Common genetic variation in multiple metabolic pathways influences susceptibility to low HDL-cholesterol and coronary heart disease.
A low level of HDL-C is the most common plasma lipid abnormality observed in men with established coronary heart disease (CHD). To identify allelic variants associated with susceptibility to low HDL-C and CHD, we examined 60 candidate genes with key roles in HDL metabolism, insulin resistance, and inflammation using samples from the Veterans Affairs HDL Intervention Trial (VA-HIT; cases, n = 699) and the Framingham Offspring Study (FOS; controls, n = 705). VA-HIT was designed to examine the benefits of HDL-raising with gemfibrozil in men with low HDL-C (≤40 mg/dl) and established CHD. After adjustment for multiple testing within each gene, single-nucleotide polymorphisms (SNP) significantly associated with case status were identified in the genes encoding LIPC (rs4775065, P < 0.0001); CETP (rs5882, P = 0.0002); RXRA (rs11185660, P = 0.0021); ABCA1 (rs2249891, P = 0.0126); ABCC6 (rs150468, P = 0.0206; rs212077, P = 0.0443); CUBN (rs7893395, P = 0.0246); APOA2 (rs3813627, P = 0.0324); SELP (rs732314, P = 0.0376); and APOC4 (rs10413089, P = 0.0425). Included among the novel findings of this study are the identification of susceptibility alleles for low HDL-C/CHD risk in the genes encoding CUBN and RXRA, and the observation that genetic variation in SELP may influence CHD risk through its effects on HDL.
Peloso
Gina M
GM
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
Demissie
Serkalem
S
Collins
Dorothea
D
Mirel
Daniel B
DB
Gabriel
Stacey B
SB
Cupples
L Adrienne
LA
Robins
Sander J
SJ
Schaefer
Ernst J
EJ
Brousseau
Margaret E
ME
D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D008076:Cholesterol, HDL / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D003327:Coronary Disease / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015248:Gemfibrozil / Q000494:pharmacology; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007333:Insulin Resistance; D008297:Male; D053858:Metabolic Networks and Pathways; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D044469:Racial Groups / Q000235:genetics*; D014481:United States; D014493:United States Department of Veterans Affairs; D044465:White People / Q000235:genetics
D008076:Cholesterol, HDL; D000960:Hypolipidemic Agents; D015248:Gemfibrozil