A Mendelian Randomization Study on the Association Between Sex Hormone‐Binding Globulin and Membranous Nephropathy Risk

ABSTRACT Aim Membranous nephropathy (MN) is the leading cause of nephrotic syndrome in adults, with 80% of cases being primary MN of unknown origin. While the influence of sex hormones on chronic kidney disease (CKD) is thoroughly established, the role of sex hormone‐binding globulin (SHBG) in MN is still uncertain. Methods We performed a Mendelian randomization (MR) analysis to assess the causal impact of SHBG on MN, utilising data from genome‐wide association studies (GWAS). The main analysis utilised the inverse variance weighted (IVW) method, while various additional and sensitivity analyses were conducted to evaluate the causal estimates. Results We obtained 51 valid instrumental variables (IVs) of SHBG from large‐scale open‐access GWASs. Genetic forecasting of SHBG notably raised the likelihood of MN in males (IVW odds ratios [OR] = 2.992, 95% confidence interval [CI] = [1.643, 5.446], p = 3.370 × 10 −4 ). Three additional MR analyses consistently demonstrated a positive causal relationship between SHBG and MN, with all p values being less than 0.05. MR ‐Egger intercept analysis showed no evidence of horizontal pleiotropy ( p > 0.05). Conclusion Elevated serum SHBG concentrations were directly associated with an increased risk of primary MN in males. Further research is needed to explore the effectiveness of SHBG in assessing and predicting MN risk.