Association of IL-10 receptor 2 (IL10RB) SNP with systemic sclerosis

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Abstract

Interleukin-10 (IL-10) signaling has been suggested to play a role in systemic sclerosis (SSc). IL10RB codes for IL-10 receptor 2 (IL-10R2), a component shared in receptor complexes for IL-10, IL-22, IL-26 and interferon (IFN)-λ. In this study, we examined association of IL10RB polymorphism with susceptibility to SSc. Genotype A/A at rs2834167 (47K/K) was significantly increased in diffuse cutaneous SSc (dcSSc) (41.3% in dcSSc, 20.9% in controls, P = 0.0018, odds ratio = 2.67). A SNP in the 5′ flanking region of IL10RB, rs999788, also showed association with dcSSc; however, this association was shown to be secondarily caused by linkage disequilibrium with rs2834167. Significant association was not observed in limited cutaneous SSc (lcSSc). Presence of anti-topoisomerase I antibody was also associated with rs2834167A/A genotype (P = 0.0019). Serum IL-10 level was significantly associated with the number of rs2834167A allele (P = 0.007). These findings suggested that signaling through IL-10R2 may play a causative role in dcSSc.

Section snippets

Materials and methods

Patients and controls. Forty-six patients with dcSSc (10 males and 36 females, average age 47.5 ± 16.1 years), 78 patients with lcSSc (4 males and 74 females, average age 54.8 ± 10.8 years), and healthy controls (229 males and 169 females, 28.6 ± 7.3 years) were studied. SSc was classified according to the American College of Rheumatology criteria [20]. Patients and healthy controls were recruited at Kanazawa University, The University of Tokyo and associated laboratories. All patients and healthy

Association of IL10RB E47 K with dcSSc

We initially focused on IL10RB rs2834167 coding for a nonsynonymous substitution E47K, because this SNP was associated with other conditions [18], [19] and considered likely to be functional. As shown in Table 1, rs2834167A/A genotype (47K/K) was significantly increased in SSc under the recessive model (P = 0.038, odds ratio [OR] = 1.61, 95% confidence interval [CI]: 1.02–2.54). The genotype frequency in our controls was compatible with Hardy–Weinberg equilibrium, and was quite similar to that in

Discussion

In the present study, we showed that rs2834167 coding for IL10RB E47K was associated with susceptibility to dcSSc. IL10RB gene has never been studied for the association of SSc. Our findings provided new evidence that supports the causal role of IL-10 or related cytokine signaling in the pathogenesis of SSc.

IL-10 stimulates B cells and T helper 2 (Th2) cells, which may result in production of autoantibodies. In the TSK/+ mouse, a genetic model for human SSc, loss of CD19 significantly decreased

Acknowledgments

This work was supported by Grant-in-Aid for Scientific Research on Priority Areas ‘Applied Genomics’ from the Ministry of Education, Culture, Sports, Science and Technology of Japan, Grant-in-Aid for Scientific Research (B) from Japan Society for the Promotion of Science (JSPS), grants from the Ministry of Health, Labour and Welfare of Japan, Japan Rheumatism Foundation and The Naito Foundation.

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