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

Chikashi Terao; Takahisa Kawaguchi; Philippe Dieude; John Varga; Masataka Kuwana; Marie Hudson; Yasushi Kawaguchi; Marco Matucci-Cerinic; Koichiro Ohmura; Gabriela Riemekasten; Aya Kawasaki; Paolo Airo; Tetsuya Horita; Akira Oka; Eric Hachulla; Hajime Yoshifuji; Paola Caramaschi; Nicolas Hunzelmann; Murray Baron; Tatsuya Atsumi; Paul Hassoun; Takeshi Torii; Meiko Takahashi; Yasuharu Tabara; Masakazu Shimizu; Akiko Tochimoto; Naho Ayuzawa; Hidetoshi Yanagida; Hiroshi Furukawa; Shigeto Tohma; Minoru Hasegawa; Manabu Fujimoto; Osamu Ishikawa; Toshiyuki Yamamoto; Daisuke Goto; Yoshihide Asano; Masatoshi Jinnin; Hirahito Endo; Hiroki Takahashi; Kazuhiko Takehara; Shinichi Sato; Hironobu Ihn; Soumya Raychaudhuri; Katherine Liao; Peter Gregersen; Naoyuki Tsuchiya; Valeria Riccieri; Inga Melchers; Gabriele Valentini; Anne Cauvet; Maria Martinez; Tsuneyo Mimori; Fumihiko Matsuda; Yannick Allanore

doi:10.1136/annrheumdis-2016-210645

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

Chikashi Terao, Takahisa Kawaguchi, Philippe Dieude, John Varga, Masataka Kuwana, Marie Hudson, Yasushi Kawaguchi, Marco Matucci-Cerinic, Koichiro Ohmura, Gabriela Riemekasten, Aya Kawasaki, Paolo Airo, Tetsuya Horita, Akira Oka, Eric Hachulla, Hajime Yoshifuji, Paola Caramaschi, Nicolas Hunzelmann, Murray Baron, Tatsuya AtsumiPaul Hassoun, Takeshi Torii, Meiko Takahashi, Yasuharu Tabara, Masakazu Shimizu, Akiko Tochimoto, Naho Ayuzawa, Hidetoshi Yanagida, Hiroshi Furukawa, Shigeto Tohma, Minoru Hasegawa, Manabu Fujimoto, Osamu Ishikawa, Toshiyuki Yamamoto, Daisuke Goto, Yoshihide Asano, Masatoshi Jinnin, Hirahito Endo, Hiroki Takahashi, Kazuhiko Takehara, Shinichi Sato, Hironobu Ihn, Soumya Raychaudhuri, Katherine Liao, Peter Gregersen, Naoyuki Tsuchiya, Valeria Riccieri, Inga Melchers, Gabriele Valentini, Anne Cauvet, Maria Martinez, Tsuneyo Mimori, Fumihiko Matsuda, Yannick Allanore

School of Medicine

Research output: Contribution to journal › Article › peer-review

36 Scopus citations

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 14â €..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 â '10 and 6.6×10 â '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.

Original language	English (US)
Pages (from-to)	1150-1158
Number of pages	9
Journal	Annals of the rheumatic diseases
Volume	76
Issue number	6
DOIs	https://doi.org/10.1136/annrheumdis-2016-210645
State	Published - Jun 1 2017

Keywords

Autoimmune Diseases
Gene Polymorphism
Systemic Sclerosis

ASJC Scopus subject areas

Rheumatology
Immunology and Allergy
Immunology
General Biochemistry, Genetics and Molecular Biology

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10.1136/annrheumdis-2016-210645

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Terao, C., Kawaguchi, T., Dieude, P., Varga, J., Kuwana, M., Hudson, M., Kawaguchi, Y., Matucci-Cerinic, M., Ohmura, K., Riemekasten, G., Kawasaki, A., Airo, P., Horita, T., Oka, A., Hachulla, E., Yoshifuji, H., Caramaschi, P., Hunzelmann, N., Baron, M., ... Allanore, Y. (2017). Transethnic meta-Analysis identifies GSDMA and PRDM1 as susceptibility genes to systemic sclerosis. Annals of the rheumatic diseases, 76(6), 1150-1158. https://doi.org/10.1136/annrheumdis-2016-210645

Terao, C, Kawaguchi, T, Dieude, P, Varga, J, Kuwana, M, Hudson, M, Kawaguchi, Y, Matucci-Cerinic, M, Ohmura, K, Riemekasten, G, Kawasaki, A, Airo, P, Horita, T, Oka, A, Hachulla, E, Yoshifuji, H, Caramaschi, P, Hunzelmann, N, Baron, M, Atsumi, T, Hassoun, P, Torii, T, Takahashi, M, Tabara, Y, Shimizu, M, Tochimoto, A, Ayuzawa, N, Yanagida, H, Furukawa, H, Tohma, S, Hasegawa, M, Fujimoto, M, Ishikawa, O, Yamamoto, T, Goto, D, Asano, Y, Jinnin, M, Endo, H, Takahashi, H, Takehara, K, Sato, S, Ihn, H, Raychaudhuri, S, Liao, K, Gregersen, P, Tsuchiya, N, Riccieri, V, Melchers, I, Valentini, G, Cauvet, A, Martinez, M, Mimori, T, Matsuda, F & Allanore, Y 2017, 'Transethnic meta-Analysis identifies GSDMA and PRDM1 as susceptibility genes to systemic sclerosis', Annals of the rheumatic diseases, vol. 76, no. 6, pp. 1150-1158. https://doi.org/10.1136/annrheumdis-2016-210645

