Abstract 11045: Genetic Variant R952Q in LRP8 is Associated with Increased Plasma Triglyceride Levels in Patients with Familial and Premature CAD and MI
Background: Our previous genome-wide linkage analysis in the GeneQuest CAD population has identified a novel significant genetic locus for plasma triglyceride (TG) levels on chromosome 1p31-32. We have also reported previously that variant R952Q in the LRP8 is associated with increased risk of familial and premature CAD. Because LRP8 resides within the 1p31-32 TG locus and an increased TG level is a risk factor for CAD, here we tested the hypothesis that LRP8 variant R952Q is also associated with plasma TG levels.
Methods: A total of 358 GeneQuest Caucasian probands with DNA samples available and TG levels measured have been selected for this study. We have also ascertained one other independent population of 134 patients with early-onset CAD/MI (males<45; females<55) (GeneBank) for follow-up replication studies. SNPs in LRP8 were genotyped using the 5′ nuclease allelic discrimination assay with an ABI Prism 7900HT Sequence Detection System. Statistical analysis for association with plasma TG levels was performed using the generalized linear model (GLM) and multivariate logistic regression analysis (MLRA).
Results: Haploview 4.0 detected five haplotype blocks that cover LRP8. Seven TagSNPs that capture all information of LRP8 variants were selected and characterized. The genotypic frequencies of all 7 LRP8 SNPs did not deviate from Hardy-Weinberg equilibrium (P>0.05). Among the 7 SNPs analyzed, only SNP R952Q (rs5174) in LD block 5 of LRP8 was strongly associated with plasma TG levels (P=0.0016) when analyzed using the GLM method, and this finding was replicated in the early-onset Genebank cohort (P=0.0098). The association remained significant when we analyzed the data using the MLRA method (P=0.0265 in GeneQuest probands and P=0.0101 in the early-onset Geneband cohort). When we divided each cohort into two groups based on individual BMI and smoking history, the association was significant in the group with higher BMI (BMI≥25) (P=0.0029) or smoking history (P=0.0004), but not in the group with lower BMI (BMI<25) or without smoking history.
Conclusions: These results suggest that genetic variant R952Q in LRP8 is associated with increased plasma TG levels in patients with familial and premature CAD and MI, overweight and history of smoking.
- © 2011 by American Heart Association, Inc.