BRIEF COMMUNICATION Interleukin-10 genotypes are associated with systemic sclerosis and influence disease-associated autoimmune responses LL Hudson 1 , KM Rocca 1 , M Kuwana 2 and JP Pandey 1 1 Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA; 2 Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan Systemic sclerosis (SSc; scleroderma) is a connective tissue disease, characterized by fibrotic, immunological, and vascular abnormalities. Interleukin-10 (IL-10) is an anti-inflammatory cytokine that modulates collagen production and B-cell survival. To determine if certain IL-10 genotypes are risk factors for the development of SSc and influence disease-associated autoimmune responses, 248 Caucasian and 264 Japanese SSc patients and controls were genotyped for three loci: 3575, 2849, and 2763. Sera from patients were characterized for SSc-associated autoantibodies. In Caucasians, at 3575 and 2763, the frequency of AA homozygotes was higher in patients as compared with controls (P ¼ 0.0005; P ¼ 0.002). In Japanese subjects, the frequency of AC heterozygotes at 2763 was higher, and that of CC homozygotes lower, in patients with diffuse SSc as compared to controls (P ¼ 0.04). Particular IL-10 genotypes were associated with SSc-related autoantibodies. These results suggest that IL-10 genotypes contribute to the etiology of scleroderma. Genes and Immunity (2005) 6, 274–278. doi:10.1038/sj.gene.6364180 Published online 17 March 2005 Keywords: systemic sclerosis; interleukin-10; scleroderma; linkage disequilibrium; autoantibodies Interleukin-10 (IL-10) is a pleiotropic cytokine produced primarily by monocytes, T cells, and B cells. IL-10 has both activating and inhibitory influences on T cells, is involved in immunoglobulin class switching, and pro- motes B-cell survival. 1 Additionally, IL-10 modulates the extracellular matrix by inhibiting fibroblast proliferation and collagen production. 2,3 The interindividual differ- ences in IL-10 production levels have a large genetic component. 4–6 Owing to these properties, there is a growing interest in determining the role of IL-10 genes in autoimmune diseases. 7 Scleroderma is an autoimmune rheumatic disease characterized by extensive fibrosis, thickened skin, vascular alterations, and immunological abnormal- ities. There are two major subtypes of systemic sclerosis (SSc). 8 Diffuse SSc is the most serious form, characterized by extensive fibrosis of skin and internal organs; development of the disease can be rapid and severe. Limited SSc is a milder disease form, as patients have less involvement of internal organs and slower disease progression. The majority of SSc patients produce antibodies directed at nuclear antigens, which are strongly associated with organ involvement and disease outcome. 9–12 Although the etiology of SSc is unknown, genetic factors are thought to be important. Several polymorphic genes—which are either risk factors for the development of SSc or influence disease-associated autoimmune responsiveness—have been identified. These include human leukocyte antigens (HLA), fibrillin-1, and GM and KM allotypes—genetic markers of g and k chains, respectively. 13–15 To determine if allelic variation at IL-10 loci is associated with SSc and SSc-related humoral autoimmune responses, DNA samples from Caucasian and Japanese patients and controls were genotyped at three IL-10 sites (3575, 2849, and 2763) and patients’ sera were characterized for disease-related autoantibo- dies. This study was approved by the Institutional Review Board/Ethical Committee for human research of the Medical University of South Carolina and the Keio University School of Medicine. All subjects provided their written informed consent. Caucasian subjects consisted of 105 SSc patients (67 limited, 38 diffuse) and 143 controls presenting at the Rheumatology Clinic of the Medical University of South Carolina. Controls consisted of unrelated patients with osteoarthritis, fibromyalgia, gout, or regional musculoskeletal pain syndromes. Controls with conditions associated with autoimmune or connective tissue diseases were ex- cluded. Japanese subjects consisted of 127 SSc patients (86 limited, 41 diffuse) presenting at Keio University School of Medicine and 137 healthy, ethnically matched controls living in the Tokyo area. All patients fulfilled the Received 29 November 2004; revised 3 February 2005; accepted 3 February 2005; published online 17 March 2005 Correspondence: Dr JP Pandey, Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425-2230, USA. E-mail: pandeyj@musc.edu Genes and Immunity (2005) 6, 274–278 & 2005 Nature Publishing Group All rights reserved 1466-4879/05 $30.00 www.nature.com/gene