Evidence for a major gene accounting for mild elevation in LDL cholesterol: The NHLBI Family Heart Study

Hilary 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

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


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.

Original languageEnglish
Pages (from-to)401-412
Number of pages12
JournalAnnals of Human Genetics
Issue number5
StatePublished - Sep 1999

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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