Association between endometriosis and the interleukin 1A (ILIA) locus

STUDY QUESTION: Are single-nucleotide polymorphisms (SNPs) at the interieukin IA (ILIA) gene locus associated with endometriosis risk? SUMMARY ANSWER: We found evidence for strong association between ILIA SNPs and endometriosis risk. WHAT IS KNOWN ALREADY: Genetic factors contribute substantially to the complex aetiology of endometriosis and the disease has an estimated heritability of similar to 51%. We, and others, have conducted genome-wide association (GWA) studies for endometriosis, which identified a total of nine independent risk loci. Recently, two small Japanese studies reported eight SNPs (rs6542095, rs11677416, rs3783550, rs3783525, rs3783553, rs2856836, rs1304037 and rsI7561) at the ILIA gene locus as suggestively associated with endometriosis risk. There is also evidence of a link between inflammation and endometriosis. STUDY DESIGN, SIZE, DURATION: We sought to further investigate the eight ILIA SNPs for association with endometriosis using an independent sample of 3908 endometriosis cases and 8568 controls of European and Japanese ancestry. The study was conducted between October 2013 and July 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: By leveraging GWA data from our previous multi-ethnic GWA meta-analysis for endometriosis, we imputed variants in the ILIA region, using a recent 1000 Genomes reference panel. After combining summary statistics for the eight SNPs from our European and Japanese imputed data with the published results, a fixed-effect meta-analysis was performed. An additional meta-analysis restricted to endometriosis cases with moderate-to-severe (revised American Fertility Society stage 3 or 4) disease versus controls was also performed. MAIN RESULTS AND THE ROLE OF CHANCE: All eight ILIA SNPs successfully replicated at P < 0.014 in the European imputed data with concordant direction and similar size to the effects reported in the original Japanese studies. Of these, three SNPs (rs6542095, rs3783550 and rs3783525) also showed association with endometriosis at a nominal P < 0.05 in our independent Japanese sample. Fixed-effect meta-analysis of the eight SNPs for moderate-to-severe endometriosis produced a genome-wide significant association for rs6542095 (odds ratio = 1.21; 95% confidence interval = 1.13-1.29; P = 3.43 x 10(-8)). LIMITATIONS, REASONS FOR CAUTION: The meta-analysis for moderate-to-severe endometriosis included results of moderate-to-severe endometriosis cases from our European data sets and all endometriosis cases from the Japanese data sets, as disease stage information was not available for endometriosis cases in the Japanese data sets. WIDER IMPLICATIONS OF THE FINDINGS: SNPrs6542095 is located similar to 2.3 kb downstream of the ILIA gene and similar to 6.9 kb upstream of cytoskeleton-associated protein 2-like (CKAP2L) gene. The ILIA gene encodes the ILIa protein, a member of the interieukin 1 cytokine family which is involved in various immune responses and inflammatory processes. These results provide important replication in an independent japanese sample and, for the first time, association of the ILIA locus in endometriosis patients of European ancestry. SNPs within the ILIA locus may regulate other genes, but if ILIA is the target, our results provide supporting evidence for a link between inflammatory responses and the pathogenesis of endometriosis.