Aims/hypothesis: Reasons for the sexual disparity in chronic kidney disease (CKD) are unclear. To provide insight we contextualised these differences within evolutionary biology, and explored sex-specific effects of insulin resistance because it may have sex-specific effects on the reproductive axis. Impaired kidney function may also cause insulin resistance. We assessed these possibilities using bi-directional, sex-specific, two-sample Mendelian randomisation (MR).
Methods: Given that fasting insulin, fasting glucose and HbA1c are related, we used MR-Bayesian model averaging (MR-BMA) to identify the best-fitting model and most influential exposure. Genetic associations with glycaemic traits were obtained from genome-wide association studies (GWAS) in Europeans without diabetes (n = 108,557 for fasting insulin, as a proxy for insulin resistance, and for fasting glucose, n = 123,665 for HbA1c in the Meta-Analyses of Glucose and Insulin-related traits Consortium [MAGIC]), and applied to GWAS of 480,698 Europeans for overall associations with CKD (cases n = 41,395) and eGFR. We also used sex-specific individual information in white British (179,917 men, 6016 CKD cases; 212,079 women, 5958 CKD cases) from the UK Biobank. Univariable or multivariable MR was used to assess the role of glycaemic trait(s) selected by MR-BMA in CKD and kidney function. Genetic variants predicting eGFR were used to assess the role of kidney function in the most influential exposure(s).
Results: Fasting insulin was selected as the most likely exposure by both overall and sex-specific MR-BMA. It increased CKD in men (OR 7.23 per pmol/l higher fasting insulin [95% CI 2.46, 21.2]) but not in women (OR 1.05 [95% CI 0.21, 5.21]), and reduced eGFR in men (-0.04 [95% CI -0.07, -0.01]) but not in women (0.01 [95% CI -0.02, 0.03]). Genetically predicted eGFR was unrelated to fasting insulin.
Conclusions/interpretation: Genetically predicted fasting insulin was sex-specifically associated with CKD and unhealthier kidney function but was not affected by kidney function. Graphical abstract.
Keywords: Insulin resistance; Mendelian randomisation; Renal function; Sex disparity.