Fan Zhengyang, Shao Changming, Kou Zhifu, Xie Feng, Wang Hongyu, Zheng Shuai, Wen Bo, Chen Zheng, Zeng Binfang
Xinjiang Medical University Institute of Traditional Chinese Medicine, Urumqi, China. .
Xinjiang Medical University Institute of Traditional Chinese Medicine, Urumqi, China.
J Gastrointestin Liver Dis. 2024 Dec 28;33(4):474-481. doi: 10.15403/jgld-5642.
Sex hormones and sex hormone-binding globulin (SHBG) have been confirmed to involve in the pathophysiology of functional gastrointestinal disorders (FGIDs), including irritable bowel syndrome (IBS) and functional dyspepsia (FD). However, causal associations have not yet been investigated. Utilizing data from Genome-wide association studies, we conducted bidirectional two-sample mendelian randomization (MR) analyses to assess the causal relationships between sex hormones, SHBG and FGIDs.
Data for sex hormones including testosterone and estradiol, and SHBG were collected from the UK Biobank and FinnGen study. Relevant single nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs). Inverse variance weighted (IVW) analysis were performed to assess the causal relationships., supplemented with MR-Egger, weighted median, and weighted mode approaches. Additionally, we used Cochran's Q test to evaluate the heterogeneity of genetic variants and implemented leave-one-out analysis to assess the impact of individual SNPs on the causal estimates. Several sensitivity analyses were conducted to assess the robustness of the results.
Significant negative causal relationship was found between genetically predicted testosterone and the risk of IBS (OR=0.90, 95%CI: 0.83-0.97; p=0.007). SHBG demonstrated an inverse correlation with the risk of IBS (OR=0.82, 95%CI: 0.68-0.98; p=0.035) and FD (OR=0.83, 95%CI: 0.69-0.99; p=0.048). However, no statistically significant association was found between testosterone and FD, while estradiol also showed no causal association with FGIDs.
Our study revealed a negative causal relationship between testosterone and IBS risk, and SHBG appears to be inversely associated with FD. This provided new ideas for the prevention and control of IBS, and future research is warranted to elucidate the underlying mechanisms driving these associations and their potential clinical implications.
性激素和性激素结合球蛋白（SHBG）已被证实在包括肠易激综合征（IBS）和功能性消化不良（FD）在内的功能性胃肠疾病（FGIDs）的病理生理学中发挥作用。然而，因果关联尚未得到研究。利用全基因组关联研究的数据，我们进行了双向两样本孟德尔随机化（MR）分析，以评估性激素、SHBG与FGIDs之间的因果关系。
从英国生物银行和芬兰基因研究中收集包括睾酮和雌二醇在内的性激素以及SHBG的数据。选择相关单核苷酸多态性（SNPs）作为工具变量（IVs）。采用逆方差加权（IVW）分析评估因果关系，并辅以MR-Egger、加权中位数和加权模式方法。此外，我们使用 Cochr an's Q检验评估遗传变异的异质性，并进行留一法分析以评估单个SNP对因果估计的影响。进行了多项敏感性分析以评估结果的稳健性。
基因预测的睾酮与IBS风险之间存在显著的负因果关系（OR = 0.90，95%CI：0.83 - 0.97；p = 0.007）。SHBG与IBS风险（OR = 0.82，95%CI：0.68 - 0.98；p = 0.035）和FD风险（OR = 0.83，95%CI：0.69 - 0.99；p = 0.048）呈负相关。然而，未发现睾酮与FD之间存在统计学显著关联，而雌二醇与FGIDs也未显示出因果关联。
我们的研究揭示了睾酮与IBS风险之间的负因果关系，并且SHBG似乎与FD呈负相关。这为IBS的预防和控制提供了新思路，未来有必要进行研究以阐明驱动这些关联的潜在机制及其潜在的临床意义。
