Background/Purpose:

The severity of joint destruction is highly variable between Rheumatoid Arthritis (RA) patients; approximately 54% of this variance is explained by genetic factors. Many of the genetic factors responsible for the severity of joint destruction are unknown.  We aimed to identify new genetic risk factors by studying genetic susceptibility loci of several auto-immune diseases.

Methods:

In the first phase, 646 Dutch RA-patients with yearly X-rays of hands and feet over 7 years of follow-up were studied. These patients were genotyped for 148,880 SNPs by Immunochip which contains 186 loci previously associated with autoimmune diseases. Following quality control, association of SNPs with MAF >0.01 (130,841 SNPS) with joint destruction was analyzed using a marginal regression model. Correction for multiple testing was done using the Bonferroni correction for the number of uncorrelated SNPs (threshold p<1.1x10^-6). In the second phase, 686 North American RA-patients with repeated hands X-rays over 15 years of 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 the Sharp van der Heijde score (ICC 0.91 and 0.98 for phase 1 and 2 respectively).

Results:

In phase 1, 109 SNPs were significantly associated with joint destruction in Dutch RA-patients (threshold p<1.1x10^-6). Of these, 76 were located in the HLA-region in chromosome 6; since the association of this region with joint damage is already known, these SNPs were not analyzed in phase 2. The other 33 non-HLA genetic variants, though several were in high LD, were studied in the North-American RA-patients. After correction for the number of number of uncorrelated SNPs (threshold p<0.0036), two variants were associated with the severity of joint destruction. These were rs451066 on chromosome 14 (p_uncorrected=0.002, MAF=0.20)) and rs11908352 on chromosome 20 (p_uncorrected=0.002, MAF=0.21). In the presence of a risk allele of rs451066 and rs11908352 respectively Dutch RA-patients had a 3.7% and 2.7% higher rate of joint destruction per year, which equals 29% and 20% more joint destruction over a seven years period.

Conclusion:

Two new risk loci for progressive joint destruction in RA were identified. The region of rs451066 on chromosome 14 has previously been linked to susceptibility to type-1 diabetes. The other SNP is located at chromosome 20 and in low LD with rs4810485 (R² 0.062), a variant that has previously been identified as RA risk locus. Altogether, the current data indicate that two loci that confer risk to other autoimmune disease may also affect the severity of RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/new-genetic-risk-loci-for-the-radiographic-severity-of-rheumatoid-arthritis/