Insulin Receptor Genetic Variants Causal Association with Type 2 Diabetes: A Mendelian Randomization Study

Ghada A Soliman; C Mary Schooling

doi:10.1093/cdn/nzac044

Insulin Receptor Genetic Variants Causal Association with Type 2 Diabetes: A Mendelian Randomization Study

Curr Dev Nutr. 2022 Mar 29;6(5):nzac044. doi: 10.1093/cdn/nzac044. eCollection 2022 May.

Authors

Ghada A Soliman¹, C Mary Schooling¹

Affiliation

¹ Department of Environmental, Occupational, and Geospatial Health Sciences, The City University of New York, Graduate School of Public Health, and Health Policy, New York, NY, USA.

Abstract

Background: Type 2 diabetes (T2D) is a prevalent chronic disease associated with several comorbidities.

Objectives: This study investigated whether the risk of T2D varied with genetically predicted insulin (INS), insulin receptor (INS-R), or insulin-like growth factor 1 receptor (IGF-1R) using genetic variants in a Mendelian randomization (MR) study.

Methods: A 2-sample MR study was conducted using summary statistics from 2 genome-wide association studies (GWASs). Genetic predictors of the exposures (INS, INS-R, and IGF-1R) were obtained from a publicly available proteomics GWAS of the INTERVAL randomized controlled trial of blood donation in the United Kingdom. For T2D, the study leveraged the DIAbetes Meta-ANalysis of Trans-Ethnic association studies (DIAMANTE) consortium. The estimated associations of INS, INS-R, and IGF-1R proteins with T2D were based on independent single nucleotide polymorphisms (SNPs) strongly (P < 5 × 10^-6) predicting each exposure. These SNPs were applied to publicly available genetic associations with T2D from the DIAMANTE case (n = 74,124) and control (n = 824,006) study of people of European descent. SNP-specific Wald estimates were meta-analyzed using inverse variance weighting with multiplicative random effects. Sensitivity analysis was conducted using the weighted median (WM) and MR-Egger.

Results: INS-R (based on 13 SNPs) was associated with a lower risk of T2D (OR: 0.95 per effect size; 95% CI: 0.92, 0.98; P = 0.001), with similar estimates from the WM and MR-Egger. Insulin (8 SNPs) and IGF-1R (10 SNPs) were not associated with T2D. However, 1 of the SNPs for INS-R was from the ABO blood group gene.

Conclusions: This study is consistent with a causally protective association of the INS-R with T2D. INS-R in RBCs regulates glycolysis and thus may affect their functionality and integrity. However, a pleiotropic effect via the blood group ABO gene cannot be excluded. The INS-R may be a target for intervention by repurposing existing therapeutics or otherwise to reduce the risk of T2D.

Keywords: Insulin receptor (INS-R); genome-wide association studies (GWAS); insulin (INS); insulin-like growth factor-1 receptor (IGF-1R); inverse variance weighted (IVW); mean corpuscular hemoglobin concentration (MCHC); single nucleotide polymorphism (SNP); type 2 diabetes (T2D); weighted median (WM).