Background The severity of joint destruction is highly variable between Rheumatoid Arthritis (RA) patients. The majority of its heritability is still unexplained. Several auto-immune diseases share genetic risk variants that may also influence disease progression.
Objectives We aimed to identify genetic risk factors for the severity of joint damage in RA by studying genetic susceptibility loci of several auto-immune diseases.
Methods In phase-1, 3143 sets of X-rays of 646 Dutch RA-patients taken over 7-years (Sharp-van der Heijde (SHS) scored) were studied. Genotyping was done by Immunochip. Associations of SNPs with MAF >0.01 and joint destruction were analyzed. In phase-2, 686 North-American RA-patients with 926 SHS-scored X-rays over 15 years of follow-up were evaluated. In both phases multiple testing corrections were done for the number of uncorrelated SNPs; the thresholds for significance were p<1.1x10-6 and p<0.0036. MMP-9 levels were measured with ELISA in baseline serum samples.
Results In phase-1, 109 SNPs associated significantly with joint destruction (p<1.1x10-6). Of these, 76 were located in the HLA-region; the 33 non-HLA variants were studied in phase-2. Here two variants were associated with the severity of joint destruction: rs451066 on chromosome 14 (p=0.002, MAF=0.20) and rs11908352 on chromosome 20 (p=0.002, MAF=0.21). Rs11908352 is located near the gene encoding Matrix Metalloproteinase-9 (MMP-9). Serum levels of MMP-9 were significantly associated with the rs11908352 genotypes (p=0.007).
Conclusions These data indicate that two loci that confer risk to other autoimmune diseases also affect the severity of joint destruction in RA. Rs11908352 may influence joint destruction via MMP-9 production.
Acknowledgements This work has been supported by grants from the Dutch Arthritis Foundation (Reumafonds) and the Dutch organization of Health research and development (Zon-MW). The authors also would like to acknowledge the RACI study group. The Immunochip analyses were supported by BBMRI-NL.
Disclosure of Interest None Declared