Interaction of Insulin Resistance and Related Genetic Variants With Triglyceride-Associated Genetic Variants

Abstract

Background Several studies suggest that some triglyceride (TG)-associated single nucleotide polymorphisms (SNPs) have pleiotropic and opposite effects on glycemic traits. This potentially implicates them in pathways such as de novo lipogenesis, which is presumably up-regulated in the context of insulin resistance. We therefore tested whether the association of TG-associated SNPs with TG levels differs according to one’s level of insulin resistance. Methods and Results In three cohort studies (combined n=12,487), we tested the interaction of established TG-associated SNPs (individually and collectively) with several traits related to insulin resistance, on TG levels. We also tested the interaction of TG SNPs with fasting insulin (FI)-associated SNPs, individually and collectively, on TG levels. We find significant interactions of a weighted genetic risk score (GRS) for TG with insulin resistance on TG (pinteraction=2.73 × 10−11 and pinteraction=2.48 × 10−11 for FI and HOMA-IR, respectively). The association of the TG GRS with TG is over 60% stronger among those in the highest tertile of HOMA-IR, compared to those in the lowest tertile. Individual SNPs contributing to this trend include those in/near GCKR, CILP2, and IRS1, while PIGV-NROB2 and LRPAP1 display an opposite trend of interaction. In the pooled dataset, we also identify a SNP-by-SNP interaction involving a TG-associated SNP, rs4722551 near MIR148A, with a FI-associated SNP, rs4865796 in ARL15 (pinteraction=4.1 × 10−5). Conclusions Our findings may thus provide genetic evidence for the upregulation of TG levels in insulin resistant individuals, in addition to identifying specific genetic loci and a SNP-by-SNP interaction implicated in this process.

Increasing insulin resistance accentuates the effect of triglyceride-associated loci on serum triglycerides during 5 years

“…Previous studies of interactions in cross-sectional settings have found comparable interactions suggesting a stronger association between the wGRS and triglycerides in obese or in more insulin-resistant individuals (14)(15)(16)(17)19). In this study, we demonstrate that the interaction with HOMA-IR is also evident in a prospective setting consolidating the results from previous studies using cross-sectional data.…”

“…We and others have reported interactions with triglyceride GRS in the cross-sectional setting, including interactions with BMI and insulin resistance using homeostatic model assessment of insulin resistance (HOMA-IR) (14)(15)(16)(17)19). Taken together these cross-sectional results point toward a bigger effect of the triglyceride GRS on triglycerides in obese individuals compared with lean individuals.…”

“…It seems likely that some loci are interacting with insulin resistance, while others are not. Specific loci have been suggested to have this pattern of interaction with obesity and insulin resistance in cross-sectional studies, e.g., GCKR and APOA5 (15,16,19). Larger studies are needed to elucidate potential interactions for all loci separately.…”

Gene-environment interactions due to quantile-specific heritability of triglyceride and VLDL concentrations

“…Environmental factors that distinguish higher vs. lower triglycerides (e.g., obesity, physical inactivity, smoking, alcohol, high-carbohydrate diets, T2DM) are predicted to produce different genetic estimates under quantile-dependent expressivity. Traditionally, these differences have been attributed to gene-environment interactions, where: 1) the effect of the genotype on the phenotype differs by environment [26][27][28][29][30][31][32][33][34][35][36][37][41][42][43][45][46][47][48][49][50][51][52][53][54][55][58][59][60][61][62][63][65][66][67][74][75][76][77][78][79][80] , or equivalently: 2) the effect of the environment on the phenotype differs by genotype 36,[38][39][40]44,…”

High Genetic Risk Scores of <b><i>ASIC2, MACROD2, CHRM3</i></b>, and <b><i>C2orf83</i></b> Genetic Variants Associated with Polycystic Ovary Syndrome Impair Insulin Sensitivity and Interact with Energy Intake in Korean Women

“…Some of these genetic variants that are relevant to functionality of PCOS do not meet the criteria of p value < 1 × 10 -6 in GWAS [14] and some genetic variants satisfying the p value have no functional link to PCOS. When studying the interactions of genetic risk with specific non-genetic physiological risk factors for a disease, it is important to select genes that link a specific pathological pathway to the genetic risk [15][16][17].…”