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- 1. RADIOLOGICAL DAMAGE IN RHEUMATOID ARTHRTITIS IS ASSOCIATED WITH IL-6 AND IL-10 GENOTYPES INDEPENDENT OF AUTOANTIBODY PRODUCTION I Marinou, J Healy, D Mewar, D J Moore, M C Dickson, M H Binks, D S Montgomery, K Walters and A G Wilson Section of Musculoskeletal Sciences, School of Medicine & Biomedical Sciences, The University of Sheffield
- 6. Associations of functional SNPs in IL-10 and IL-6 genes with radiographic severity of RA * Median modified Larsen scores †Cuzic’s test for trend 31 259 (30.1%) GG 0.01 † 27 415 (48.3%) AG (n=860) 24 186 (21.6%) AA IL-10-1082 32 587 (63.3%) CC 0.006 22 309 (33.3%) AC (n=928) 28 32 (3.4%) AA IL-10-592 34 282 (30.3%) GG 0.005 † 27 482 (51.8%) CG (n=930) 25 166 (17.8%) CC IL-6-174 p LS * Cases n (%) Genotype Gene D’=0.89 R 2 =0.24
- 7. Functional SNPs in IL-10 and IL-6 are not associated with autoantibody production The presence of anti-CCP and RF was compared for each SNP with reference to the commonest genotype 78 159 57 191 GG 0.8 1.0 (0.7-1.4) 129 253 0.2 0.8 (0.5-1.1) 113 291 AG 0.6 1.1 (0.7-1.8) 52 120 0.6 1.1 (0.7-1.9) 36 138 AA IL-10-1082 169 375 138 432 CC 0.5 0.9 (0.7-1.2) 96 191 0.9 1.0 (.07-1.4) 72 222 AC 0.6 1.4 (0.6-3.7) 8 25 0.5 1.5 (06-4.5) 6 28 AA IL-10-592 77 184 64 207 GG 0.6 0.9 (0.6-1.3) 140 304 0.9 1.0 (0.7-1.4) 112 351 CG 0.1 0.7 (0.5-1.1) 56 98 0.7 0.9 (0.6-1.5) 40 120 CC IL-6-174 p OR (95%CI) RF-ve RF+ve p OR (95%CI) CCP-ve CCP+ve Genotype Gene RF status CCP status
- 8. Associations of SNPs with RA severity are influenced by RF and CCP status Radiographic damage and genotypes stratified by CCP and RF status. Median LS is compared across genotypes according to CCP and RF status. 0.05 40 375 CC 0.002** 16 135 CC 0.002** 19 168 CC 11 103 AA/AC RF- 31 216 AA/AC RF+ 6 76 AA/AC CCP- 0.06 37 431 CC 29 250 AA/AC CCP+ IL-10 -592 p LS n Genotype Antibody status SNP
- 9. Radiographic damage and genotypes stratified by CCP and RF status. Median LS is compared across genotypes according to CCP and RF status. 13 76 GG 0.5 17 139 GC 13 56 CC RF- 44 184 GG 0.01** 34 304 GC 30 98 CC RF+ 10 63 GG 0.9 13 109 GC 13 39 CC CCP- 41 207 GG 0.004** 32 350 GC 29 120 CC CCP+ IL-6 -174 p LS n Genotype Antibody status SNP
Editor's Notes
- The role of genetics in RA susceptibility is clearly established. However less is known of the genetic influences on disease severity. A relatively few reports have addressed the role of genetics to radiological joint damage. A relationship between DRB1 alleles and severity has been reported but recent evidence suggests that it is secondary to production of anti-CCP antibodies particularly in RF-ve patients.
- A central feature of RA is the imbalance of cytokine production with relative excess of proinflammatory cytokines compared to anti-inflammatory mediators. We hypothesized that genetic variants associated with cytokine production may influence disease severity and we seek for associations between functional SNPs in candidate genes and joint damage.
- Radiographic damage was measured using the modified Larsen score in a cross-sectional cohort of 965 RA patient all fulfilling the ARC criteria and had a minimum disease duration of 3 yrs. Radiographs of hands and feet were score blind by a single radiologist. To check consistency of the scoring 10% of the films were rescored. Taqman genotyping assays were designed for functional SNPs in IL-1, IL-6 and IL-10. Levels of RF and CCP antibodies were also measured.
- We fist look for associations between functional SNPs in candidate genes and radiographic severity of RA. Carriers of the IL-6 -174G allele had more severe radiographic damage compared to those having the C allele. Strong LD was detected between the 2 IL-10 SNPs as measured by D’ and r2. Patients having a copy of the IL-10 -592 C allele had increased median Larsen score compared to those having a copy of the C allele. A similar pattern, although not that significant, was observed for IL-10 -1082. Patients carrying the IL-10 -1082G allele had more severe radiographic damage compared to patients carrying the A allele.
- We then investigated if the presence of autoantibody-producing B-cells confound the association between genotypes and disease severity. No association between genotypes and autoantibodies was observed suggesting that the initial association with x-ray damage is not confounded by autoantibody production.
- The relationship between antibody status, genotypes and radiological damage was then investigated. Stratification by RF and CCP status showed that the IL-10 -592C association with LS was restricted to either RF-ve or CCP-ve patients.
- However the association of IL-6 -174G was only present if RF+ve or CCP+ve patients
- The IL-6 -174G allele was associated with more severe x-ray damage. This could be a consequence of the higher gene expression that has been previously associated with this allele. The IL-0 -592C allele was significantly associated with increase joint damage. This association could be a result of lower production levels of this anti-inflammatory cytokine. Variation in IL-10 production has been extensively associated with individual promoter SNP genotypes or haplotypes Seropositivity for both RF and CCP are associated with a more severe RA raising the possibility that our findings of IL-6/IL-10 association with median LS may be independent to the production of these severity markers. RF and CCP were not associated with either IL-6 and IL-10 genotypes suggesting that they may be independent of these severity markers. The association between IL-6 and LS was restricted to either RF+ or CCP+ patients i.e. those with more severe disease Association of IL-10 with x-ray damage was only present in RF- or CCP- patients i.e. those with milder disease
- Genotyping of these cytokines represent novels markers of RA severity that complement established biomarkers such as RF and CCP. These results could be useful in therapeutic targeting of expensive anti-rheumatic drugs to patients at risk of developing more severe RA