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

Sapkota, Yadav, Low, Siew-Kee, Attia, John, Gordon, Scott D., Henders, Anjali K., Holliday, Elizabeth G., MacGregor, Stuart, Martin, Nicholas G., McEvoy, Mark, Morris, Andrew P., Takahashi, Atsushi, Scott, Rodney J., Kubo, Michiaki, Zondervan, Krina T., Montgomery, Grant W. and Nyholt, Dale R. (2015) Association between endometriosis and the interleukin 1A (IL1A) locus. Human Reproduction, 30 1: 239-248. doi:10.1093/humrep/deu267

Author Sapkota, Yadav
Low, Siew-Kee
Attia, John
Gordon, Scott D.
Henders, Anjali K.
Holliday, Elizabeth G.
MacGregor, Stuart
Martin, Nicholas G.
McEvoy, Mark
Morris, Andrew P.
Takahashi, Atsushi
Scott, Rodney J.
Kubo, Michiaki
Zondervan, Krina T.
Montgomery, Grant W.
Nyholt, Dale R.
Title Association between endometriosis and the interleukin 1A (IL1A) locus
Formatted title
Association between endometriosis and the interleukin 1A (IL1A) locus
Journal name Human Reproduction   Check publisher's open access policy
ISSN 1460-2350
Publication date 2015-01-01
Year available 2014
Sub-type Article (original research)
DOI 10.1093/humrep/deu267
Open Access Status Not yet assessed
Volume 30
Issue 1
Start page 239
End page 248
Total pages 10
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Language eng
Subject 2743 Reproductive Medicine
2742 Rehabilitation
2729 Obstetrics and Gynaecology
Abstract STUDY QUESTION: Are single-nucleotide polymorphisms (SNPs) at the interieukin IA (ILIA) gene locus associated with endometriosis risk?
Formatted 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 IL 1a 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 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.
Keyword Endometriosis
Genome-wide association studies
Immune responses
Interleukin 1A
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID 241944
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
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