Fang Yingxin, Gu Qiuhua, Jia Junya, Yan Tiekun
Department of Nephrology, Tianjin Medical University General Hospital, Tianjin, China.
Nephrology (Carlton). 2025 May;30(5):e70049. doi: 10.1111/nep.70049.
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.
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.
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). 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).
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.
膜性肾病（MN）是成人肾病综合征的主要病因，80%的病例为病因不明的原发性MN。虽然性激素对慢性肾脏病（CKD）的影响已得到充分证实，但性激素结合球蛋白（SHBG）在MN中的作用仍不明确。
我们利用全基因组关联研究（GWAS）的数据进行孟德尔随机化（MR）分析，以评估SHBG对MN的因果影响。主要分析采用逆方差加权（IVW）方法，同时进行了各种额外的和敏感性分析以评估因果估计值。
我们从大规模开放获取的GWAS中获得了51个有效的SHBG工具变量（IVs）。SHBG的基因预测显著提高了男性患MN的可能性（IVW比值比[OR]=2.992，95%置信区间[CI]=[1.643，5.446]，p=3.370×10）。另外三项MR分析一致表明SHBG与MN之间存在正因果关系，所有p值均小于0.05。MR-Egger截距分析未显示水平多效性的证据（p>0.05）。
男性血清SHBG浓度升高与原发性MN风险增加直接相关。需要进一步研究以探索SHBG在评估和预测MN风险方面的有效性。
