Background and Objectives The severity of joint destruction is highly variable between Rheumatoid Arthritis (RA) patients. We aimed to identify new genetic risk factors by studying genetic susceptibility loci of several auto-immune diseases.
Patients and Methods In phase-1, 646 Dutch RA-patients with yearly X-rays of hands and feet over 7 years follow-up were genotyped for 148,880 SNPs by Immunochip which contains 186 loci previously associated with autoimmune diseases. Association of SNPs with MAF > 0.01 (130,841 SNPS) with joint destruction was analysed using a marginal regression model. Correction for multiple testing was done by Bonferroni correction for the number of uncorrelated SNPs (threshold p < 1.1 × 10–6). In phase-2, 686 North American RA-patients with repeated hands X-rays over 15 years follow-up, for which Immunochip genotyping data were also available, were studied. SNPs that were significantly associated in phase-1 were selected and evaluated. All X-rays were scored by Sharp van der Heijde score (ICC 0.91 and 0.98 for phase-1 and 2 respectively). MMP-9 levels were measured in baseline serum by ELISA (Ebioscience) in 120 RA-patients that were selected on the Rs11908352-genotype.
Results In phase-1, 109 SNPs were significantly associated with joint destruction (p < 1.1 × 10–6). Of these, 76 variants were on the HLA region. The 33 non-HLA genetic variants, though several were in high LD, were studied in the North-American RA-patients. Here, after correction for the number of uncorrelated SNPs (threshold p < 0.0036), two variants were associated with the severity of joint destruction: Rs451066 on chromosome 14 (puncorrected = 0.002, MAF = 0.20) and Rs11908352 on chromosome 20 (puncorrected = 0.002, MAF = 0.21). The region of Rs451066 on chromosome 14 has previously been linked to type-1 diabetes susceptibility. Presence of a risk allele was associated with a 3.7% higher rate of joint destruction per year; this equaled 29% over 7-years. Rs11908352 is located at the MMP-9 region on chromosome 20. Patients with a risk allele had a 2.7% higher radiological progression rate per year, which equaled 20% more joint destruction over a 7-years period. Furthermore, the minor genotype was associated with significantly higher levels of MMP-9 compared to the common genotype (p = 0.007).
Conclusions Two new risk loci for progressive joint destruction in RA were identified (Rs451066 and Rs1190852). The risk allele in Rs11908352 also associated with higher serum MMP-9 levels, indicating to a role for MMP-9 in progression of joint destruction in RA.
Acknowledgements RACI study group, Dutch Arthritis Foundation, Netherlands organisation for scientific research.