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.
- Systemic Sclerosis
- Gene Polymorphism
- Autoimmune Diseases
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Handling editor Tore K Kvien
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Contributors Wrote the paper: CT, YA. Performed imputation and analyses: CT, TK, MM Performed the experimental work: CT, AK, AO, MS, AC. Conceived and designed the study: CT, TM, FM, YA. Substantial contribution to acquired samples and creation of data in GWAS: CT, TK, PD, MK, YK, KO, TH, HY, TA, TT, MT, YT, MS, AT, AC, MM, TM, FM, YA. Substantial contribution to acquired samples and creation of data in replication study: CT, PD, JV, MH, MMC, KO, GR, AK, PA, TH, AO, EH, HY, PC, NH, MB, TA, PH, TT, MT, YT, MS, NA, HY, HF, ST, MH, MF, OI, TY, DG, YA, MJ, HE, HT, KT, SS, HI, SR, KL, PG, NT, VR, IM, GV, AC, TM, FM, YA. Contribution to collection of clinical information: CT, PD, JV, MK, MH, YK, MMC, KO, GR, PA, TH, AO, EH, PC, NH, MB, TA, PH, YT, AT, NA, HY, HF, ST, MH, MF, OI, TY, DG, YA, MJ, HE, HT, KT, SS, HI, VR, IM, GV, AC, TM, FM, YA. All authors revised and approved the manuscript to be published.
Funding This study was supported by JSPS KAKENHI Grant Number JP16H06251, KANAE foundation for the promotion of medical science, Research Project of Genetic Studies for Intractable Diseases, Nagao Memorial Fund, The Uehara Memorial Foundation, The John Mung Advanced Program, Kyoto University and Associattion des Sclerodermie de France, INSERM, CNRS, ATIP AVENIR Programme, Agence Nationale pour la Recherche (Project ANR-08-GENO-016-1).
Competing interests None declared.
Ethics approval This study was approved by local ethical committees.
Provenance and peer review Not commissioned; externally peer reviewed.