Zhang Zhenhui, Li Xuelan, Guo Shuntian, Chen Xin
Reproductive Medicine Center, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, China.
Transl Androl Urol. 2024 Sep 30;13(9):2005-2015. doi: 10.21037/tau-24-187. Epub 2024 Sep 13.
Male infertility is a global health problem. There is an increasing attention on the association of metabolic status with spermatogenesis. However, the impacts of metabolic factors on semen parameters are still unclear. To provide evidence for developing appropriate interventions on disease screening and prevention, we performed a Mendelian randomization (MR) analysis to assess causality between various metabolic factors and abnormal spermatozoa.
We conducted a two-sample MR study to appraise the causal effects of 16 metabolic factors (including indexes of metabolic traits, glucose metabolism, lipid profile, adipokines, uric acid and metabolic diseases) on abnormal spermatozoa from genome-wide association studies (GWASs). Filtering with strict criteria, eligible genetic instruments closely associated with each of the factors were extracted. We employed inverse variance weighted for major analysis, with supplement MR methods including MR-Egger and weighted median. Heterogeneity and pleiotropy tests were further used to detect the reliability of analysis.
After rigorous quality control in this MR framework, we identified that body fat percentage [odds ratio (OR) =1.49, 95% confidence interval (CI): 1.01-2.20, P=0.046] and resistin (OR =1.55, 95% CI: 1.11-2.19, P=0.01) were causally associated with a higher risk of abnormal spermatozoa. In terms of other indexes of metabolic traits, glucose metabolism, serum lipid profile and uric acid and metabolic diseases including type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD), no causal effects were observed (P>0.05).
Our MR analysis provides robust evidence that body fat percentage and resistin are risk factors for abnormal spermatozoa, suggesting implications of identifying them for potential interventions and clinical therapies in male infertility. Further investigation in larger-scale GWASs on subgroups of abnormal spermatozoa will verify impacts of metabolic factors on spermatogenesis.
男性不育是一个全球性的健康问题。代谢状态与精子发生之间的关联日益受到关注。然而，代谢因素对精液参数的影响仍不明确。为了为制定疾病筛查和预防的适当干预措施提供证据，我们进行了一项孟德尔随机化（MR）分析，以评估各种代谢因素与异常精子之间的因果关系。
我们进行了一项两样本MR研究，以评估16种代谢因素（包括代谢特征指标、糖代谢、血脂谱、脂肪因子、尿酸和代谢疾病）对全基因组关联研究（GWAS）中异常精子的因果效应。通过严格标准进行筛选，提取与各因素密切相关的合格遗传工具变量。主要分析采用逆方差加权法，并辅以MR-Egger和加权中位数等MR方法。进一步使用异质性和多效性检验来检测分析的可靠性。
在该MR框架下经过严格的质量控制后，我们发现体脂百分比[比值比（OR）=1.49，95%置信区间（CI）：1.01-2.20，P=0.046]和抵抗素（OR =1.55，95%CI：1.11-2.19，P=0.01）与异常精子的较高风险存在因果关联。对于其他代谢特征指标、糖代谢、血清血脂谱、尿酸以及包括2型糖尿病（T2DM）和非酒精性脂肪性肝病（NAFLD）在内的代谢疾病，未观察到因果效应（P>0.05）。
我们的MR分析提供了有力证据，表明体脂百分比和抵抗素是异常精子的危险因素，这提示识别它们对于男性不育的潜在干预和临床治疗具有重要意义。在更大规模的GWAS中对异常精子亚组进行进一步研究将验证代谢因素对精子发生的影响。
