DOI: 10.1097/SPV.0b013e3181f33306
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Issn Print: 2151-8378
Publication Date: 2010/09/01
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Excerpt
Objectives: There is increasing evidence that both environmental and genetic factors contribute to pelvic organ prolapse (POP). Genome-wide association studies (GWAS) are the most common analytical tool in looking for genetic contributions to complex diseases. We sought genetic variants underlying POP by conducting a GWAS in women with POP.
Methods: We recruited women who had been evaluated and treated for POP, usually surgically, at our University from 1996-2008; demographic details and family history were collected, medical records were obtained to confirm the treatment, and blood collected. Cases were genotyped on an Illumina 610Q platform; after genotype cleaning we analyzed 497,303 single nucleotide polymorphisms (SNPs). We genetically matched 2,976 iControls available from Illumina to use as controls. Case-control association analyses for five association tests (genotype, trend, allele, recessive, and dominant) were performed using PLINK, a GWAS analysis toolset. However, as our data contains related cases, significant SNPs identified using PLINK were re-analyzed using PedGenie, a platform which allows for joint analysis of both related and unrelated cases using simulation. A second set of 264 local controls was identified containing subjects genotyped in our state for breast cancer, prostate cancer, melanoma, and commercially available HapMap CEPH controls whose POP rates are assumed to be similar to a general population rate for our state. Significance is reported as p<0.000205 to correct for multiple testing. IRB approval was in place and all subjects gave consent.
Results: The study sample included 115 strictly defined POP cases treated for POP, in most cases with surgery (n=78) or repeat surgery (n=35). Mean age at diagnosis was 48.8 ± 14.2 yrs (range 21-75, n=85), mean parity was 4.3 ± 2.4 (range 0-13, n=104), and mean BMI at time of phenotyping was 26.6 kg/m2 (range 16-47, n=105). All subjects in this analysis were Caucasian. Many of the 115 POP cases had multiple pelvic floor disorders: 72 had been treated for stress urinary incontinence, 37 had been treated for overactive bladder, and 13 also had hernias. Although all subjects selected for genotyping had a family history of pelvic floor disorders, 23 were the only case sampled from their family, and the remaining 92 women were from families containing 2 to 8 sampled cases. We identified 133 unique markers with significance under (at least) one model using PLINK. After accounting for relatedness using PedGenie, 7 of these SNPs still showed significant association. The 7 SNPs were located at 4q21, 8q24, 9q22, 11q14, 15q11, 20p13, and 21q22. When the 7 SNPs were tested using the second control population, 6 of the 7 SNPs were significant after accounting for multiple testing.
Conclusions: This is the first report of a genome-wide association analysis for POP, and 7 SNPs have been identified that are significantly associated with POP. Further confirmation of these SNPs in other genetic samples of POP is underway. These GWAS results provide additional evidence for a genetic contribution to POP.
1Unless otherwise indicated, all abstract authors have nothing to disclose.
