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Science 6 August 2004:
Vol. 305. no. 5685, pp. 869 - 872
DOI: 10.1126/science.1099870
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Reports

Multiple Rare Alleles Contribute to Low Plasma Levels of HDL Cholesterol

Jonathan C. Cohen,1,2,3*{dagger} Robert S. Kiss,5* Alexander Pertsemlidis,1 Yves L. Marcel,5{dagger} Ruth McPherson,5 Helen H. Hobbs1,3,4

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.

1 Donald W. Reynolds Cardiovascular Clinical Research Center and McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
2 Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
3 Department of Internal Medicine and Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
4 Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
5 Lipoprotein and Atherosclerosis Research Group, University of Ottawa Heart Institute, Ottawa, Ontario K7Y4W7, Canada.



* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: jonathan.cohen{at}utsouthwestern.edu (J.C.C.); ymarcel{at}ottawaheart.ca (Y.L.M.)

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Haplotypes produced from rare variants in the promoter and coding regions of angiotensinogen contribute to variation in angiotensinogen levels.
X. Zhu, L. Fejerman, A. Luke, A. Adeyemo, and R. S. Cooper (2005)
Hum. Mol. Genet. 14, 639-643
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Genetic Factors in Type 2 Diabetes: The End of the Beginning?.
S. O'Rahilly, I. Barroso, and N. J. Wareham (2005)
Science 307, 370-373
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Polygenic Inherited Predisposition to Breast Cancer.
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