Genetic Mutation that May Contribute to Failure of Prolapse Surgery in White Women: A Case-Control Study

Abstract

Objective: To identify a potential genetic basis for early failure after prolapse surgery.

Design: Case-control study (Canadian Task Force classification II).

Setting: This study was carried out in 1 academic community medical center referral practice, and all patients had surgery at 1 of 2 hospitals.

Patients: Ten women with early, multicompartment prolapse recurrence after robotic sacrocolpopexy compared with 40 control subjects with known success after the same procedure.

Interventions: Patients were treated with robotic sacrocolpopexy.

Measurements and main results: DNA was isolated and initially genotyped on a single nucleotide polymorphism (SNP) array to direct more detailed exome analyses. Exome sequences were mapped to the Human Genome Reference Sequence (GRCh37), and variants were compared between groups and to participants in the 1000 Genomes Project. Statistical analyses were performed using a software package commonly used in genetics research. TaqMan assay was used for verification, and p values were adjusted using the false discovery rate. Demographics of groups were compared using χ(2), Mann-Whitney U, and t tests. A SNP [rs171821] located near the ZFYVE16 gene was associated with patients but not control subjects, and the false discovery rate-adjusted p value was .046 (odds ratio, 45.2; 95% confidence interval, 5.06-403). Exome analyses of this gene yielded another SNP [rs249038 (G/A)] in 6 of 10 patients and none of the control subjects (p = .02). This SNP causes a heterozygous missense mutation of glycine to serine predicted to be deleterious by the Protein Variation Effect Analyzer and was also very rare among participants in the 1000 Genomes Project (p < .001).

Conclusions: Two SNPs located near the ZFYVE16 gene on chromosome 5 may have played a role in the early, multicompartment sacrocolpopexy failure experienced by our patients. (www.clinicaltrials.gov Identifier: NCT01614587).

Keywords: Genetics; Prolapse; Robotic sacrocolpopexy; Surgical failure.