THU0014 A Regulatory Variant in CCR6 is Associated with Anti-Topoisomerase Positive Systemic Sclerosis Susceptibility
Authors: E. Koumakis, M. Bouaziz, P. Dieudé, G. Riemekasten, P. Airo, M. Matucci-Cerinic, Y. Allanore
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Systemic sclerosis (SSc) is a rare autoimmune disease (AID) with a complex genetic etiology. Evidence for a shared pathogenesis across AIDs is supported by the well-known pleiotropism of autoimmune genes. Polymorphisms of the <i>CCR6</i> gene, encoding chemokine receptor 6, a surface marker for Th17 cells, were reproducibly found to be associated with RA susceptibility. Importantly, the causal variant, a functional triallelic dinucleotide polymorphism of <i>CCR</i>6 (<i>CCR6DNP</i>), was recently identified. Indeed, the <i>CCR6DNP</i> was correlated with CCR6 mRNA expression, was associated with IL-17 detection in the sera of RA patients and exhibited effects on gene transcription (1). In SSc, several lines of evidence point to a role of Th17 cells in the early stage of disease. <h3>Objectives</h3> To investigate whether <i>CCR6</i> polymorphisms are associated with SSc. <h3>Methods</h3> Twelve Tag SNPs of <i>CCR6</i>, including rs3093023 for which convincing association was reported with RA, were genotyped in a total of 2,393 SSc patients and 7,064 healthy individuals from three European populations (France, Italy, and Germany). A meta-analysis was performed to assess whether an association exists between <i>CCR6</i> polymorphisms and SSc or its main subtypes. Thereafter, direct sequencing was performed in a sample of the French cohort to study whether the functional dinucleotide found in RA was in linkage disequilibrium with the rs3093023 SNP. <h3>Results</h3> The combined analyses revealed an association between the rs10946216 SNP and SSc susceptibility: P<sub>adj</sub>=0.012, OR=1.13 (95%CI 1.05 to 1.21). The rs3093023 A and rs10946216 T alleles were in high linkage disequilibrium (r<sup>2</sup> 0.93) and were both found to confer susceptibility to the anti-topoisomerase-positive SSc subset: P<sub>adj</sub>=6.6x10<sup>-4</sup>, OR=1.27 (95% CI 1.13 to 1.42), and P<sub>adj</sub>=4.1x10<sup>-5</sup>, OR=1.32 (95% CI 1.17 to 1.48), respectively. In addition, intra-cohort analyses found that the <i>CCR6</i> rs3093023 A and rs10946216 T allele frequencies were significantly increased in anti-topoisomerase positive SSc compared with anti-topoisomerase negative SSc: 50.9% vs 45.3%, p=0.0009, OR=1.25 (95% CI 1.09 to 1.42) for rs3093023, and 51.9% vs 46.5%, p=0.0014, OR=1.24 (95% CI 1.08 to 1.41) for rs10946216. Direct sequencing revealed that the <i>CCR6DNP</i> TG/TG genotype was correlated with the rs3093023 A/A genotype in 100% of cases, supporting that the recently discovered regulatory dinucleotide is the causal variant <h3>Conclusions</h3> Our study establishes <i>CCR6</i> as a new susceptibility factor for anti-topoisomerase-positive SSc patients, in a European Caucasian population, confirming the shared genetic background in SSc and RA. It also underlines the potential role of IL-17 pathway in SSc. <h3>References</h3> Kochi Y, Okada Y, Suzuki A, Ikari K, Terao C, Takahashi A, et al. A regulatory variant in CCR6 is associated with rheumatoid arthritis. Nat Genet. 2010;42(6):515-9. <h3>Disclosure of Interest</h3> None Declared