on October 9, 2003
Published online before print October 9, 2003, doi: 10.1161/01.ATV.0000099881.83261.D4
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Submitted on August 20, 2003
Accepted on September 12, 2003
Linkage and Association Between Distinct Variants of the APOA1/C3/A4/A5 Gene Cluster and Familial Combined Hyperlipidemia
Sophie Eichenbaum-Voline ;
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.
* To whom correspondence should be addressed. E-mail: carol.shoulders{at}csc.mrc.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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