Multiple rare alleles contribute to low plasma levels of HDL cholesterol

Jonathan C. Cohen, Robert S. Kiss, Alexander Pertsemlidis, Yves L. Marcel, Ruth McPherson, Helen H. Hobbs

Research output: Contribution to journalArticlepeer-review

908 Scopus citations


Heritable variation in complex traits is generally considered to be conferred by common DNA sequence polymorphisms. We tested whether rare DNA sequence variants collectively contribute to variation in plasma levels of high-density lipoprotein cholesterol (HDL-C). We sequenced three candidate genes (ABCA1, APOA1, and LCAT) that cause Mendelian forms of low HDL-C levels in individuals from a population-based study. Nonsynonymous sequence variants were significantly more common (16% versus 2%) in individuals with low HDL-C (<fifth percentile) than in those with high HDL-C (>95th percentile). Similar findings were obtained in an independent population, and biochemical studies indicated that most sequence variants in the low HDL-C group were functionally important. Thus, rare alleles with major phenotypic effects contribute significantly to low plasma HDL-C levels in the general population.

Original languageEnglish (US)
Pages (from-to)869-872
Number of pages4
Issue number5685
StatePublished - Aug 6 2004
Externally publishedYes

ASJC Scopus subject areas

  • General


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