Genetic Epidemiology, Psychiatric Genetics, Asthma Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
25336714
TITLE
Association between endometriosis and the interleukin 1A (IL1A) locus.
ABSTRACT
STUDY QUESTION NlmCategory: OBJECTIVE
Are single-nucleotide polymorphisms (SNPs) at the interleukin 1A (IL1A) gene locus associated with endometriosis risk?
SUMMARY ANSWER NlmCategory: CONCLUSIONS
We found evidence for strong association between IL1A SNPs and endometriosis risk.
WHAT IS KNOWN ALREADY NlmCategory: 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.
STUDY DESIGN, SIZE, DURATION NlmCategory: 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.
PARTICIPANTS/MATERIALS, SETTING, METHODS NlmCategory: 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 NlmCategory: 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)).
LIMITATIONS, REASONS FOR CAUTION NlmCategory: 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.
WIDER IMPLICATIONS OF THE FINDINGS NlmCategory: 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.
STUDY FUNDING/COMPETING INTERESTS NlmCategory: 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.
The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
DATE PUBLISHED
2015 Jan
HISTORY
PUBSTATUS PUBSTATUSDATE
aheadofprint 2014/10/21
entrez 2014/10/23 06:00
pubmed 2014/10/23 06:00
medline 2016/04/05 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Sapkota Y Sapkota Yadav Y QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia yadav.sapkota@qimrberghofer.edu.au.
Low SK Low Siew-Kee SK Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, The Institute of Physical and Chemical Research (RIKEN), Yokohama, Japan.
Attia J Attia John J 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.
Gordon SD Gordon Scott D SD QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Henders AK Henders Anjali K AK QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Holliday EG Holliday Elizabeth G EG 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.
MacGregor S MacGregor Stuart S QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Martin NG Martin Nicholas G NG QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
McEvoy M McEvoy Mark M 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.
Morris AP Morris Andrew P AP Genetic and Genomic Epidemiology Unit, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Takahashi A Takahashi Atsushi A Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, The Institute of Physical and Chemical Research (RIKEN), Yokohama, Japan.
Scott RJ Scott Rodney J RJ 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.
Kubo M Kubo Michiaki M Laboratory for Genotyping Development, Center for Integrative Medical Sciences, The Institute of Physical and Chemical Research (RIKEN), Yokohama, Japan.
Zondervan KT Zondervan Krina T KT 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.
Montgomery GW Montgomery Grant W GW QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Nyholt DR Nyholt Dale R DR QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
INVESTIGATORS
JOURNAL
VOLUME: 30
ISSUE: 1
TITLE: Human reproduction (Oxford, England)
ISOABBREVIATION: Hum. Reprod.
YEAR: 2015
MONTH: Jan
DAY:
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1460-2350
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Hum Reprod
COUNTRY: England
ISSNLINKING: 0268-1161
NLMUNIQUEID: 8701199
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Meta-Analysis
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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GRANTS
GRANTID AGENCY COUNTRY
084766 Wellcome Trust United Kingdom
085235 Wellcome Trust United Kingdom
090532 Wellcome Trust United Kingdom
WT084766/Z/08/Z Wellcome Trust United Kingdom
GENERAL NOTE
KEYWORDS
KEYWORD
endometriosis
genome-wide association studies
immune responses
inflammation
interleukin 1A
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Case-Control Studies
Endometriosis genetics
Female genetics
Genome-Wide Association Study genetics
Humans genetics
Interleukin-1alpha genetics
Polymorphism, Single Nucleotide genetics
Risk Factors genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 IL1A protein, human
0 Interleukin-1alpha
OTHER ID's
OTHERID SOURCE
PMC4262465 NLM