Abstract 2322: Genetic Risk for Low HDL-cholesterol or High LDL-cholesterol Concentrations
Introduction. A low serum concentration of HDL-cholesterol and a high serum concentration of LDL-cholesterol are risk factors for atherosclerosis. Our goal was to identify genetic variants that confer susceptibility to a low serum concentration of HDL-cholesterol (<1.04 mmol/L) or a high serum concentration of LDL-cholesterol (≥3.64 mmol/L).
Methods. A total of 5213 individuals from two independent populations was examined: Subject panel A comprised 3794 individuals who either visited outpatient clinics of or were admitted to the participating hospitals because of various symptoms or for a health checkup; subject panel B comprised 1419 community-dwelling elderly individuals. The genotypes for 100 polymorphisms of 65 candidate genes were determined. Given the multiple comparisons of genotypes with these conditions, we adopted the criterion of a false discovery rate (FDR) of <0.05 for significant association in initial screening with the chi-square test.
Results. Examination of genotype distributions by the chi-square test and subsequent multivariable logistic regression analysis with adjustment for age and sex revealed that six [−1131T→C, −3A→G, and 553G→T (Gly185Cys) of APOA5; −250G→A and −515C→T of LIPC; 13989A→G (Ile119Val) of CYP3A4] and three [4070C→T (Arg158Cys) and 3932T→C (Cys112Arg) of APOE; 190G→A (Val64Ile) of CCR2] polymorphisms were significantly (FDR < 0.05) associated with low HDL-cholesterol and high LDL-cholesterol, respectively, in subject panel A. To validate these associations, we examined the same polymorphisms in subject panel B. The three polymorphisms of APOA5 and two polymorphisms of APOE were significantly associated with low HDL-cholesterol and high LDL-cholesterol, respectively. The serum concentrations of HDL-cholesterol and LDL-cholesterol differed significantly (P < 0.01, ANOVA) among genotypes of the corresponding polymorphisms in both subject panels. The polymorphisms of APOA5 and APOE were each in linkage disequilibrium.
Conclusions. Polymorphisms of APOA5 and APOE are determinants of low HDL-cholesterol and high LDL-cholesterol, respectively. Genotyping of these polymorphisms may prove informative for prediction of the genetic risk for these conditions.