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

Area of Science:

• Genetics
• Metabolic Diseases
• Molecular Biology

Background:

• Type 2 diabetes (T2D) is a widespread chronic condition with numerous associated comorbidities.
• Understanding the genetic underpinnings of T2D is crucial for developing effective prevention and treatment strategies.

Purpose of the Study:

• To investigate the causal relationship between genetically predicted insulin (INS), insulin receptor (INS-R), and insulin-like growth factor 1 receptor (IGF-1R) and the risk of T2D.
• To utilize Mendelian randomization (MR) to assess these genetic associations.

Main Methods:

• A 2-sample MR study design was employed, using summary statistics from genome-wide association studies (GWASs).
• Genetic predictors for INS, INS-R, and IGF-1R were identified from a proteomics GWAS.
• Associations with T2D were analyzed using data from the DIAbetes Meta-ANalysis of Trans-Ethnic association studies (DIAMANTE) consortium, focusing on European descent populations.

Main Results:

• Genetically predicted INS-R was significantly associated with a lower risk of T2D (OR: 0.95; 95% CI: 0.92, 0.98; P=0.001).
• No significant association was found between genetically predicted INS or IGF-1R and T2D risk.
• A potential pleiotropic effect of INS-R via the ABO blood group gene was noted.

Conclusions:

• The findings support a causally protective role of INS-R in relation to T2D.
• INS-R's function in red blood cells (RBCs) may influence glycolysis, impacting cellular integrity and potentially T2D risk.
• INS-R presents a potential therapeutic target for T2D intervention, possibly through repurposing existing medications.