Abstract 16602: Genetic Variation in Liver X Receptor Alpha Predicts Risk of Ischemic Vascular Disease in 60,000 Individuals from the General Population
Objectives: Liver × receptor alpha (LXRα) is a nuclear receptor which plays important roles in both lipid metabolism and inflammation. While animal studies indicate that LXRα might influence risk of ischemic vascular disease, corresponding human data are scarce. We hypothesized that genetic variation in LXRαpredicted risk of ischemic vascular disease in the general population.
Methods: We resequenced LXRα in 190 individuals with either extremely low or high plasma levels of HDL cholesterol. Identified genetic variants were genotyped in 10,300 individuals from the general population, the Copenhagen City Heart Study(CCHS), followed for up to 33 years, and the associations with plasma lipid and lipoprotein levels and risk of ischemic vascular disease were determined as a function of genotypes. Positive associations were validated in a cross-sectional study, the Copenhagen General Population Study(CGPS), comprising 51,500 individuals.
Results: In the CCHS, homozygosity (3%) for two promoter variants, −840C>A and −115G>A (in complete linkage disequilibrium), predicted hazard ratios of, respectively, 1.3(95% confidence interval: 1.0-1.7) for ischemic heart disease(IHD), 1.6(1.1-2.2) for myocardial infaction(MI), 1.7(1.2-2.3) for ischemic cerebrovascular disease(ICVD), and 1.9(1.3-2.6) for ischemic stroke(IS) (Figure). Corresponding odds ratios in the CGPS were 1.1(0.9-1.4) for IHD, 1.5(1.1-2.0) for MI, and 1.1(0.9-1.5) for ICVD. In the combined studies (n=61,800), odds ratios were 1.2(1.0-1.4) for IHD, 1.5(1.2-1.9) for MI, and 1.3(1.1-1.6) for ICVD. None of the variants associated with plasma lipid and lipoprotein levels.
Conclusion: This is the first study to suggest that genetic variation in LXRα predicts risk of ischemic vascular disease in the general population. The lack of association with lipid and lipoprotein levels may suggest mediation via inflammatory pathways.
- © 2010 by American Heart Association, Inc.