We have identified six SNPs that are significantly associated with POP in a dataset of 115 women with a strong family history of pelvic floor disorders and diagnosed with strictly defined POP.
Genome-wide association studies test the hypothesis that common variants in the population (i.e., variants with typically 1– 5% frequency) increase the susceptibility to a common disease such as POP. An association study using large pedigrees that segregate a small set of variants increases the likelihood that some of these more rare variants become detectable. While our case sample size in this study is small compared to the thousands of individuals typically used in a GWAS, the use of women from high-risk POP families increases the likelihood that these cases have a genetic component to their disease, and hence increases the likelihood that rare disease-contributing variants could be detected in an association analysis.
We previously performed a linkage analysis using some of the same affected individuals who were included in this GWAS, and reported significant linkage of POP to chromosome region 9q21.23
One of 6 SNPs identified in the association analysis at 9q22 (rs430794) is just outside this previous significant linkage region. Linkage analysis is most ideal for detecting highly-penetrant rare loci in high-risk families whereas association analysis is most useful for detecting common loci in a case-control cohort. We assume that a complex disease such as POP involves multiple loci, some common and some rare. Linkage analysis and an association analysis have different strengths and can provide complementary information for study of a complex disease such POP.
Two of the six SNPs were located within genes; rs1036819 is located in the ZFAT
gene [MIM: 610931] and rs2236479 is located in the COL18A1
gene [MIM: 120328]. The ZFAT
gene has been found to play a transcriptional regulator role for immune regulation and apoptosis.30
ZFAT might be involved in development of mesodermal cells,31
and hence may affect development of muscle and connective tissue of the pelvic floor. The collagen XVIII (COL18A1
) gene is another interesting candidate gene for POP. Endostatin, the C-terminal fragment of collagen XVIII, and its precursor collagen XVIII may play a role in the structural organization of basement membranes.32, 33
In mouse models of wound healing, mice overexpressing endostatin showed delayed healing, delayed formation of the epidermal basement membrane, and a more disorganized epidermal and capillary basement membrane structure.34
In the pelvic floor, endostatin and collagen XVIII may play a role in basement membrane organization and response to both minor and major insults.
The other four SNPs identified are intergenic, but one of them is also close to a gene of interest for POP. The SNP rs1455311 at 4q21 is approximately 0.85 Mb away from the anthrax toxin receptor 2 (ANTXR2
) gene [MIM: 608041] which binds to collagen IV and laminin, suggesting that it may be involved in extracellular matrix adhesion.35
Although we were unable to conclusively validate the Utah findings, we obtained some nominally significant results in the validation set from Holland. There are a number of factors that might explain the lack of strong validation findings including lack of available control data matched to the Dutch POP cases, a small sample size for the Dutch cohort, and phenotype differences between the Utah and the Dutch POP cases (e.g., Utah cases were more likely to have a mixed pelvic floor disorder phenotype). Another explanation for the lack of strong validation findings is that some or all of the Utah results may be false positives; the Utah sample size is small relative to most other GWAS. Despite these limitations, we note that the Dutch Genetic Resource is a close match to the Utah subjects used in this study: the majority of Utahns are of Northern European descent similar to the Caucasian residents of Holland, and the Dutch resource included familial POP cases as did the Utah cohort. There are very few investigators in the world who are collecting blood from POP cases for genetic studies and even fewer who are collecting blood from families with an excess of POP cases. Future replication studies will need to include more familial cases and use appropriate controls.
While these results still require additional replication, it is likely that one day genetic screening tests will be available to assess genetic risk for POP. Understanding more about the genetic etiology of POP could improve prevention and treatment of this condition, such as studying at-risk groups for preventative strategies (e.g., managing constipation or changing delivery modes). Patients might benefit from changing management algorithms, such as whether surgery is considered early or late in an individual woman’s clinical course.
In conclusion, this work provides evidence for a genetic contribution to POP. We have identified six SNPs that are significantly associated with POP in women with a strong family history of pelvic floor disorders. While we were unable to conclusively replicate our results, we have identified at least three strong candidate genes for POP that warrant follow-up. This association study furthers our understanding of the genetic underpinnings of POP.