|
|
| PMID |
|
|
| 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 |
|
|
| 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 |
|
|
