Association between endometriosis and the interleukin 1A (IL1A) locus

Abstract

Study question: Are single-nucleotide polymorphisms (SNPs) at the interleukin 1A (IL1A) gene locus associated with endometriosis risk?

Summary answer: We found evidence for strong association between IL1A 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 ∼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 rs17561) at the IL1A 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 IL1A 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 IL1A 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 IL1A 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 × 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: SNP rs6542095 is located ∼2.3 kb downstream of the IL1A gene and ∼6.9 kb upstream of cytoskeleton-associated protein 2-like (CKAP2L) gene. The IL1A gene encodes the IL1a protein, a member of the interleukin 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 IL1A locus in endometriosis patients of European ancestry. SNPs within the IL1A locus may regulate other genes, but if IL1A is the target, our results provide supporting evidence for a link between inflammatory responses and the pathogenesis of endometriosis.

Study funding/competing interests: 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.

Keywords: endometriosis; genome-wide association studies; immune responses; inflammation; interleukin 1A.

Figure 1

Evidence of association in ‘All’ endometriosis from the fixed-effect meta-analysis of the eight IL1A variants, using imputed data from QIMRHCS, OX and BBJ and published results from Adachi et al. (2010) and Hata et al. (2013). Circles in the plot represent SNPs with no functional annotations. Squares represent SNPs located in either coding or untranslated regions. Inverted triangles denote non-synonymous SNPs. SNP names in red font are reported by Adachi et al. (2010) and SNP names in green font are reported by Hata et al. (2013). The most significant SNP (rs6542095) is represented by a purple circle. All other SNPs are colour coded according to the strength of LD with the best SNP (as measured by r² in the European 1000 Genomes data).

Figure 2

Evidence of association in ‘Grade_B’ endometriosis from the fixed-effect meta-analysis of the eight IL1A variants, using imputed data from QIMRHCS, OX and BBJ and published results from Adachi et al. (2010) and Hata et al. (2013). Circles in the plot represent SNPs with no functional annotations. Squares represent SNPs located in either coding or untranslated regions. Inverted triangles denote non-synonymous SNPs. SNP names in red font are reported by Adachi et al. (2010) and SNP names in green font are reported by Hata et al. (2013). The most significant SNP (rs6542095) is represented by a purple circle. All other SNPs are colour coded according to the strength of LD with the best SNP (as measured by r² in the European 1000 Genomes data).

Figure 3

UCSC Genome Browser snapshot of rs3783525, with 250 bp flanking regions on its either side. Tracks displayed from top to bottom include genome base position (hg19), UCSC Genes, Layered H3K4Me3 mark on seven cell lines from ENCODE, Layered H3K4Me1 mark on seven cell lines from ENCODE, Layered H3K27Ac mark on seven cell lines from ENCODE, DNaseI Hypersensitivity Clusters in 125 cell types from ENCODE, Transcription factor CHIP-seq (161 factors) from ENCODE, All SNPs (138), Human mRNAs and Spliced ESTs, respectively.