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

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 CPE 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 AL132709.5 (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 DPP6 gene (rs11243354, OR:1.36; p = 4.2x10-7) in the grade 0 vs 1–3 analyses and for SNPs around PGBD5 (rs740494, OR:2.17; p = 8.6x10-7) and SHC3 (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

Unilateral Labial Hypertrophy in Adolescents: when should we Interfere? Two Case Reports

Synopsis: Adolescent and pre-menarchal patients with symptomatic unilateral labial hypertrophy should be counselled extensively prior to surgical management regarding risks of recurrence or contralateral occurrence. Purpose: Present the management of two unique cases of adolescent girls with unilateral labial hypertrophy. Case 1: 9 year-old pre-menarchal patient with a five-month history of unilateral labial hypertrophy causing discomfort that limited daily activities. External pelvic examination revealed grossly asymmetric labia minora. The left labia minora measured 5 cm in length. After counseling, the patient underwent unilateral labioplasty with resolution of symptoms. Patient returned after two years complaining of contralateral labial hypertrophy.The patient again underwent surgical management due to discomfort and interference with normal daily activities. Case 2: 12 year-old post-menarchal patient with a history of unilateral labial hypertrophy causing irritation and discomfort starting prior to menarche. External pelvic exam revealed grossly asymmetric labia minora. The right labia minora measured 4.5cm in length. The patient underwent unilateral labioplasty with resolution of her symptoms. After 2 years of follow up, patient remained asymptomatic. Conclusion: Adolescence unilateral labial hypertrophy may represent a normal variant and surgery should be delayed until achieving full puberty. However, when it causes significant discomfort or interferes with normal daily activities, surgical management should be considered after counseling regarding recurrence or contralateral occurrence

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

ORs and minor allele frequencies of six statistically significant SNPs evaluated by ^*Allen-Brady et al. in current analyses evaluating Grade 0 vs. 2–3 POP analyses using data from the Women’s Health Initiative.

<p>MAF = Minor allele frequency; OR = odds ratio; 1000G = 1000 Genomes Project; NA = Not applicable as SNP was not assessed due to low minor allele frequency</p><p>*Refers to SNPs published in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0141647#pone.0141647.t002" target="_blank">Table 2</a> of article by Allen-Brady et al. [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0141647#pone.0141647.ref019" target="_blank">19</a>]</p><p>**Source for reference population minor allele frequencies: <a href="http://www.ncbi.nlm.nih.gov/variation/tools/1000genomes/" target="_blank">http://www.ncbi.nlm.nih.gov/variation/tools/1000genomes/</a></p><p>ORs and minor allele frequencies of six statistically significant SNPs evaluated by ^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0141647#t005fn002" target="_blank">*</a>}Allen-Brady et al. in current analyses evaluating Grade 0 vs. 2–3 POP analyses using data from the Women’s Health Initiative.</p

Regional association plots showing–log10(p-values) against base-pair position for Hispanic (HP) women considering grade 0 vs. 1–3 analyses.

<p>Regional association plots showing–log10(p-values) against base-pair position for Hispanic (HP) women considering grade 0 vs. 1–3 analyses.</p

Regional association plots showing–log10(p-values) against base-pair position for African American (AA) women considering grade 0 vs. 1–3 analyses.

<p>Regional association plots showing–log10(p-values) against base-pair position for African American (AA) women considering grade 0 vs. 1–3 analyses.</p

Regional association plots showing–log10(p-values) against base-pair position for African American (AA) (top) and Hispanic (HP) (bottom) women considering grade 0 vs. 1–3 analyses.

<p>Regional association plots showing–log10(p-values) against base-pair position for African American (AA) (top) and Hispanic (HP) (bottom) women considering grade 0 vs. 1–3 analyses.</p

Quantile-quantile (Q-Q) plot of association analysis results.

<p>Expected–log10 p values are on the x-axis and the observed–log10 p values are on the y-axis. A) African Americans grade 0 vs. 1–3; B) Hispanics grade 0 vs. 1–3; C) African Americans grade 0 vs. 2&3; D) Hispanics grade 0 vs. 2&3.</p

Top genetic loci associated with any pelvic organ prolapse (grade 0 vs. 1–3) 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</p><p>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 any pelvic organ prolapse (grade 0 vs. 1–3) in African American (AA) and Hispanic (HP) women from the Women’s Health Initiative.</p

The flow chart presents an overview of sample and SNP inclusion/exclusion during quality control.

<p>The flow chart presents an overview of sample and SNP inclusion/exclusion during quality control.</p