Background Several studies have tested the hypothesis that RA susceptibility variants associate with radiological progression. Their findings are often not replicated; additionally they have examined only a proportion of risk loci and evaluated each locus separately, despite limited power. Two recent meta-analyses of genome-wide association studies have expanded the number of genetic loci and HLA amino acid polymorphisms associated with RA susceptibility [1, 2]. Our aim was to establish if these variants correlated with radiological progression in early active RA patients enrolled to a clinical trial. We evaluated their association both individually and cumulatively, using a weighted genetic risk score (wGRS) combining risk loci.
Objectives To establish if genetic predictors of RA susceptibility also associate with radiological progression in early active RA.
Methods We evaluated 421 RA patients previously enrolled to the Combination Anti-Rheumatic Drugs in Early RA (CARDERA) trial. Hand/feet radiographs were read for modified Larsen scores every 6 months for 2 years. We evaluated the association of validated genetic risk variants (69 SNPs, 17 four-digit HLA-DRB1 alleles and polymorphisms in 6 HLA amino acid positions) with log-transformed Larsen scores over time using a linear mixed-effects model. Loge (Larsen score + 1) was the response variable. Time, treatment, age, disease duration, ACPA status, genotype and a genotype*time interaction, were the fixed-effects predictor variables. Genotype was coded additively. All β-estimates were back-transformed to the original Larsen scale. The genotype*time β provided information on the annual increase in Larsen score per risk allele copy relative to the reference genotype; P-values for this term provided information on the variant's role in radiological progression. We assessed the association between a wGRS incorporating susceptibility SNPs and radiological progression by replacing the linear model's genotype term with a wGRS. Ethical approval was obtained; all patients provided consent.
Results Two SNPs, one HLA-DRB1 allele and two HLA-DRβ1 protein amino acid polymorphisms had P-values <0.05 (Table). None attained Bonferroni corrected significance. No association was seen between a wGRS and Larsen score progression (P=0.0680).
Conclusions RA susceptibility loci did not have a clinically relevant association with radiological progression in European ancestry, early, active RA patients recruited to this trial. This suggests the genetic architectures of RA susceptibility and severity differ.
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Raychaudhuri S et al. Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat Genet 2012;44:291-6.
Acknowledgements Arthritis Research UK (Grant Reference Number 19739 to ICS); National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London.
Disclosure of Interest None declared