No evidence for genetic association with the let-7 microRNA-binding site or other common KRAS variants in risk of endometriosis

Abstract

STUDY QUESTIONIs there a contribution of the minor allele at the KRAS single nucleotide polymorphism (SNP) rs61764370 in the let-7 microRNA-binding site to endometriosis risk?SUMMARY ANSWERWe found no evidence for association between endometriosis risk and rs61764370 or any other SNPs in KRAS.WHAT IS KNOWN ALREADYThe rs61764370 SNP in the 3′ untranslated region of the KRAS gene is predicted to disrupt a complementary binding site (LCS6) for the let-7 microRNA, and was recently reported to be at a high frequency (31%) in 132 women of varying ancestry with endometriosis compared with frequencies in a database of population controls (up to 7.6% depending on ancestry), suggesting a strong effect of this KRAS SNP in the aetiology of endometriosis.STUDY DESIGN, SIZE AND DURATIONThis was a case–control study with a total of 11 206 subjects. The study was performed between February 2012 and July 2012.PARTICIPANTS/MATERIALS, SETTING AND METHODSWe first investigated a possible association between common markers in KRAS and endometriosis risk from our genome-wide association (GWA) data in 3194 surgically confirmed endometriosis cases and 7060 controls of European ancestry. Although rs61764370 was not genotyped on the GWA arrays, five SNPs typed in the study were highly correlated with this variant. The rs61764370 and two SNPs highly correlated with rs61764370 were then genotyped in 933 endometriosis cases and 952 controls using the Sequenom MassARRAY platform.MAIN RESULTS AND THE ROLE OF CHANCEThere was no evidence for an association between rs61764370 and endometriosis risk P = 0.411 and odds ratio = 1.10 (95% confidence intervals: 0.88–1.36). We also found no evidence for an association between the highly correlated SNP rs17387019 and endometriosis. Their minor allele frequencies in cases and controls were of 0.087–0.091 similar to the population frequency reported previously for this variant in controls. Analyses of endometriosis cases with revised American Fertility Society stage III/IV disease also showed no evidence for an association between these SNPs and endometriosis risk.LIMITATIONS AND REASONS FOR CAUTIONThe GWA and genotyped data sets were not independent since individuals and cases from some families overlap. Controls in our GWA study were not screened for endometriosis.WIDER IMPLICATIONS OF THE FINDINGSThe key SNP, rs61764370, was genotyped in a subset of samples. Our results do not support the suggestion that carrying the minor allele at rs61764370 contributes to a significant number of endometriosis cases and rs61764370 is, therefore, unlikely to be a useful marker of endometriosis risk.STUDY FUNDING/COMPETING INTEREST(S)The research was funded by grants from the Australian National Health and Medical Research Council and Wellcome Trust. None of the authors has competing interests for the study.

Recent insights on the genetics and epigenetics of endometriosis

“…In women harboring this KRAS variant, altered miRNA binding leads to increased proliferation of endometrial stroma cells, invasion, abnormal endometrial growth and finally endometriosis . However, these results were not replicated in a much larger study, without finding a large difference between cases and controls allele frequency . It was recently demonstrated that decreased H19 lncRNA in the endometrium of endometriotic women increases let‐7 miRNA activity, which in turn inhibits Igf1r expression at the post‐transcriptional level.…”

Genetic Characterization of Endometriosis Patients: Review of the Literature and a Prospective Cohort Study on a Mediterranean Population

“…SNP rs61764370 interrupts the link between the LCS6 complementary site and let-7 miRNA, altering the expression of the KRAS gene and favouring the development of the disease. The analysis conducted in 2012 by Hien Luong and Painter denied this risk association [73]. A meta-analysis of the GWASs of the IEC and the Japanese group, carried out in 2012, confirmed the associations previously reported in the respective studies and identified further significant new loci of association localized on GREB1 genes, involved in estrogenic regulation; VEZT, involved in cell growth, migration and adhesion; and ID4, an ovarian tumour suppressor [17].…”

Evaluation of KRAS Gene Expression and LCS6 Variant in Genomic and Cell-Free DNA of Iranian Women With Endometriosis

“…Based on genome-wide association study, the same finding was reported by a European report. 16 In addition to geographical variations, other contributing factors such as probable somatic alteration of KRAS LCS6 SNP in endometriosis tissue, help explain the controversy.…”