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title = "Transethnic meta-Analysis identifies GSDMA and PRDM1 as susceptibility genes to systemic sclerosis",

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{\^a} €..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 {\^a} '10 and 6.6×10 {\^a} '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-na{\"i}ve 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",

author = "Chikashi Terao and Takahisa Kawaguchi and Philippe Dieude and John Varga and Masataka Kuwana and Marie Hudson and Yasushi Kawaguchi and Marco Matucci-Cerinic and Koichiro Ohmura and Gabriela Riemekasten and Aya Kawasaki and Paolo Airo and Tetsuya Horita and Akira Oka and Eric Hachulla and Hajime Yoshifuji and Paola Caramaschi and Nicolas Hunzelmann and Murray Baron and Tatsuya Atsumi and Paul Hassoun and Takeshi Torii and Meiko Takahashi and Yasuharu Tabara and Masakazu Shimizu and Akiko Tochimoto and Naho Ayuzawa and Hidetoshi Yanagida and Hiroshi Furukawa and Shigeto Tohma and Minoru Hasegawa and Manabu Fujimoto and Osamu Ishikawa and Toshiyuki Yamamoto and Daisuke Goto and Yoshihide Asano and Masatoshi Jinnin and Hirahito Endo and Hiroki Takahashi and Kazuhiko Takehara and Shinichi Sato and Hironobu Ihn and Soumya Raychaudhuri and Katherine Liao and Peter Gregersen and Naoyuki Tsuchiya and Valeria Riccieri and Inga Melchers and Gabriele Valentini and Anne Cauvet and Maria Martinez and Tsuneyo Mimori and Fumihiko Matsuda and Yannick Allanore",

note = "Publisher Copyright: {\textcopyright} Published by the BMJ Publishing Group Limited.",

year = "2017",

month = jun,

day = "1",

doi = "10.1136/annrheumdis-2016-210645",

language = "English (US)",

volume = "76",

pages = "1150--1158",

journal = "Annals of the rheumatic diseases",

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TY - JOUR

T1 - Transethnic meta-Analysis identifies GSDMA and PRDM1 as susceptibility genes to systemic sclerosis

AU - Terao, Chikashi

AU - Kawaguchi, Takahisa

AU - Dieude, Philippe

AU - Varga, John

AU - Kuwana, Masataka

AU - Hudson, Marie

AU - Kawaguchi, Yasushi

AU - Matucci-Cerinic, Marco

AU - Ohmura, Koichiro

AU - Riemekasten, Gabriela

AU - Kawasaki, Aya

AU - Airo, Paolo

AU - Horita, Tetsuya

AU - Oka, Akira

AU - Hachulla, Eric

AU - Yoshifuji, Hajime

AU - Caramaschi, Paola

AU - Hunzelmann, Nicolas

AU - Baron, Murray

AU - Atsumi, Tatsuya

AU - Hassoun, Paul

AU - Torii, Takeshi

AU - Takahashi, Meiko

AU - Tabara, Yasuharu

AU - Shimizu, Masakazu

AU - Tochimoto, Akiko

AU - Ayuzawa, Naho

AU - Yanagida, Hidetoshi

AU - Furukawa, Hiroshi

AU - Tohma, Shigeto

AU - Hasegawa, Minoru

AU - Fujimoto, Manabu

AU - Ishikawa, Osamu

AU - Yamamoto, Toshiyuki

AU - Goto, Daisuke

AU - Asano, Yoshihide

AU - Jinnin, Masatoshi

AU - Endo, Hirahito

AU - Takahashi, Hiroki

AU - Takehara, Kazuhiko

AU - Sato, Shinichi

AU - Ihn, Hironobu

AU - Raychaudhuri, Soumya

AU - Liao, Katherine

AU - Gregersen, Peter

AU - Tsuchiya, Naoyuki

AU - Riccieri, Valeria

AU - Melchers, Inga

AU - Valentini, Gabriele

AU - Cauvet, Anne

AU - Martinez, Maria

AU - Mimori, Tsuneyo

AU - Matsuda, Fumihiko

AU - Allanore, Yannick

PY - 2017/6/1

Y1 - 2017/6/1

N2 - 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 14â €..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 â '10 and 6.6×10 â '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.

AB - 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 14â €..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 â '10 and 6.6×10 â '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.

KW - Autoimmune Diseases

KW - Gene Polymorphism

KW - Systemic Sclerosis

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U2 - 10.1136/annrheumdis-2016-210645

DO - 10.1136/annrheumdis-2016-210645

M3 - Article

C2 - 28314753

AN - SCOPUS:85019248276

SN - 0003-4967

VL - 76

SP - 1150

EP - 1158

JO - Annals of the rheumatic diseases

JF - Annals of the rheumatic diseases

IS - 6

ER -

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

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