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A genetic study on C5-TRAF1 and progression of joint damage in rheumatoid arthritis

2015; BioMed Central; Volume: 17; Issue: 1 Linguagem: Inglês

10.1186/s13075-014-0514-0

1478-6362

H.W. van Steenbergen, Luis Rodríguez‐Rodríguez, Ewa Berglin, Alexandra Zhernakova, Rachel Knevel, J. Ivorra Cortés, T. Huizinga, Benjamín Fernández‐Gutiérrez, Peter K. Gregersen, Solbritt Rantapää‐Dahlqvist, Annette H M van der Helm–van Mil,

Cytokine Signaling Pathways and Interactions

Introduction:The severity of joint damage progression in rheumatoid arthritis (RA) is heritable.Several genetic variants have been identified, but together explain only part of the total genetic effect.Variants in Interleukin-6 (IL-6), Interleukin-10 (IL-10), C5-TRAF1, and Fc-receptor-like-3 (FCRL3) have been described to associate with radiographic progression, but results of different studies were incongruent.We aimed to clarify associations of these variants with radiographic progression by evaluating six independent cohorts.Methods: In total 5,895 sets of radiographs of 2,493 RA-patients included in six different independent datasets from the Netherlands, Sweden, Spain and North-America were studied in relation to rs1800795 (IL-6), rs1800896 (IL-10), rs2900180 (C5-TRAF1) and rs7528684 (FCRL3).Associations were tested in the total RA-populations and in anti-citrullinated peptide antibodies (ACPA)-positive and ACPA-negative subgroups per cohort, followed by meta-analyses.Furthermore, the associated region C5-TRAF1 was fine-mapped in the ACPA-negative Dutch RA-patients.Results: No associations were found for rs1800795 (IL-6), rs1800896 (IL-10) and rs7528684 (FCRL3) in the total RA-population and after stratification for ACPA.Rs2900180 in C5-TRAF1 was associated with radiographic progression in the ACPA-negative population (P-value meta-analysis = 5.85 × 10 -7 ); the minor allele was associated with more radiographic progression.Fine-mapping revealed a region of 66Kb that was associated; the lowest P-value was for rs7021880 in TRAF1.The P-value for rs7021880 in meta-analysis was 6.35 × 10 -8 .Previous studies indicate that the region of rs7021880 was associated with RNA expression of TRAF1 and C5. Conclusion:Variants in IL-6, IL-10 and FCRL3 were not associated with radiographic progression.Rs2900180 in C5-TRAF1 and linked variants in a 66Kb region were associated with radiographic progression in ACPA-negative RA.