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Ann Rheum Dis. 2017 Jun;76(6):1150-1158. doi: 10.1136/annrheumdis-2016-210645. Epub 2017 Mar 17.

Transethnic meta-analysis identifies GSDMA and PRDM1 as susceptibility genes to systemic sclerosis.

Author information

1
Department of Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
2
Center for the Promotion of Interdisciplinary Education and Research, Kyoto University Graduate School of Medicine, Kyoto, Japan.
3
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, USA.
4
Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
5
Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
6
Rheumatology Bichat Hospital, Paris 7 University, Paris, France.
7
Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
8
Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
9
Jewish General Hospital and Lady Davis Research Institute, Montreal, Quebec, Canada.
10
Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan.
11
Division of Rheumatology AOUC, Department of Experimental and Clinical Medicine, Department of Medical & Geriatrics Medicine, University of Florence, Firenze, Italy.
12
Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
13
Clinic for Rheumatology, University of Lübeck, Lübeck, Germany.
14
German Lung Center Borstel, Leibniz Institute, Germany.
15
Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
16
Rheumatology Unit, Spedali Civili, Brescia, Italy.
17
Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
18
The Institute of Medical Science, Tokai University, Isehara, Japan.
19
Internal Medicine Department, FHU Immune-Mediated Inflammatory Diseases and Targeted Therapies, Lille University, Lille, France.
20
Rheumatology Department, University of Verona, Azienda Ospedaliera Universitaria Integrata, Italy.
21
Dermatology Department, University of Koln, Koln, Germany.
22
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
23
Torii Clinic, Kyoto, Japan.
24
Department of Rheumatology, National Hospital Organization, Utano National Hospital, Kyoto, Japan.
25
Clinical Research Center for Allergy and Rheumatology, Sagamihara Hospital, National Hospital Organization, Sagamihara, Japan.
26
Division of Medicine, Faculty of Medical Sciences, Department of Dermatology, University of Fukui, Fukui, Japan.
27
Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
28
Department of Dermatology, Gunma University Graduate School of Medicine, Gunma, Japan.
29
Department of Dermatology, Fukushima Medical University, Fukushima, Japan.
30
Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
31
Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
32
Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
33
Division of Rheumatology, Department of Internal Medicine, School of Medicine, Toho University, Tokyo, Japan.
34
Department of Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan.
35
Department of Dermatology, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan.
36
Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.
37
Robert S. Boas Center for Genomics and Human Genetics, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
38
Sapienza University of Rome, Rome, Italy.
39
University Medical Center, Freiburg, Germany.
40
Department of Clinical and Experimental Medicine, Rheumatology Section, Second University of Naples, Naples, Italy.
41
INSERM U1016/UMR 8104, Cochin Institute, Paris Descartes University, Paris, France.
42
INSERM U1220-IRSD-Batiment B Purpan Hospital Toulouse, Paris, France.
43
Rheumatology A Department, INSERM U1016/UMR 8104, Cochin Institute, Paris Descartes University, Paris, France.

Abstract

OBJECTIVES:

Systemic sclerosis (SSc) is an autoimmune disease characterised by skin and systemic fibrosis culminating in organ damage. Previous genetic studies including genome-wide association studies (GWAS) have identified 12 susceptibility loci satisfying genome-wide significance. Transethnic meta-analyses have successfully expanded the list of susceptibility genes and deepened biological insights for other autoimmune diseases.

METHODS:

We performed transethnic meta-analysis of GWAS in the Japanese and European populations, followed by a two-staged replication study comprising a total of 4436 cases and 14 751 controls. Associations between significant single nuclear polymorphisms (SNPs) and neighbouring genes were evaluated. Enrichment analysis of H3K4Me3, a representative histone mark for active promoter was conducted with an expanded list of SSc susceptibility genes.

RESULTS:

We identified two significant SNP in two loci, GSDMA and PRDM1, both of which are related to immune functions and associated with other autoimmune diseases (p=1.4×10-10 and 6.6×10-10, respectively). GSDMA also showed a significant association with limited cutaneous SSc. We also replicated the associations of previously reported loci including a non-GWAS locus, TNFAIP3. PRDM1 encodes BLIMP1, a transcription factor regulating T-cell proliferation and plasma cell differentiation. The top SNP in GSDMA was a missense variant and correlated with gene expression of neighbouring genes, and this could explain the association in this locus. We found different human leukocyte antigen (HLA) association patterns between the two populations. Enrichment analysis suggested the importance of CD4-naïve primary T cell.

CONCLUSIONS:

GSDMA and PRDM1 are associated with SSc. These findings provide enhanced insight into the genetic and biological basis of SSc.

KEYWORDS:

Autoimmune Diseases; Gene Polymorphism; Systemic Sclerosis

PMID:
28314753
DOI:
10.1136/annrheumdis-2016-210645
[Indexed for MEDLINE]

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