DOI: 10.1126/science.1099870. Multiple Rare Alleles Contribute to Low Plasma Levels of HDL Cholesterol

Multiple Rare Alleles Contribute to Low Plasma Levels of HDL Cholesterol

10.1126/science.1099870

Crossref journal-article

American Association for the Advancement of Science (AAAS)

Science (221)

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.

Bibliography

Cohen, J. C., Kiss, R. S., Pertsemlidis, A., Marcel, Y. L., McPherson, R., & Hobbs, H. H. (2004). Multiple Rare Alleles Contribute to Low Plasma Levels of HDL Cholesterol. Science, 305(5685), 869â872.

Authors 6

Jonathan C. Cohen (first)
Robert S. Kiss (additional)
Alexander Pertsemlidis (additional)
Yves L. Marcel (additional)
Ruth McPherson (additional)
Helen H. Hobbs (additional)

References 20 Referenced 860

10.1038/ng1071
10.1086/321272
10.1016/S0168-9525(01)02410-6
G. Assmann, A. von Eckardstein, H. Funke, Circulation87, III28 (1993). / Circulation (1993)
M. R. Haydenet al., Curr. Opin. Lipidol.11, 117 (2000). (10.1097/00041433-200004000-00003) / Curr. Opin. Lipidol. (2000)
J. A. Kuivenhovenet al., J. Lipid Res.38, 191 (1997). (10.1016/S0022-2275(20)37433-2) / J. Lipid Res. (1997)
G. K. Hovinghet al., J. Lipid Res.44, 1251 (2003). (10.1194/jlr.M300080-JLR200) / J. Lipid Res. (2003)
S. Mottet al., Atherosclerosis152, 457 (2000). (10.1016/S0021-9150(99)00498-0) / Atherosclerosis (2000)
10.1016/j.amjcard.2004.02.058
R. R. Singaraja, L. R. Brunham, H. Visscher, J. J. Kastelein, M. R. Hayden, Arterioscler. Thromb. Vasc. Biol.23, 1322 (2003). (10.1161/01.ATV.0000078520.89539.77) / Arterioscler. Thromb. Vasc. Biol. (2003)
Information about this program is available at www.bork.embl-heidelberg.de/PolyPhen/.
S. Sunyaevet al., Hum. Mol. Genet.10, 591 (2001). (10.1093/hmg/10.6.591) / Hum. Mol. Genet. (2001)
V. Ramensky, P. Bork, S. Sunyaev, Nucleic Acids Res.30, 3894 (2002). (10.1093/nar/gkf493) / Nucleic Acids Res. (2002)
J. C. Cohen H. H. Hobbs unpublished observation.
L. A. Pennacchioet al., Hum. Mol. Genet.11, 3031 (2002). (10.1093/hmg/11.24.3031) / Hum. Mol. Genet. (2002)
D. A. Tregouetet al., Arterioscler. Thromb. Vasc. Biol.24, 775 (2004). (10.1161/01.ATV.0000121573.29550.1a) / Arterioscler. Thromb. Vasc. Biol. (2004)
Details of each sequence variant are provided at http://pga.swmed.edu.
Single-letter abbreviations for the amino acid residues are as follows: A Ala; C Cys; D Asp; E Glu; F Phe; G Gly; H His; I Ile; K Lys; L Leu; M Met; N Asn; P Pro; Q Gln; R Arg; S Ser; T Thr; V Val; W Trp; and Y Tyr.
A detailed explanation of PolyPhen scoring criteria is available at http://tux.embl-heidelberg.de/ramensky/doc/pph_help.html.
We thank R. Wilson S. Niu and J. Horton for DNA sequencing; J. Schageman N. Prikhodko and A. Patel for analysis of the sequence data; and M. Brown J. Goldstein and S. Sunyaev for helpful discussions. This study was supported by grants from NIH (HL53917) National Heart Lung and Blood Institute Program for Genomic Applications (UO1-HL66880) Fondation Le Ducq Heart and Stroke Foundation of Canada and Canadian Institutes of Health Research (64519 CIHR-RD and DOP-51714).

Dates

Type	When
Created	21 years ago (Aug. 5, 2004, 4:18 p.m.)
Deposited	1 year, 7 months ago (Jan. 9, 2024, 9:09 p.m.)
Indexed	1 day, 20 hours ago (Aug. 30, 2025, 12:19 p.m.)
Issued	21 years ago (Aug. 6, 2004)
Published	21 years ago (Aug. 6, 2004)
Published Print	21 years ago (Aug. 6, 2004)

Funders 0

None

BibTeX

@article{Cohen_2004, title={Multiple Rare Alleles Contribute to Low Plasma Levels of HDL Cholesterol}, volume={305}, ISSN={1095-9203}, url={http://dx.doi.org/10.1126/science.1099870}, DOI={10.1126/science.1099870}, number={5685}, journal={Science}, publisher={American Association for the Advancement of Science (AAAS)}, author={Cohen, Jonathan C. and Kiss, Robert S. and Pertsemlidis, Alexander and Marcel, Yves L. and McPherson, Ruth and Hobbs, Helen H.}, year={2004}, month=aug, pages={869–872} }

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  "abstract": "<jats:p>\n            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 (\n            <jats:italic>ABCA1, APOA1</jats:italic>\n            , and\n            <jats:italic>LCAT</jats:italic>\n            ) 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 (&lt;fifth percentile) than in those with high HDL-C (&gt;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.\n          </jats:p>",
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