Sex-specific associations of insulin resistance with chronic kidney disease and kidney function: a bi-directional Mendelian randomisation study

Abstract

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 HbA 1c 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 HbA 1c 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.

Differentiating Associations of Glycemic Traits with Atherosclerotic and Thrombotic Outcomes: Mendelian Randomization Investigation

“…Our null findings for genetically predicted FG and HbA 1c in relation to chronic kidney disease agree with the results of previous MR studies (18). Although we observed a positive association between genetically predicted FI and chronic kidney disease, this association seemed to be sex specific (17). Given lack of sex-specific data on chronic kidney disease in the used data sets, we could not confirm this sex-specific association.…”

“…In previous MR studies investigators have found a consistent influence of certain glycemic traits, such as glucose and glycated hemoglobin (HbA 1c ), on risk of coronary artery disease (9)(10)(11)(12)(13). Nevertheless, results of studies of the associations of glycemic traits with other atherosclerotic diseases, such as ischemic stroke (13)(14)(15)(16) and chronic kidney disease (17)(18)(19), were inconsistent, and there is a scarcity of data on the MR associations for peripheral artery disease as well as other atherosclerotic and thrombotic outcomes (13).…”

Contribution of Predictive and Prognostic Biomarkers to Clinical Research on Chronic Kidney Disease

“…Analyses of the UK biobank provided a great contribution to the prognostic research in CKD. For example, genetically predicted testosterone and fasting insulin, with the latter being an expression of insulin resistance, were found to be associated with CKD and worse kidney function in men, thus highlighting the possible reasons for discrepancy in CKD prevalence and CKD progression among men and women [84,85]. Intriguingly, a genome-wide association study of UK biobank showed that albumin-to-creatinine ratio (ACR) is dependent on multiple pathways and that an ACR genetic risk score may improve the prediction of hypertension and stroke [86].…”

Associations of endogenous androgens and sex hormone-binding globulin with kidney function and chronic kidney disease

“…Based on further MR reports, genetically-predicted higher SHBG may lower insulin resistance and T2D risk in men and women ( 49 – 51 ). Moreover, in men, elevated fasting insulin has been linked to impaired kidney function, but not vice versa ( 52 ). Further studies that can provide sex-specific mechanistic insights to the SHBG-kidney relationship are warranted.…”