Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, United Kingdom.
Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
PLoS Med. 2022 Feb 1;19(2):e1003679. doi: 10.1371/journal.pmed.1003679. eCollection 2022 Feb.
Obesity is observationally associated with altered risk of many female reproductive conditions. These include polycystic ovary syndrome (PCOS), abnormal uterine bleeding, endometriosis, infertility, and pregnancy-related disorders. However, the roles and mechanisms of obesity in the aetiology of reproductive disorders remain unclear. Thus, we aimed to estimate observational and genetically predicted causal associations between obesity, metabolic hormones, and female reproductive disorders.
Logistic regression, generalised additive models, and Mendelian randomisation (MR) (2-sample, non-linear, and multivariable) were applied to obesity and reproductive disease data on up to 257,193 women of European ancestry in UK Biobank and publicly available genome-wide association studies (GWASs). Body mass index (BMI), waist-to-hip ratio (WHR), and WHR adjusted for BMI were observationally (odds ratios [ORs] = 1.02-1.87 per 1-SD increase in obesity trait) and genetically (ORs = 1.06-2.09) associated with uterine fibroids (UF), PCOS, heavy menstrual bleeding (HMB), and pre-eclampsia. Genetically predicted visceral adipose tissue (VAT) mass was associated with the development of HMB (OR [95% CI] per 1-kg increase in predicted VAT mass = 1.32 [1.06-1.64], P = 0.0130), PCOS (OR [95% CI] = 1.15 [1.08-1.23], P = 3.24 × 10-05), and pre-eclampsia (OR [95% CI] = 3.08 [1.98-4.79], P = 6.65 × 10-07). Increased waist circumference posed a higher genetic risk (ORs = 1.16-1.93) for the development of these disorders and UF than did increased hip circumference (ORs = 1.06-1.10). Leptin, fasting insulin, and insulin resistance each mediated between 20% and 50% of the total genetically predicted association of obesity with pre-eclampsia. Reproductive conditions clustered based on shared genetic components of their aetiological relationships with obesity. This study was limited in power by the low prevalence of female reproductive conditions among women in the UK Biobank, with little information on pre-diagnostic anthropometric traits, and by the susceptibility of MR estimates to genetic pleiotropy.
We found that common indices of overall and central obesity were associated with increased risks of reproductive disorders to heterogenous extents in a systematic, large-scale genetics-based analysis of the aetiological relationships between obesity and female reproductive conditions. Our results suggest the utility of exploring the mechanisms mediating the causal associations of overweight and obesity with gynaecological health to identify targets for disease prevention and treatment.
肥胖与许多女性生殖疾病的风险改变有关。这些疾病包括多囊卵巢综合征（PCOS）、异常子宫出血、子宫内膜异位症、不孕和与妊娠相关的疾病。然而，肥胖在生殖障碍发病机制中的作用和机制仍不清楚。因此，我们旨在估计肥胖、代谢激素与女性生殖障碍之间的观察和遗传预测的因果关联。
使用逻辑回归、广义加性模型和孟德尔随机化（MR）（2 样本、非线性和多变量），对英国生物库中多达 257,193 名欧洲血统女性的肥胖和生殖疾病数据以及公开的全基因组关联研究（GWAS）进行了分析。体重指数（BMI）、腰围与臀围比（WHR）和 WHR 按 BMI 调整后与子宫肌瘤（UF）、PCOS、月经过多（HMB）和子痫前期呈观察性相关（OR[1-SD 中肥胖特征每增加 1 个单位的比值比] = 1.02-1.87）和遗传相关（OR[1-SD 中肥胖特征每增加 1 个单位的比值比] = 1.06-2.09）。遗传预测的内脏脂肪组织（VAT）质量与 HMB 的发生有关（每增加 1kg 预测的 VAT 质量的 OR[95%CI] = 1.32[1.06-1.64]，P=0.0130）、PCOS（OR[95%CI]=1.15[1.08-1.23]，P=3.24×10-05）和子痫前期（OR[95%CI]=3.08[1.98-4.79]，P=6.65×10-07）。腰围增加比臀围增加对这些疾病和 UF 的遗传风险更高（OR[95%CI] = 1.16-1.93）。瘦素、空腹胰岛素和胰岛素抵抗分别介导肥胖与子痫前期之间遗传预测关联的 20%-50%。生殖疾病根据其与肥胖的病因关系的共同遗传成分聚类。本研究的局限性在于英国生物库中女性生殖疾病的患病率较低，对预诊断人体测量特征的信息较少，并且易受 MR 估计的遗传多效性的影响。
我们发现，在对肥胖与女性生殖疾病之间病因关系进行系统的、大规模的遗传分析中，常见的整体和中心肥胖指数与生殖障碍的风险增加呈不同程度的相关性。我们的研究结果表明，探索超重和肥胖与妇科健康之间因果关联的中介机制具有实用性，可以确定疾病预防和治疗的目标。
