We observed a 35% reduction in the presence of endometriosis among carriers of the +331 T allele (95% CI 2%–57%). The +331C/T has been shown to influence the transcription of PR-B relative to PR-A with the T allele favoring PR-B (9
). PR-B acts as a classic hormone receptor, mediating the effects of progesterone whereas PR-A acts as a repressor of PR-B and as a result, the presence of the +331 T allele is hypothesized to lead to a greater effect of progesterone. Our finding of a reduced risk is biologically plausible since endometriosis is responsive to progesterone.
Attia and colleagues also showed lower levels of PR-B in endometriotic lesions (11
) which would be consistent with a protective role of a variant that increased PR-B and therefore progesterone responsiveness. Also, an association between the +331C/T variant and ovarian cancer was observed with both clear cell and endometrioid ovarian cancers, but not the other histological subtypes (OR=0.81, p=0.058) (10
The existing literature on the +331 T allele is contradictory. After Berchuck and colleagues (12
) first suggested a reduced risk of endometriosis associated with the T allele of the +331 variant, Treloar et al. (15
) conducted a large study which included more than 900 families (child-parent trios) and found no association. Van Kaam and colleagues (13
) reported a 33% decreased risk for deep infiltrating endometriosis in women who carry the +331 T allele (13
), but this is in the opposite direction from that reported by Gentilini et al (14
). However, both the studies of van Kaam et al. and Gentilini et al. were hospital-based and utilized controls with gynecological conditions and those referred for genetic testing so it is possible that the differences found were due to inadequate control selection. Also, both studies were small, with less than 100 and 200 cases, respectively. Furthermore, the CT and TT combined genotype frequencies reported for the general White control populations (those referred for genetic testing) by van Kaam et al. (18.3%) (13
) and Gentilini et al. (4.3%) (14
) are high and low, respectively, compared to that found in the eight White populations included in our study (8%–14%), including the European MALOVA study (14%). This difference in genotype frequencies may account for the difference in findings between these two studies. Also, genotyping quality control measures are not adequately described for either the van Kaam et al. or Gentilini et al. studies (13
). All of these design issues make the results of these two studies difficult to interpret. However, the null study from Treloar and colleagues for which all women with endometriosis were surgically confirmed does not suffer from such design issues (15
), leaving open the possibility that our finding is due to chance, particularly given the borderline statistically significant p-value that we observed (p=0.042). Further research is warranted to clarify the role of the +331 variant in the development of endometriosis.
There was no association between the PROGINS allele and risk of endometriosis (p=0.56). While these findings fail to support three previous studies which suggested an increase in susceptibility to endometriosis in women carrying the PROGINS allele (16
), they are in accordance with the results found by Treloar et al. (15
), van Kaam et al. (13
) and Govindan et al. (19
). The observation of no association may not be surprising given that the association between the PROGINS and ovarian cancer risk was observed with endometrioid ovarian cancer, but not the clear cell subtype.
This study was conducted among controls from a set of eight ovarian cancer case-control studies. The prevalence of endometriosis reported among control women is compatible with most population estimates of endometriosis (1
) and our study is large compared with most other reports in the literature. The controls appear representative of women in the areas where these studies were conducted. Importantly, there was also no evidence of heterogeneity among the eight studies pooled for this analysis supporting the validity of the findings.
All of the endometriosis data are based on self-report of a physician diagnosis. There is undoubtedly some misclassification of endometriosis diagnosis among affected individuals given that the condition was not necessarily surgically confirmed. Similarly, it is possible that women who reported no endometriosis could have the disease, but not have been diagnosed or informed of this diagnosis by their physician. The major limitation of this study is the small number of women with endometriosis (n=348) which restricts the statistical power to detect associations at very stringent levels of significance. The number of OCAC members is growing and represent a powerful forum in which to conduct genetic association studies as well as to explore in more detail the association between ovarian cancer risk and endometriosis. Extensive questionnaire data are available from many of the OCAC studies which allows for the evaluation of other factors such as oral contraceptive use. Additionally, we are able to examine the role of ovarian cancer histological subtype associated with endometriosis in this collaborative effort. Such studies are underway.
We have provided suggestive evidence for a role of variation in the PGR gene with endometriosis. The clinical implications of this finding are not clear at this point, but our results indicate that progesterone signaling may be important in this disease. Additional follow-up is warranted to further examine this relationship with endometriosis and the +331 variant as well as to explore the potential synergistic relationship between endometriosis, PGR variation and ovarian cancer risk.