Session Information
Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's - Pathogenesis, Animal Models and Genetics
Session Type: Abstract Submissions (ACR)
Background/Purpose: Systemic sclerosis (SSc), also known as scleroderma, is an inflammatory autoimmune disease characterized by fibrosis of the skin and internal organs, vascular damage and altered immune responses with autoantibody production (especially anticentromere (ACA) and antitopoisomerase I (ATA)). As a complex disease, SSc, is caused by a combination of genetic and environmental factors. In recent years, the number of new susceptibility loci associated with SSc has remarkably grown due to genome-wide association studies (GWAS). Nevertheless, the current knowledge of the influence of SSc risk loci in the clinical sub-phenoytpes is limited and one of the main reasons is the low sample size in sub-phenotypes that triggers a lower statistical power. In this regard, ATA+ SSc patients have been recently associated with CCR6 gene variants and the main limitations of the study was the low sample size due to the low frequency of ATA among SSc patients (around 20%). Thus, in order to confirm the CCR6 association with ATA+ SSc, we performed an independent replication study in populations of European ancestry and a meta-analysis with the previous data published.
Methods: We selected for replication SNP rs3093024, in high linkage disequilibrium with the SNPs previously associated with ATA+ SSc, rs3093023 (r2=1) and rs10946216 (r2=0.96). We designed a replication study with two phases: In phase I, we analyzed 454 ATA+ SSc cases and 4,867 controls from available GWAS genotyped platform by Radstake et al. and in phase II, 446 ATA+ SSc cases and 2,998 controls from five additional European cohorts were genotyped using TaqMan SNP® genotyping assay. Approval of local ethical committees and informed written consent was obtained for all participants. The meta-analysis of our study with the previous one included 1,548 ATA+ SSc cases and 14,777 controls and reached statistical power of the analysis to 99% (OR 1.16, MAF 0.43, at the 5% significant level).
Results: Results obtained in meta-analysis showed significant association between SNP rs3093024 and ATA+ SSc patients (P= 1.0 x 10-4, OR=1.16) (Table 1). Thus we confirm the association previously observed between CCR6 and ATA+ SSc patients harnessing the largest cohort of patients. The relevance of CCR6 gene lies in its function as specific marker for Th17 cells. These cells are characterized by the production of interleukin-17 (IL- 17) which has been found to be increased in patients with SSc. Besides serum levels of IL-17 and ATA presence have been both correlated with disease severity. Interestingly, CCR6 expression levels and IL-17 levels showed correlation with a CCR6 functional variant which was in high linkage disequilibrium with SNP rs3093024 in rheumatoid arthritis patients.
Conclusion: Taken all together, our findings suggest that the presence of the risk variant of rs3093024 in CCR6 gene may acts as a marker of severity in SSc patients.
Disclosure:
J. Martin,
None;
E. Ochoa,
None;
J. E. Martin,
None;
S. Assassi,
None;
L. Beretta,
None;
P. Carreira,
None;
C. P. Simeon,
None;
E. Koumakis,
None;
P. Dieude,
None;
Y. Allanore,
None;
F. J. García-Hernández,
None;
G. Espinosa,
None;
I. Castellvi Barranco,
None;
L. Trapiella,
None;
L. Rodriguez Rodriguez,
None;
M. A. González-Gay,
None;
M. V. Egurbide,
None;
L. Saez,
None;
J. L. Callejas,
None;
J. Vargas-Hitos,
None;
N. Hunzelmann,
None;
G. Riemekasten,
None;
T. Witte,
None;
J. H. Distler,
None;
A. Kreuter,
None;
C. Lunardi,
None;
A. Santaniello,
None;
F. K. Tan,
None;
F. C. Arnett,
None;
P. Shiels,
None;
A. L. Herrick,
None;
J. Worthington,
None;
M. C. Vonk,
None;
B. P. C. Koeleman,
None;
T. R. D. J. Radstake,
None;
M. Mayes,
None.
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