Department of Critical Care Medicine, Wuhan Jinyintan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430023, Hubei Province, People's Republic of China.
Department of Tuberculosis, Wuhan Jinyintan Hospital, Tongji Medical College of Huazhong, University of Science and Technology, Wuhan, 430023, Hubei Province, People's Republic of China.
BMC Med Genomics. 2023 Jun 9;16(1):125. doi: 10.1186/s12920-023-01560-5.
Although observational studies have established some socioeconomic traits to be independent risk factors for pelvic organ prolapse (POP), they can not infer causality since they are easily biased by confounding factors and reverse causality. Moreover, it remains ambiguous which one or several of socioeconomic traits play predominant roles in the associations with POP risk. Mendelian randomization (MR) overcomes these biases and can even determine one or several socioeconomic traits predominantly accounting for the associations.
We conducted a multivariable Mendelian randomization (MVMR) analysis to disentangle whether one or more of five categories of socioeconomic traits, "age at which full-time education completed (abbreviated as "EA")", "job involving heavy manual or physical work ("heavy work")", "average total household income before tax (income)", "Townsend deprivation index at recruitment (TDI)", and "leisure/social activities" exerted independent and predominant effects on POP risk.
We first screened single-nucleotide polymorphisms (SNPs) as proxies for five individual socioeconomic traits and female genital prolapse (FGP, approximate surrogate for POP due to no GWASs for POP) to conduct Univariable Mendelian randomization (UVMR) analyses to estimate causal associations of five socioeconomic traits with FGP risk using IVW method as major analysis. Additionally, we conducted heterogeneity, pleiotropy, and sensitivity analysis to assess the robustness of our results. Then, we harvested a combination of SNPs as an integrated proxy for the five socioeconomic traits to perform a MVMR analysis based on IVW MVMR model.
UVMR analyses based on IVW method identified causal effect of EA (OR 0.759, 95%CI 0.629-0.916, p = 0.004), but denied that of the other five traits on FGP risk (all p > 0.05). Heterogeneity analyses, pleiotropy analyses, "leave-one-out" sensitivity analyses and MR-PRESSO adjustments did not detect heterogeneity, pleiotropic effects, or result fluctuation by outlying SNPs in the effect estimates of six socioeconomic traits on FGP risk (all p > 0.05). Further, MVMR analyses determined a predominant role of EA playing in the associations of socioeconomic traits with FGP risk based on both MVMR Model 1 (OR 0.842, 95%CI 0.744-0.953, p = 0.006) and Model 2 (OR 0.857, 95%CI 0.759-0.967, p = 0.012).
Our UVMR and MVMR analyses provided genetic evidence that one socioeconomic trait, lower educational attainment, is associated with risk of female genital prolapse, and even independently and predominantly accounts for the associations of socioeconomic traits with risk of female genital prolapse.
尽管观察性研究已经确定了一些社会经济特征是盆腔器官脱垂（POP）的独立危险因素，但由于易受混杂因素和反向因果关系的影响，它们并不能推断出因果关系。此外，哪种或几种社会经济特征在与 POP 风险的关联中起主要作用仍不清楚。孟德尔随机化（MR）克服了这些偏差，甚至可以确定一种或几种社会经济特征在关联中起主要作用。
我们进行了多变量孟德尔随机化（MVMR）分析，以厘清五类社会经济特征，“完成全日制教育的年龄（简称“EA”）”、“从事重体力或体力劳动的工作（“重体力工作”）”、“税前平均家庭总收入（收入）”、“招募时的汤森剥夺指数（TDI）”和“休闲/社会活动”，是否对 POP 风险有独立和主要的影响。
我们首先筛选出单核苷酸多态性（SNP）作为五个个体社会经济特征和女性生殖器脱垂（FGP，由于没有针对 POP 的 GWAS，因此近似于 POP 的代表）的代表，以进行单变量孟德尔随机化（UVMR）分析，使用 IVW 方法作为主要分析方法，估计五个社会经济特征与 FGP 风险的因果关系。此外，我们还进行了异质性、多效性和敏感性分析，以评估我们结果的稳健性。然后，我们采集了一组 SNP 作为五个社会经济特征的综合代表，基于 IVW MVMR 模型进行 MVMR 分析。
基于 IVW 方法的 UVMR 分析确定了 EA（OR 0.759，95%CI 0.629-0.916，p=0.004）的因果效应，但否认了其他五个特征对 FGP 风险的因果效应（均 p>0.05）。异质性分析、多效性分析、“逐个剔除”敏感性分析和 MR-PRESSO 调整均未检测到六个社会经济特征对 FGP 风险的效应估计值存在异质性、多效性效应或由异常 SNP 引起的结果波动（均 p>0.05）。此外，MVMR 分析基于 MVMR 模型 1（OR 0.842，95%CI 0.744-0.953，p=0.006）和模型 2（OR 0.857，95%CI 0.759-0.967，p=0.012）确定了 EA 在社会经济特征与 FGP 风险关联中起主要作用。
我们的 UVMR 和 MVMR 分析提供了遗传证据，表明一种社会经济特征，即较低的教育程度，与女性生殖器脱垂的风险相关，甚至独立且主要与女性生殖器脱垂的风险相关。
