Comprehensive Analysis of Established Dyslipidemia-Associated Loci in the Diabetes Prevention Program

Abstract

Background We assessed whether 234 established dyslipidemia-associated loci modify the effects of metformin treatment and lifestyle intervention (vs. placebo control) on lipid and lipid sub-fraction levels in the Diabetes Prevention Program (DPP) randomized controlled trial. Methods and Results We tested gene-treatment interactions in relation to baseline adjusted follow-up blood lipid concentrations (high and low density lipoprotein cholesterol [HDL-C, LDL-C], total cholesterol, triglycerides) and lipoprotein sub-fraction particle concentrations and size in 2,993 participants with pre-diabetes. Of the previously reported SNP associations, 32.5% replicated at P<0.05 with baseline lipid traits. Trait-specific genetic risk scores (GRS) were robustly associated (3×10−4>P>1.1×10−16) with their respective baseline traits for all but two traits. Lifestyle modified the effect of the GRS for large HDL particle numbers, such that each risk allele of the GRSHDL-large was associated with lower concentrations of large HDL particles at follow-up in the lifestyle arm (β=−0.11 μmol/l per GRS risk allele; 95%CI −0.188, −0.033; P=5×10−3; Pinteraction=1×10−3 for lifestyle vs. placebo), but not in the metformin or placebo arms (P>0.05). In the lifestyle arm, participants with high genetic risk had more favorable or similar trait levels at 1-yr compared to participants at lower genetic risk at baseline for 17 of the 20 traits. Conclusions Improvements in large HDL particle concentrations conferred by lifestyle may be diminished by genetic factors. Lifestyle intervention, however, was successful in offsetting unfavorable genetic loading for most lipid traits.

Diabetes and dyslipidemia: characterizing lipoprotein metabolism

“…It has recently been shown that lifestyle intervention can offset unfavorable genetic loading for most lipid traits, including the size of HDL. 133 The understanding of functionality of HDL may become clearer following the description of the use of atomic force microscopy to examine the organization of apoA1. 134 …”

Interaction of diabetes genetic risk and successful lifestyle modification in the Diabetes Prevention Programme

“…Genetic risk for diabetes was estimated as an additive GRS using 67 SNPs previously found to be associated with type 2 diabetes at genome‐wide significance in genome‐wide association studies (GWAS) 7 . Genotyping in the DPP has been described previously, and details are provided in the Online Supplementary Material 11,16,17 . If the index SNP reported in GWAS was not available, a proxy in strong linkage disequilibrium was selected (r 2 > 0.8).…”

“…7 Genotyping in the DPP has been described previously, and details are provided in the Online Supplementary Material. 11,16,17 Table S3). We examined the GRS as a continuous variable, such that associations with incident diabetes reflected the average effect per risk allele, and categorized into tertiles, with the first tertile representing the lowest genetic risk of diabetes and the third tertile representing the highest genetic risk of diabetes.…”

“…7 Genotyping in the DPP has been described previously, and details are provided in the Online Supplementary Material. 11,16,17 If the index SNP reported in GWAS was not available, a proxy in strong linkage disequilibrium was selected (r 2 > 0.8). Of 72 candidate SNPs for the GRS, 7 67 were present or had suitable proxies that passed genotyping quality control on the Illumina MetaboChip or the Illumina Human Core Exome Array (Online Supplementary Material, Table S2).…”

Genetic Risk and Altering Lipids With Lifestyle Changes and Metformin

“…4 Participants in the intensive lifestyle intervention received extensive education taught by case managers on a one-to-one basis in order to achieve a weight reduction of at least 7 percent of initial body weight and were expected to engage in physical activity of moderate intensity for at least 150 minutes per week. Lifestyle intervention and metformin reduced the incidence of diabetes by 58% and 31% respectively.…”