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THU0014 A Regulatory Variant in CCR6 is Associated with Anti-Topoisomerase Positive Systemic Sclerosis Susceptibility
  1. E. Koumakis1,2,
  2. M. Bouaziz3,
  3. P. Dieudé4,
  4. G. Riemekasten5,
  5. P. Airo6,
  6. M. Matucci-Cerinic7,
  7. Y. Allanore1,2,
  1. 1Rheumatology A department, Cochin Hospital, APHP
  2. 2INSERM U1016, Paris Descartes University, Institut Cochin, Sorbonne Paris Cité
  3. 3UMR CNRS-8071/INRA-1152, Université d’Evry Val d’Essonne
  4. 4Rheumatology Department, Hôpital Bichat Claude Bernard, Paris, France
  5. 5Department of Rheumatology and Clinical Immunology, Charité University Hospital, Charité University Hospital, Berlin, Germany
  6. 6Rheumatology and Clinical Immunology, Spedali Civili, Brescia
  7. 7Department of Biomedicine & Division of Rheumatology AOUC, Department of Rheumatology AVC, Department of Medicine & Denothe centre, University of Florence, Florence, Italy


Background 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 CCR6 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 CCR6 (CCR6DNP), was recently identified. Indeed, the CCR6DNP 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.

Objectives To investigate whether CCR6 polymorphisms are associated with SSc.

Methods Twelve Tag SNPs of CCR6, 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 CCR6 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.

Results The combined analyses revealed an association between the rs10946216 SNP and SSc susceptibility: Padj=0.012, OR=1.13 (95%CI 1.05 to 1.21). The rs3093023 A and rs10946216 T alleles were in high linkage disequilibrium (r2 0.93) and were both found to confer susceptibility to the anti-topoisomerase-positive SSc subset: Padj=6.6x10-4, OR=1.27 (95% CI 1.13 to 1.42), and Padj=4.1x10-5, OR=1.32 (95% CI 1.17 to 1.48), respectively. In addition, intra-cohort analyses found that the CCR6 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 CCR6DNP 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

Conclusions Our study establishes CCR6 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.


  1. 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.

Disclosure of Interest None Declared

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