© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Replication of Linkage of Familial Combined Hyperlipidemia to Chromosome 1q With Additional Heterogeneous Effect of Apolipoprotein A-I/C-III/A-IV Locus
The NHLBI Family Heart Study
From the Department of Psychiatry (H.C.), Cardiovascular Genetics (S.C.H.), Department of Internal Medicine, and the Department of Human Genetics (M.F.L.), University of Utah, Salt Lake City; the Section of Preventive Medicine and Epidemiology (R.H.M., L.D.), Evans Department of Medicine, Boston University School of Medicine, Boston, Mass; the Division of Biostatistics (I.B.B., M.A.P.), Washington University, St. Louis, Mo; and the Division of Epidemiology (D.K.A.), School of Public Health, University of Minnesota, Minneapolis.
Correspondence to Hilary Coon, Department of Psychiatry, University of Utah, Red Butte Health Center, Suite 2201, 546 Chipeta Way, Box 896, Salt Lake City, UT 84108-1241. E-mail hilary{at}wilbur.med.utah.edu
Abstract—Familial combined hyperlipidemia (FCHL), the most common familial dyslipidemia, is implicated in up to 20% of cases of premature coronary heart disease. Although underlying mutations for FCHL have yet to be identified, several candidate genes/regions have been identified. A positive linkage to chromosome 1q markers has been reported, with the highest lod score of 5.93 occurring at a location between D1S104 and D1S1677. Using the same diagnostic criteria, the Family Heart Study (FHS) has defined 71 FCHL families, comprising 170 cases, for a total of 137 possible affected sibling pairs. The FCHL criteria require elevation in serum low density lipoprotein cholesterol and triglyceride levels within the family, with at least 2 affected first-degree relatives. Markers D1S104 and D1S1677 were typed, and significant allele sharing was found in FCHL sibships (multipoint lod score with use of the model from the Finnish study was 2.52, and multipoint nonparametric score was 2.48; P=0.007), replicating linkage in this chromosome 1 region. In addition, previously reported linkage of FCHL to apolipoprotein A-I/C-III/A-IV has been investigated in FHS families. FHS results revealed positive but nonsignificant allele sharing among FCHL sibships with apolipoprotein A-I/C-III/A-IV by use of marker D11S4127 (nonparametric linkage score 1.11, P=0.13). Two-locus analyses of D1S104 and D11S4127 suggested possible heterogeneity rather than epistasis, with a maximum 2-locus lod score of 3.05. A nonparametric 2-locus analysis revealed significant improvement in the 2-locus versus single-locus scores. Finally, no linkage was found with markers near the lipoprotein lipase gene region.
Key Words: genetic linkage • coronary disease • hyperlipidemia
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