Medical Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China.
PLoS One. 2024 May 30;19(5):e0303827. doi: 10.1371/journal.pone.0303827. eCollection 2024.
To explore the causal relationship between ulcerative colitis (UC) and male infertility using Mendelian randomization method with single nucleotide polymorphism (SNP) as the instrumental variables.
Genetic loci closely associated with UC were extracted as instrumental variables and male infertility was the outcome variable in pooled data from the gene-wide association study (GWAS),which was derived from European ethnic groups. The UC data(ebi-a-GCST003045) contained a total sample size of 27432 individuals and 110944 SNPs, and the male infertility data(finn-b-N14_MALEINFERT) contained a total sample size of 73479 individuals and 16377329 SNPs. The SNPs highly correlated with UC were screened from ebi-a-GCST003045(P<5×10-8 as the screening condition, the linkage disequilibrium coefficient was 0.001,and the width of the linkage disequilibrium area was 10000 kb).SNPs related to male infertility from finn-b-N14_MALEINFERT (the minimum r2>0.8,replacing the missing SNPs with SNPs with high linkage, and deleting SNPs without substitution sites) were extracted. MR analysis was performed using MR-Egger regression, the weighted median and the inverse-variance weighted (IVW) respectively, and the causal relationship between UC and male infertility was evaluated by OR and 95% CI, and the Egger-intercept method was used to test for horizontal multiplicity, and the sensitivity analysis was performed using "leave-one-out method". Finally, we used Bayesian Weighted Mendelian Randomization (BWMR) approach to test the results of MR study.
A total of 86 SNPs were included as IVs, with OR and 95% CI of 1.095(0.8201.462)、1.059(0.8991.248)、1.125(1.002~1.264) for MR-Egger, the weighted median and IVW results respectively, and P value of less than 0.05 for IVW, indicating that a causal relationship between UC and male infertility was causally related. The results of MR analysis combined with BWMR analysis also showed positive genetic causal relationship between UC and male infertility.MR-Egger regression showed an intercept of -2.21×10-3 with a standard error of 0.006 and P = 0.751, there was no horizontal pleiotropy for the IVs of exposure factors. Heterogeneity tests showed no heterogeneity and the results of the "leave-one-out" sensitivity analysis were stable.
There is a causal association between UC and male infertility, which increases the risk of developing male infertility.
利用单核苷酸多态性（SNP）作为工具变量，采用孟德尔随机化方法探讨溃疡性结肠炎（UC）与男性不育之间的因果关系。
从全基因组关联研究（GWAS）中提取与 UC 密切相关的遗传基因座作为工具变量，以男性不育为结局变量，该 GWAS 数据来源于欧洲人群。UC 数据（ebi-a-GCST003045）总样本量为 27432 人，SNP 数量为 110944 个；男性不育数据（finn-b-N14_MALEINFERT）总样本量为 73479 人，SNP 数量为 16377329 个。从 ebi-a-GCST003045 中筛选出与 UC 高度相关的 SNP（筛选条件为 P<5×10-8，连锁不平衡系数为 0.001，连锁不平衡区域宽度为 10000 kb）。从 finn-b-N14_MALEINFERT 中提取与男性不育相关的 SNP（最小 r2>0.8，用高连锁 SNP 替换缺失 SNP，删除无替换位点的 SNP）。分别采用 MR-Egger 回归、加权中位数和逆方差加权（IVW）进行 MR 分析，并通过 OR 和 95%CI 评估 UC 与男性不育之间的因果关系，采用 Egger 截距法检验水平多重性，采用“逐一剔除法”进行敏感性分析。最后，采用贝叶斯加权孟德尔随机化（BWMR）方法检验 MR 研究结果。
共纳入 86 个 SNP 作为 IVs，MR-Egger、加权中位数和 IVW 的 OR 和 95%CI 分别为 1.095（0.8201.462）、1.059（0.8991.248）、1.125（1.002~1.264），IVW 的 P 值<0.05，表明 UC 和男性不育之间存在因果关系。MR 分析结合 BWMR 分析的结果也显示 UC 和男性不育之间存在阳性遗传因果关系。MR-Egger 回归显示暴露因素 IVs 的截距为-2.21×10-3，标准误差为 0.006，P=0.751，不存在水平多效性。异质性检验无异质性，“逐一剔除法”敏感性分析结果稳定。
UC 与男性不育之间存在因果关系，UC 增加了男性不育的发病风险。
