Multiple rare alleles contribute to low plasma levels of HDL cholesterol.
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.
Cohen
Jonathan C
JC
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. jonathan.cohen@utsouthwestern.edu
Kiss
Robert S
RS
Pertsemlidis
Alexander
A
Marcel
Yves L
YL
McPherson
Ruth
R
Hobbs
Helen H
HH
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000483:Alleles; D019943:Amino Acid Substitution; D016632:Apolipoprotein A-I / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D044383:Black People / Q000235:genetics; D008076:Cholesterol, HDL / Q000097:blood*; D005260:Female; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D019655:Quantitative Trait, Heritable; D044465:White People / Q000235:genetics
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D007862:Phosphatidylcholine-Sterol O-Acyltransferase