Common susceptibility loci in both systemic sclerosis and localized scleroderma identified using genetic analysis

摘要

Scleroderma is an autoimmune fibrosing disorder that can be further subclassified as localized scleroderma (LSc) and systemic sclerosis (SSc). LSc is characterized by sclerotic and pigmented skin lesions, while SSc is a more generalized disorder of the connective tissue involving a number of organs. SSc is characterized by the thickening of dermal collagen bundles, fibrosis, and vascular abnormalities in the visceral organs.[1] Despite the differences in their morphologic features and clinical presentation, these two diseases do share some characteristics including endothelial cell dysfunction, T helper 2 (Th2) cell dominance during immune activation and excess fibrosis of the skin with similar pathologic findings, leading to the hypothesis that SSc and LSc share an underlying mechanism of pathogensis. Currently, multiple lines of evidence suggest that genetic factors may contribute to SSc susceptibility.[2] Human leukocyte antigen (HLA) genes are closely linked to SSc susceptibility, with studies describing some correlation between SSc and HLA-B, HLA-C, HLA-DRA, HLA-DRB1, HLA-DRB5, HLA-DQA1, HLA-DQB1, HLA-DMB, HLA-DOA, HLA-DPA1, HLA-DPB1, and HLA-DPB2.[2] A large number of non-HLA genes have also been reported to be associated with the development of SSc, these include connective tissue growth factor gene (TGF), signal transducer and activator of transcription gene (STAT4) amongst others [Supplementary Table 1]. However, only some of these results could be verified in additional studies and similar studies in the Chinese population remain extremely limited. Interestingly, genes like interleukin 1 (IL-1), ras homolog family member B (RHOB), family with sequence similarity 167-member A-BLK proto-oncogene (FAM167A-BLK), STAT4, interferon regulatory factor 5 gene (IRF5), HLA-DPB1, and keratin1 (KRT1) have all been linked to SSc susceptibility in the Chinese population.[3] Although it has been reported that LSc tends to exhibit some form of familial inheritance, there have been no clearly identified heritable traits for this disease. Additionally, no study, to our knowledge, has investigated the common genetic factors for LSc and SSc. Thus, it would be of significant interest to examine the susceptibility of LSc and determine whether there are any correlations between the genetic profiles of SSc and LSc. This study aimed to identify the genetic profile of LSc patients and any shared genetic features of SSc and LSc in the Chinese population. Furthermore, this study evaluated the occurance of previously described SSc loci in the Chinese population and compared their frequency with those reported in other ethnic communities.