title: Association between endometriosis and the interleukin 1A (IL1A) locus.
abstract: OBJECTIVE
  Are single-nucleotide polymorphisms (SNPs) at the interleukin 1A (IL1A) gene locus associated with endometriosis risk?
  
  
  CONCLUSIONS
  We found evidence for strong association between IL1A SNPs and endometriosis risk.
  
  
  BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  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.
  
  
  RESULTS
  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)).
  
  
  CONCLUSIONS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  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.
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia yadav.sapkota@qimrberghofer.edu.au.
authors.forename: Yadav
authors.initials: Y
authors.lastname: Sapkota
authors.affiliation: Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, The Institute of Physical and Chemical Research (RIKEN), Yokohama, Japan.
authors.forename: Siew-Kee
authors.initials: SK
authors.lastname: Low
authors.affiliation: Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia Public Health Research Program, Hunter Medical Research Institute, Newcastle, New South Wales, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Attia
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Gordon
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Anjali K
authors.initials: AK
authors.lastname: Henders
authors.affiliation: Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia Public Health Research Program, Hunter Medical Research Institute, Newcastle, New South Wales, Australia.
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Holliday
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Stuart
authors.initials: S
authors.lastname: MacGregor
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.affiliation: Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia Public Health Research Program, Hunter Medical Research Institute, Newcastle, New South Wales, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: McEvoy
authors.affiliation: Genetic and Genomic Epidemiology Unit, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Morris
authors.affiliation: Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, The Institute of Physical and Chemical Research (RIKEN), Yokohama, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takahashi
authors.affiliation: Public Health Research Program, Hunter Medical Research Institute, Newcastle, New South Wales, Australia School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia Division of Genetics, Hunter Area Pathology Service, Newcastle, New South Wales, Australia.
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Scott
authors.affiliation: Laboratory for Genotyping Development, Center for Integrative Medical Sciences, The Institute of Physical and Chemical Research (RIKEN), Yokohama, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.affiliation: Genetic and Genomic Epidemiology Unit, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK Nuffield Department of Obstetrics and Gynaecology, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors.forename: Krina T
authors.initials: KT
authors.lastname: Zondervan
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Dale R
authors.initials: DR
authors.lastname: Nyholt
mesh_terms: D016022:Case-Control Studies; D004715:Endometriosis / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D053582:Interleukin-1alpha / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: C508584:IL1A protein, human; D053582:Interleukin-1alpha
keywords: endometriosis; genome-wide association studies; immune responses; inflammation; interleukin 1A