Evidence for a Gene-Gene Interaction: The Association Between the LRP-1 I10701 Polymorphism and Body Mass Index is Modified by an Interaction with ApoE Genotype

Abstract

Introduction The LDL-like receptor protein (LRP) shows high affinity for the ApoE on the surface of chylomicron remnants, resulting in the clearance of triglyceride-rich lipoproteins (TGRL) from the plasma. In animal studies, variations in the LRP-1 and the ensuing disturbances in this clearance are associated with obesity, but no such association has yet been reported in humans. Hypotheses Differences in single nucleotide polymorphisms (SNPs) on the LRP-1 gene will be associated with variation in body mass index (BMI) in humans, and this association will be mediated by polymorphisms on the ApoE gene. Methods BMI, genetic and demographic data, as well as information on alcohol intake and smoking status were included from 1,036 men and women, (mean age(plus or minus)SD = 49(plus or minus)16 y) forming the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study population. Mixed linear models which controlled for age, sex, alcohol intake and smoking, as well as family pedigree and center of data collection were run. BMI (logarithmically transformed) was the outcome variable. Initial models used three polymorphisms on the LRP-1 as predictors, and subsequent models additionally included ApoE genotypes and an interaction term between LRP-1 and ApoE genotypes as predictors of BMI. Results Models that used only LRP-1 genotype as a predictor revealed that individuals who were homozygous for the minor allele for the LRP-1 I10701 SNP (rs715948 ) had BMIs, on average, 1.03 ((plus or minus)SD 0.57 Kg/m2) higher than major allele carriers (P=0.03). In subsequent mixed linear models that included main effects of each LRP-1 SNP and ApoE variations, and an interaction term between the LRP-1 and ApoE genotype, there was a trend interaction between at the I70701 SNP, such that differences in BMI associated with the I10701 SNP disappeared when individuals were carriers of the wild type ({varepsilon}3) ApoE polymorphism (P=0.06). Conclusions This has implications for understanding one pathway to obesity and, given the implicated role of TGRLs in this pathway, which arise from dietary fat ingestion, for the identification of gene-environment interactions that affect BMI. This could lead to targeting individualized interventions aimed at reducing BMI.