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(Circulation Research. 2004;94:993.)
© 2004 American Heart Association, Inc.

Clinical Research

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

Rebecca Mar, Päivi Pajukanta, Hooman Allayee, Martine Groenendijk, Geesje Dallinga-Thie, Ronald M. Krauss, Janet S. Sinsheimer, Rita M. Cantor, Tjerk W.A. de Bruin, Aldons J. Lusis

From the Departments of Human Genetics (R.M., P.P., H.A., J.S.S., R.M.C., A.J.L.), Microbiology and Molecular Genetics (A.J.L.), Medicine (A.J.L.), and Pediatrics (R.M.C.) and Molecular Biology Institute (A.J.L.), Biostatistics (J.S.S.) and Biomathematics (J.S.S.), University of California, Los Angeles; Department of Vascular Medicine (M.G., G.D.-T.), University Medical Center Utrecht, Utrecht, the Netherlands; Genome Sciences Department (R.M.K.), Lawrence Berkeley National Laboratory, Berkeley, California; and the Department of Medicine and the Cardiovascular Research Institute Maastricht (T.W.A.d.B.), Academic Hospital, Maastricht, the Netherlands.

Correspondence to Rebecca Mar, Department of Human Genetics, 695 Charles Young Dr South, Gonda Genetics Research Center, Room 6524, Los Angeles, CA 90095. E-mail beccamar{at}ucla.edu

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.

Key Words: genetics • coronary artery disease • apolipoproteins

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