclerosis Thrombosis and Vascular Biology 24(1) , 167-174 (Jan 2004)

Author(s):

Eichenbaum-Voline, S., Olivier, M., Jones, E. L., Naoumova, R. P., Jones, B., Gau, B., Patel, H. N., Seed, M., Betteridge, D. J., Galton, D. J., Rubin, E. M., Scott, J., Shoulders, C. C., Pennacchio, L. A.

DOI:

Doi 10.1161/01.Atv.0000099881.83261.D4

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.

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