Transethnic meta-analysis identifiesGSDMAandPRDM1as susceptibility genes to systemic sclerosis.
OBJECTIVE
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,GSDMAandPRDM1, both of which are related to immune functions and associated with other autoimmune diseases (p=1.4×10-10and 6.6×10-10, respectively).GSDMAalso showed a significant association with limited cutaneous SSc. We also replicated the associations of previously reported loci including a non-GWAS locus,TNFAIP3. PRDM1encodes BLIMP1, a transcription factor regulating T-cell proliferation and plasma cell differentiation. The top SNP inGSDMAwas 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
GSDMAandPRDM1are associated with SSc. These findings provide enhanced insight into the genetic and biological basis of SSc.
Department of Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.|Center for the Promotion of Interdisciplinary Education and Research, Kyoto University Graduate School of Medicine, Kyoto, Japan.|Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
Chikashi
C
Terao
Department of Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Takahisa
T
Kawaguchi
Rheumatology Bichat Hospital, Paris 7 University, Paris, France.
Philippe
P
Dieude
Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
John
J
Varga
Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
Masataka
M
Kuwana
Jewish General Hospital and Lady Davis Research Institute, Montreal, Quebec, Canada.
Marie
M
Hudson
Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan.
Yasushi
Y
Kawaguchi
Division of Rheumatology AOUC, Department of Experimental and Clinical Medicine, Department of Medical & Geriatrics Medicine, University of Florence, Firenze, Italy.
Marco
M
Matucci-Cerinic
Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Koichiro
K
Ohmura
Clinic for Rheumatology, University of Lübeck, Lübeck, Germany.|German Lung Center Borstel, Leibniz Institute, Germany.
Gabriela
G
Riemekasten
Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
Aya
A
Kawasaki
Rheumatology Unit, Spedali Civili, Brescia, Italy.
Paolo
P
Airo
Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Tetsuya
T
Horita
The Institute of Medical Science, Tokai University, Isehara, Japan.
Akira
A
Oka
Internal Medicine Department, FHU Immune-Mediated Inflammatory Diseases and Targeted Therapies, Lille University, Lille, France.
Eric
E
Hachulla
Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Hajime
H
Yoshifuji
Rheumatology Department, University of Verona, Azienda Ospedaliera Universitaria Integrata, Italy.
Paola
P
Caramaschi
Dermatology Department, University of Koln, Koln, Germany.
Nicolas
N
Hunzelmann
Jewish General Hospital and Lady Davis Research Institute, Montreal, Quebec, Canada.
Murray
M
Baron
Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Tatsuya
T
Atsumi
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Paul
P
Hassoun
Torii Clinic, Kyoto, Japan.
Takeshi
T
Torii
Department of Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Meiko
M
Takahashi
Department of Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Yasuharu
Y
Tabara
Department of Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Masakazu
M
Shimizu
Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan.
Akiko
A
Tochimoto
Department of Rheumatology, National Hospital Organization, Utano National Hospital, Kyoto, Japan.
Naho
N
Ayuzawa
Department of Rheumatology, National Hospital Organization, Utano National Hospital, Kyoto, Japan.
Hidetoshi
H
Yanagida
Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.|Clinical Research Center for Allergy and Rheumatology, Sagamihara Hospital, National Hospital Organization, Sagamihara, Japan.
Hiroshi
H
Furukawa
Clinical Research Center for Allergy and Rheumatology, Sagamihara Hospital, National Hospital Organization, Sagamihara, Japan.
Shigeto
S
Tohma
Division of Medicine, Faculty of Medical Sciences, Department of Dermatology, University of Fukui, Fukui, Japan.
Minoru
M
Hasegawa
Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Manabu
M
Fujimoto
Department of Dermatology, Gunma University Graduate School of Medicine, Gunma, Japan.
Osamu
O
Ishikawa
Department of Dermatology, Fukushima Medical University, Fukushima, Japan.
Toshiyuki
T
Yamamoto
Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
Daisuke
D
Goto
Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Yoshihide
Y
Asano
Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Masatoshi
M
Jinnin
Division of Rheumatology, Department of Internal Medicine, School of Medicine, Toho University, Tokyo, Japan.
Hirahito
H
Endo
Department of Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan.
Hiroki
H
Takahashi
Department of Dermatology, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan.
Kazuhiko
K
Takehara
Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Shinichi
S
Sato
Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Hironobu
H
Ihn
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.|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.
Soumya
S
Raychaudhuri
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Katherine
K
Liao
Robert S. Boas Center for Genomics and Human Genetics, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
Peter
P
Gregersen
Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
Naoyuki
http://orcid.org/0000-0002-6776-5580
N
Tsuchiya
Sapienza University of Rome, Rome, Italy.
Valeria
V
Riccieri
University Medical Center, Freiburg, Germany.
Inga
I
Melchers
Department of Clinical and Experimental Medicine, Rheumatology Section, Second University of Naples, Naples, Italy.
Gabriele
G
Valentini
INSERM U1016/UMR 8104, Cochin Institute, Paris Descartes University, Paris, France.
Anne
A
Cauvet
INSERM U1220-IRSD-Batiment B Purpan Hospital Toulouse, Paris, France.
Maria
M
Martinez
Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Tsuneyo
T
Mimori
Department of Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Fumihiko
F
Matsuda
Rheumatology A Department, INSERM U1016/UMR 8104, Cochin Institute, Paris Descartes University, Paris, France.
Yannick
Y
Allanore
D016022:Case-Control Studies; D005060:Europe / Q000453:epidemiology; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006680:HLA Antigens / Q000235:genetics; D006801:Humans; D007564:Japan / Q000453:epidemiology; D009363:Neoplasm Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D000074462:Positive Regulatory Domain I-Binding Factor 1; D012097:Repressor Proteins / Q000235:genetics*; D012595:Scleroderma, Systemic / Q000208:ethnology / Q000235:genetics*; D000094524:Gasdermins
D006680:HLA Antigens; D009363:Neoplasm Proteins; D000074462:Positive Regulatory Domain I-Binding Factor 1; D012097:Repressor Proteins; C485887:GSDMA protein, human; D000094524:Gasdermins; C087042:PRDM1 protein, human
Autoimmune Diseases; Gene Polymorphism; Systemic Sclerosis