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

Abstract

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.

Genome-wide Significance Thresholds for Admixture Mapping Studies

“…A related approach involves a Bonferroni correction on the estimated effective number of independent tests; 13,19,31,32 however, a number of authors [33][34][35] have suggested that this approach does not always guarantee family-wise error rate control in genome-wide association studies. Permutation-based 22,24,36,37 and simulation-based 20,38,39 multiple testing correction procedures are often considered to be the gold standard for genetic association studies but can be very computationally intensive. Alternatives to these procedures, based on the multivariate normal distribution, have been suggested to speed up computation time.…”

Korelasi Kekuatan Otot Menggenggam dengan Otot Levator Ani pada Penderita Prolapsus Organ Panggul

“…Pada suatu studi Women's Health Initiative (WHI) di Amerika menunjukkan sebanyak 40% wanita mengalami POP setelah menopause dengan 20% wanita dilakukan operasi pada usia 80 tahun. 1,2 Menurut laporan tahunan Rumah Sakit Dr. Hasan Sadikin Bandung didapatkan prevalensi prolapsus organ panggul sebesar 20%, sedangkan penelitian di Rumah Sakit Dr. Moewardi Surakarta dari tahun 2013-2015 didapatkan 258 pasien dengan prolapsus uteri. 3 Faktor risiko terjadinya POP bersifat multifaktorial antara lain paritas, persalinan pervaginam, usia, obesitas, kelainan jaringan ikat, status menopause, dan konstipasi kronis yang menyebabkan kelemahan pada otot dasar panggul.…”