Multiple Rare Alleles Contribute to Low Plasma Levels of HDL Cholesterol
Abstract
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 highdensity 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.
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Rare nonsynonymous mutations in ABCA1 are more common in patients with extremely low HDL than in those with high HDL.
“Rare nonsynonymous mutations in ABCA1 are more common in patients with extremely low HDL than in those with high HDL (130).”
From Genetic Mapping in Human Disease (2008) · cites this paper as [130]
Early data on rare single-nucleotide and structural variants indicate that similarly large samples will be needed to achieve the levels of statistical significance required to detect rare events in a genome-wide search.
“Moreover, early data on rare single-nucleotide (130, 131) and structural variants (133, 134, 136) indicate that similarly large samples will be needed to achieve the levels of statistical significance required to detect rare events in a genome-wide search.”
From Genetic Mapping in Human Disease (2008) · cites this paper as [130]
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- Authors
- Cohen, J. C., Kiss, R. S., Pertsemlidis, A., Marcel, Y. L., McPherson, R., & Hobbs, H. H.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Cohen, Jonathan C.
- Kiss, Robert S.
- Marcel, Yves L.
- Venue
- Science
- Published
- 2004-08-06
- Volume
- 305
- Issue
- 5685
- Pages
- 869-872
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2015849111
- Cited by
- 1,108
- References
- 14
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 7 · 2023: 15 · 2022: 9 · 2021: 16 · 2020: 13 · 2019: 21 · 2018: 18 · 2017: 29 · 2016: 31 · 2015: 45 · 2014: 57 · 2013: 78 · 2012: 85
- FWCI
- 48.93
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01hl053917-09)
- National Heart, Lung, and Blood Institute (U01HL066880, HL53917, UO1-HL66880)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- low HDL cholesterol, rare alleles, non-synonymous mutations, ABCA1, apolipoprotein A-I, lecithin:cholesterol acyltransferase, genetic variants, plasma lipids, monogenic disorders, functional variants
- MeSH terms
- Adult, Aged, Alleles, Female, Haplotypes, Humans, Phosphatidylcholine-Sterol O-Acyltransferase, Cholesterol, HDL, Male, Middle Aged, Genetic Variation, Apolipoprotein A-I, ATP-Binding Cassette Transporters, Quantitative Trait, Heritable, Amino Acid Substitution, Black People, White People, ATP Binding Cassette Transporter 1
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