Evidence for a major gene accounting for mild elevation in LDL cholesterol: The NHLBI Family Heart Study |
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| Authors: | H. COON M. F. LEPPERT F. KRONENBERG M. A. PROVINCE R. H. MYERS D. K. ARNETT J. H. ECKFELDT G. HEISS R. R. WILLIAMS S. C. HUNT |
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| Affiliation: | Department of Psychiatry, University of Utah, Salt Lake City, UT 84108;Department of Human Genetics, University of Utah, Salt Lake City, UT;Cardiovascular Genetics, Department of Internal Medicine, University of Utah, Salt Lake City, UT;Division of Biostatistics, Washington University, St. Louis, MO;Section of Preventive Medicine and Epidemiology, Boston University, Framingham, MA;Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis, MN;Department of Laboratory Medicine and Pathology, Medical School, University of Minnesota, Minneapolis, MN;Department of Epidemiology, University of North Carolina, Chapel Hill, NC |
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| Abstract: | Studies of rare Mendelian disorders of low density lipoprotein cholesterol (LDL-C) metabolism have identified specific genetic mutations in the LDL receptor and apolipoprotein B. Although these rare mutations account for a small proportion of LDL-C variation, twin and adoption studies indicate that at least 50% of the overall LDL-C observed variation is genetically determined. In a heterogeneous sample of 3227 subjects from the NHLBI Family Heart Study collected from four US centres, we find evidence for a common major gene accounting for mild elevations (1.25 standard deviations) in LDL-C. The analysis favored a recessive model with a frequency of 0.52 for the gene influencing elevated LDL-C, phenotypic means of 113 mg/dl for the normal genotypes and 146 mg/dl for the abnormal genotype, and a significant polygenic heritability. This statistically-inferred major gene accounted for 24% of the variation in LDL-C, with polygenes accounting for another 28% of the variation. Using parameters for major gene transmission estimated in the segregation analysis, LDL-C showed no linkage to the LDL receptor gene ( LDLR ), nor to the apolipoprotein E gene ( APOE ), nor to the cholesterol 7α-hydroxylase gene ( CYP7A1 ), indicating the major gene effect influencing mild elevation in LDL-C is not explained by any of these candidate loci. |
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