Published online before print March 21, 2002, doi: 10.1161/01.RES.0000015885.27134.F0
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Submitted on December 6, 2001
Revised on February 8, 2002
Accepted on March 6, 2002
Locus for Elevated Apolipoprotein B Levels on Chromosome 1p31 in Families With Familial Combined Hyperlipidemia
Hooman Allayee *;
From the Departments of Human Genetics (H.A., P.P., R.M.C., R.M., J.I.R., L.P., A.J.L.), Microbiology and Molecular Genetics (K.L.K., A.J.L.), Medicine (K.L.K., J.I.R., A.J.L.), and Pediatrics (R.M.C., J.I.R.) and the Molecular Biology Institute (A.J.L.), University of California, Los Angeles; the Department of Medicine and the Cardiovascular Research Institute Maastricht (C.J.H.v.d.K., T.W.A.d.B.), Academic Hospital, Maastricht, the Netherlands; and the Division of Medical Genetics (J.I.R.), Steven Spielberg Pediatric Research Center and Cedars-Sinai Research Institute, Los Angeles, Calif.
* To whom correspondence should be addressed. E-mail: hallayee{at}ucla.edu.
Familial combined hyperlipidemia (FCH), a common cause of premature coronary artery disease, is genetically complex and poorly understood. Recently, a major locus on chromosome 1q21-23 exhibiting highly significant linkage was identified in Finnish FCH families by use of a parametric analysis. We now report highly significant evidence of linkage (maximum LOD score 3.8, recombination fraction 0) of an important FCH phenotype, elevated apolipoprotein B (apoB) levels, to a distinctly separate locus on chromosome 1p31 in Dutch pedigrees. ApoB is the major protein on very low density and low density lipoproteins, and elevated apoB levels have been used as a surrogate trait for FCH. Additional microsatellite markers in the 1p31 region were genotyped, and evidence of linkage improved (maximum LOD score 4.7) in a multipoint analysis of two markers in the peak region. The leptin receptor gene resides within this locus and is involved in obesity and insulin/glucose homeostasis. However, there was no evidence of an association between leptin receptor and apoB levels, raising the possibility that another gene on this chromosomal region contributes to elevated apoB levels in this Dutch population. This is one of the first loci identified for apoB levels in humans and is the second major locus implicated in the genetic etiology of FCH.
Key words: apolipoprotein B • genetics • hyperlipoproteinemia • coronary artery disease
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