Characteristics of African American POP cases and controls.

<p>Characteristics of African American POP cases and controls.</p

Genetic Determinants of Pelvic Organ Prolapse among African American and Hispanic Women in the Women’s Health Initiative

<div><p>Current evidence suggests a multifactorial etiology to pelvic organ prolapse (POP), including genetic predisposition. We conducted a genome-wide association study of POP in African American (AA) and Hispanic (HP) women from the Women’s Health Initiative Hormone Therapy study. Cases were defined as any POP (grades 1–3) or moderate/severe POP (grades 2–3), while controls had grade 0 POP. We performed race-specific multiple logistic regression analyses between SNPs imputed to 1000 genomes in relation to POP (grade 0 vs 1–3; grade 0 vs 2–3) adjusting for age at diagnosis, body mass index, parity, and genetic ancestry. There were 1274 controls and 1427 cases of any POP and 317 cases of moderate/severe POP. Although none of the analyses reached genome-wide significance (p<5x10^-8), we noted variants in several loci that met p<10⁻⁶. In race-specific analysis of grade 0 vs 2–3, intronic SNPs in the <i>CPE</i> gene (rs28573326, OR:2.14; 95% CI 1.62–2.83; p = 1.0x10^-7) were associated with POP in AAs, and SNPs in the gene <i>AL132709</i>.<i>5</i> (rs1950626, OR:2.96; 95% CI 1.96–4.48, p = 2.6x10^-7) were associated with POP in HPs. Inverse variance fixed-effect meta-analysis of the race-specific results showed suggestive signals for SNPs in the <i>DPP6</i> gene (rs11243354, OR:1.36; p = 4.2x10^-7) in the grade 0 vs 1–3 analyses and for SNPs around <i>PGBD5</i> (rs740494, OR:2.17; p = 8.6x10^-7) and <i>SHC3</i> (rs2209875, OR:0.60; p = 9.3x10^-7) in the grade 0 vs 2–3 analyses. While we did not identify genome-wide significant findings, we document several SNPs reaching suggestive statistical significance. Further interrogation of POP in larger minority samples is warranted.</p></div

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

<div><p>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 <i>RGMA</i>, 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 <i>TBCE</i>, and <i>ACTA1</i>. Unique non-overlapping European and African ancestry-specific susceptibility loci may be associated with increased POP risk.</p></div

Top genetic loci associated with severe pelvic organ prolapse (grade 0 vs. 2–3) in African American (AA) and Hispanic (HP) women from the Women’s Health Initiative.

<p>CHR = Chromosome; SNP = Single Nucleotide Polymorphism; EA = Effect Allele; RA = Reference Allele</p><p>*SNP is on gene; EAF = Effect Allele Frequency for Controls; OR = Odds Ratio; CI = Confidence Interval; P = p-value from logistic regression; Logistic regression models were adjusted for age at ascertainment, BMI (continuous), parity continuous) and 4 genetic ancestry components (continuous)</p><p>Top genetic loci associated with severe pelvic organ prolapse (grade 0 vs. 2–3) in African American (AA) and Hispanic (HP) women from the Women’s Health Initiative.</p

Admixture mapping peaks for chromosome 10 in context with previously reported linkage peak.

<p>Blue horizontal line: suggestive p-value threshold; Red horizontal line: permutation based p-value threshold; Black peaks: case-control admixture mapping; Green peaks: case-only admixture mapping.</p

Association between European-ancestry percent in relation to POP in African American women.

<p>Association between European-ancestry percent in relation to POP in African American women.</p

Signals from any-POP case-control admixture mapping and imputed SNPs for chromosome 1q42.1–42.3 region.

<p>Blue horizontal line: suggestive p-value threshold; Red horizontal line: permutation based p-value threshold. Solid black line represents admixture mapping signal prior to conditional analysis. Red dots represents log10(p-values) for genotyped and imputed SNPs within the admixture mapping peak. Blue dot represents SNP rs78992478, the most significant SNP directly below the admixture mapping peak. Green dot represents SNP rs2501094, the second-most significant SNP directly below the admixture mapping peak. Dashed blue line represents admixture mapping signal after adjustment for SNP rs78992478. Dashed green line represents admixture mapping signal after adjustment for SNP rs2501094. Dashed grey line represents admixture mapping signal after adjustment for both SNPs.</p

Admixture mapping peaks for chromosome 15 from case-only and case-control designs considering moderate/severe POP (grades 2–3) in African Americans.

<p>Blue horizontal line: suggestive p-value threshold; Red horizontal line: permutation based p-value threshold.</p

Associations between local European ancestry and POP in top regions.

<p>Associations between local European ancestry and POP in top regions.</p

Associations between genetic markers and POP in top regions identified from admixture mapping.

<p>Associations between genetic markers and POP in top regions identified from admixture mapping.</p