Published online before print October 9, 2003, doi: 10.1161/01.ATV.0000099881.83261.D4
© 2004 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Linkage and Association Between Distinct Variants of the APOA1/C3/A4/A5 Gene Cluster and Familial Combined Hyperlipidemia
From the Genomic and Molecular Medicine Group (S.E.-V., E.L.J., R.P.N., B.J., H.N.P., J.S., C.C.S.), Medical Research Council Clinical Sciences Centre, Hammersmith Hospital; Department of Cardiovascular Medicine (M.S.), Charing Cross Hospital; and Genetics and Genomics Research Institute (J.S.), Imperial College London; Department of Medicine (D.J.B.), Royal Free and University College Medical School, University College London; and Department of Metabolism and Genetics (D.J.G.), St Bartholomew’s Hospital, London, UK; Human and Molecular Genetics Centre (M.O., B.G.), Medical College of Wisconsin, Milwaukee, Wisc; Genome Sciences Department (E.M.R., L.A.P.), Lawerence Berkeley National Laboratory, Berkeley, Calif; and Joint Genome Institute (E.M.R., L.A.P.), Department of Energy, Walnut Creek, Calif.
Correspondence to Dr Carol C. Shoulders, Genomic & Molecular Medicine Group, MRC Clinical Sciences Centre, Hammersmith Hospital, DuCane Rd, London W12 ONN, or Professor James Scott, Genetics and Genomics Research Institute, Imperial College, London, Armstrong Road, London SW7 2AZ, UK. E-mail carol.shoulders{at}csc.mrc.ac.uk or j.scott@imperial.ac.uk
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, APOA5c.56G and APOC3c.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 APOA5c.56G genotype accounted for 7.3% to 13.8% of the variance in plasma triglyceride levels in probands (P<0.004). The APOC3c.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.
Key Words: apolipoproteins • genes • risk factors • genetics • hyperlipoproteinemia
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