Multiple rare alleles contribute to low plasma levels of HDL cholesterol

• Published in: Science (American Association for the Advancement of Science) 2004-08, Vol.305 (5685), p.869-872
• Main Authors: Cohen, J.C, Kiss, R.S, Pertsemlidis, A, Marcel, Y.L, McPherson, R, Hobbs, H.H
• Format: Article
• Language: English
• Subjects: Adult; African Continental Ancestry Group - genetics; Aged; Alleles; Amino Acid Substitution; Amino acids; Apolipoprotein A-I - chemistry; Apolipoprotein A-I - genetics; Apolipoprotein A-I - metabolism; Atherosclerosis; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters - chemistry; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Biological and medical sciences; blood lipids; Cholesterol; Cholesterol, HDL; Cholesterol, HDL - blood; Cholesterols; Classical genetics, quantitative genetics, hybrids; Coding; Deoxyribonucleic acid; DNA; DNA damage; European Continental Ancestry Group - genetics; Female; Fundamental and applied biological sciences. Psychology; Genes; Genetic aspects; Genetic mutation; Genetic Variation; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genotype & phenotype; Haplotypes; HDL cholesterol; HDL lipoproteins; high density lipoprotein; Human; human genetics; human physiology; Humans; Male; Middle Aged; nonsynonymous sequence variation; nucleotide sequences; Phenotypic traits; Phosphatidylcholine-Sterol O-Acyltransferase - chemistry; Phosphatidylcholine-Sterol O-Acyltransferase - genetics; Phosphatidylcholine-Sterol O-Acyltransferase - metabolism; Physiological aspects; Plasma; Polymorphism; Quantitative Trait, Heritable; Quantitative traits; Racial Composition; Risk factors; White people
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1099870

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 (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.