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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1935.)
© 2004 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Quantitative Trait Loci for Apolipoprotein B, Cholesterol, and Triglycerides in Familial Combined Hyperlipidemia Pedigrees

Rita M. Cantor; Tjerk de Bruin; Naoko Kono; Susan Napier; Atila van Nas; Hooman Allayee; Aldons J. Lusis

From the Departments of Human Genetics (R.M.C., N.K., S.N., A.v.N., H.A., A.J.L.) and Medicine (A.J.L.), David Geffen School of Medicine at UCLA, Los Angeles, Calif; and the Department of Medicine and Cardiovascular Research Institute (T.B.), Academic Hospital, Maastricht, the Netherlands.

Correspondence to Dr Rita M. Cantor, Department of Human Genetics, David Geffen School of Medicine at UCLA, 695 Charles E. Young Dr. South, Los Angeles, CA 90095-7088. E-mail rcantor{at}mednet.ucla.edu

Objective— Familial combined hyperlipidemia (FCHL) is a genetically complex lipid disorder that is diagnosed in families by combinations of increased cholesterol, triglycerides, and/or apolipoprotein B (apoB) levels in patients and their first-degree relatives. Identifying the predisposing genes promises to reveal the primary risk factors and susceptibility pathways and suggest methods of prevention and treatment. As with most genetically complex disorders, a clinical definition of disease may not be the most useful phenotype for finding the complement of predisposing genes, and the quantitative traits used to define the disorder can provide important information. This is a report of a quantitative trait loci (QTL) analysis of FCHL.

Methods and Results— A full genome scan of 377 multi-allelic markers genotyped at 10 centimorgan (cM) intervals was conducted in 150 sibling pairs from 22 nuclear families in FCHL pedigrees. These data were analyzed by 2 multipoint QTL linkage methods using the nonparametric and Haseman–Elston procedures of the Genehunter software. Using a criterion of P<0.001 by the nonparametric analysis, we found evidence of 2 apoB QTL at 1p21-31 (P<0.000009) and 17p11-q21 (P<0.000009), a total serum cholesterol QTL at 12p13 (P<0.0001), and a serum triglycerides QTL at 4p15-16 (P<0.0002). Using the criterion of P<0.03 for at least 2 traits at the same locus, additional evidence for cholesterol (P<0.01) and a triglycerides P<0.02) was observed at 17p11-21, as well as suggestive evidence for apoB (P<0.02) and triglycerides (P<0.01) at 4q34-35, and cholesterol (P<0.01) and triglycerides (P<0.02) and a binary FCHL trait (lod=1.5) at 16p12-13.

Conclusions— QTL analyses of the traits that define FCHL are effective for localizing disease-predisposing genes.

FCHL QTL were identified at 1p21-31 and 17p11-q21 for apolipoprotein B, 12p13 for total serum cholesterol, and 4p15-16 for serum triglycerides by nonparametric linkage analyses of a full genome scan of 150 sibpairs in 22 familial combined hyperlipidemia sibships. Multiple QTL were observed at 4q34-35, 16p12-13, and 17p11-q21.

Key Words: FCHL • QTL • apolipoprotein B • cholesterol • triglycerides

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