Admixture mapping of pelvic organ prolapse in African Americans from the Women’s Health Initiative Hormone Therapy trial

Evidence suggests European American (EA) women have two- to five-fold increased odds of having pelvic organ prolapse (POP) when compared with African American (AA) women. However, the role of genetic ancestry in relation to POP risk is not clear. Here we evaluate the association between genetic ancestry and POP in AA women from the Women’s Health Initiative Hormone Therapy trial. Women with grade 1 or higher classification, and grade 2 or higher classification for uterine prolapse, cystocele or rectocele at baseline or during follow-up were considered to have any POP (N = 805) and moderate/severe POP (N = 156), respectively. Women with at least two pelvic exams with no indication for POP served as controls (N = 344). We performed case-only, and case-control admixture-mapping analyses using multiple logistic regression while adjusting for age, BMI, parity and global ancestry. We evaluated the association between global ancestry and POP using multiple logistic regression. European ancestry at the individual level was not associated with POP risk. Case-only and case-control local ancestry analyses identified two ancestry-specific loci that may be associated with POP. One locus (Chromosome 15q26.2) achieved empirically-estimated statistical significance and was associated with decreased POP odds (considering grade ≥2 POP) with each unit increase in European ancestry (OR: 0.35; 95% CI: 0.30, 0.57; p-value = 1.48x10-5). This region includes RGMA, a potent regulator of the BMP family of genes. The second locus (Chromosome 1q42.1-q42.3) was associated with increased POP odds with each unit increase in European ancestry (Odds ratio [OR]: 1.69; 95% confidence interval [CI]: 1.28, 2.22; p-value = 1.93x10-4). Although this region did not reach statistical significance after considering multiple comparisons, it includes potentially relevant genes including TBCE, and ACTA1. Unique non-overlapping European and African ancestry-specific susceptibility loci may be associated with increased POP risk.

现有证据表明，与非裔美国（African American, AA）女性相比，欧裔美国（European American, EA）女性罹患盆腔器官脱垂（pelvic organ prolapse, POP）的风险较其高出2至5倍。然而，遗传祖源与盆腔器官脱垂患病风险之间的关联机制尚未明确。本研究针对妇女健康倡议激素治疗试验（Women’s Health Initiative Hormone Therapy trial）中的非裔美国女性，评估遗传祖源与盆腔器官脱垂的关联。基线或随访期间被分级为子宫脱垂、膀胱膨出或直肠膨出1级及以上的女性，被归类为任意盆腔器官脱垂病例组（N=805）；而被分级为上述病症2级及以上的女性，则被归类为中重度盆腔器官脱垂病例组（N=156）。以至少完成两次盆腔检查且未提示盆腔器官脱垂迹象的女性作为对照（N=344）。本研究采用仅病例分析与病例-对照祖源混合定位分析方法，通过多元逻辑回归模型校正年龄、体质量指数（Body Mass Index, BMI）、产次及全局祖源等混杂因素。同时利用多元逻辑回归分析全局祖源与盆腔器官脱垂的关联。个体层面的欧洲祖源与盆腔器官脱垂患病风险无显著关联。仅病例分析与病例-对照局部祖源分析共识别出2个可能与盆腔器官脱垂相关的祖源特异性位点。其中一个位点（15号染色体q26.2区域）经经验估算具有统计学显著性：欧洲祖源每增加1个单位，中重度盆腔器官脱垂（定义为≥2级）的患病比值比（OR）下降（OR=0.35；95%置信区间（confidence interval, CI）：0.30, 0.57；p值=1.48×10^-5）。该区域包含RGMA基因，其作为骨形态发生蛋白（Bone Morphogenetic Protein, BMP）家族基因的强效调控因子发挥功能。另一个位点（1号染色体q42.1-q42.3区域）与欧洲祖源每增加1个单位的盆腔器官脱垂患病风险升高相关（比值比[OR]=1.69；95%置信区间[CI]：1.28, 2.22；p值=1.93×10^-4）。尽管该区域在校正多重比较后未达到统计学显著性，但其中包含TBCE与ACTA1等潜在相关基因。本研究结果表明，独特且非重叠的欧洲与非洲祖源特异性易感位点，可能与盆腔器官脱垂的患病风险相关。