Background/Purpose Understanding the mechanisms underlying the inter-individual differences in radiographic progression is relevant and heritability studies have shown that genetic factors explain part of these inter-individual differences. Indeed, some genetic variants have been identified and replicated in independent studies or found significant in meta-analyses. The literature on genetic variants and joint destruction in RA was systematically reviewed recently; for genetic variants in IL-6, IL-10, C5-TRAF1, and FCRL3 the existing literature was indefinite on whether these variants are associated with joint destruction. We aimed to clarify associations of genetic variants in IL-6, IL-10, C5-TRAF1 and FCRL3 with radiographic progression by evaluating six independent cohorts.

Methods In total 5,895 sets of radiographs of 2,493 RA patients included in the Leiden EAC, Umeå, HCSC-RAC, Wichita, NDB and NARAC cohorts were studied in relation to rs1800795 (IL-6), rs1800896 (IL-10), rs2900180 (C5-TRAF1) and rs7528684 (FCLR3). Associations with radiographic progression rates were tested per cohort using an additive model, adjusting for age, gender and treatment when appropriate. The results on yearly radiographic progression rates were combined in inverse variance weighted meta-analyses. Analyses were done on the total RA population and after stratification for anti-citrullinated peptide antibodies (ACPA).  Furthermore, the associated region C5-TRAF1 was fine-mapped.

Results No associations were found for rs1800795 (IL-6), rs1800896 (IL-10) and rs7528684 (FCLR3) in the total RA population and after stratification for ACPA. Also the directionality of the effects was diverse. Although for rs2900180 in C5-TRAF1 no significance was obtained in the total population or in ACPA-positive RA, an association was observed in ACPA-negative RA (p value meta-analysis 5.85×10^-7). In all data sets with ACPA-negative RA, the minor allele was associated with more radiographic progression. Fine-mapping revealed a region of 66 Kb that was associated with radiographic progression; 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 in monocytes after lipopolysaccharide stimulation.

Conclusion In contrast to initial reports, variants in IL-6, IL-10 and FCLR3 were not associated with radiographic progression in the present large meta-analyses. Although an association between rs2900180 in C5-TRAF1 and joint destruction was initially identified in the total RA population, we here replicated an association of rs2900180 in C5-TRAF1 and linked variants in a 66 Kb region with radiographic progression in ACPA-negative RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/genetic-variants-in-il-6-il-10-c5-traf1-and-fcrl3-and-progression-of-joint-damage-in-rheumatoid-arthritis-a-study-on-six-cohorts/