New cohort studies presented today at the European League Against Rheumatism Annual Congress (EULAR 2014) have shown the amino acid valine at position 11 of HLA-DRB1 gene to be the strongest independent genetic determinant of radiological damage in rheumatoid arthritis (RA).1 In addition, positions 71 and 74 were found to represent independent predictors, with the three positions together: 11, 71 and 74 strongly associated with disease outcomes.1
According to lead author Dr Sebastien Viatte of the Arthritis Research UK Centre for Genetics and Genomics, Manchester, United Kingdom, "this major advance in genetics might allow stratification of RA patients at the onset of their disease to identify those at risk of joint damage and early death, and also those who are more likely to respond to anti-TNF biological therapy."
RA is a common chronic inflammatory autoimmune disease characterised by inflammation of synovial joints leading to damage to the inside of the joint and surrounding soft tissues. The cause of RA is largely unknown, but both environmental factors and genetic susceptibility appear to be involved.
Although the prevalence of RA is relatively constant in most countries at between 0.5-1.0 percent, the higher occurrence among native American-Indian populations and very low occurrence in China and Japan supports the strong influence of genotype on the epidemiology.2 Previously, a group of alleles on the HLA DRB1 gene, known as the 'shared epitope' was thought to have the strongest effect on RA susceptibility. More recently, position 11 outside the classical shared epitope had been shown to be a stronger predictor of RA susceptibility.3
"This new evidence from our multi-centre cohort studies has shown that positions 11, 71 and 74 on the HLA-DRB1 gene now supersede the classical shared epitope," Dr Viatte concluded. Three independent multi-centre prospective cohort studies: the Norfolk Arthritis Register-NOAR (1691 patients with 2811 X-rays); the Early Rheumatoid Arthritis Study-ERAS (421 patients with 3758 X-rays); and a cohort from 57 UK centres-BRAGGSS (Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate) (1846 patients with treatment response) were used to assess whether HLA-DRB1 positions 11, 71, 74 could predict radiological outcome, anti-TNF response and mortality in patients with RA.
The finding that the amino acid valine at position 11 of HLA-DRB1 (Val11) was the strongest independent genetic determinant of radiological damage in RA was replicated in separate cohorts. Three positions 11, 71 and 74, which together define 16 haplotypes (combinations of gene segments), were strongly associated with disease outcome, superseding the shared epitope. The hierarchy, ranging from risk to protective effects, was perfectly correlated with that observed for disease susceptibility.
HLA-DRB1 haplotypes associated with RA susceptibility and severe outcome were also predictors of good treatment response with anti-TNF therapy. For example, the Val11Lys71Ala74-haplotype, carried by 52% of patients, was associated with a good EULAR response†. On average, 17 patients needed to be treated with anti-TNF to see one more patient responding better, based solely on the carriage of this haplotype. Both all-cause and cardiovascular mortality was also predicted by the 16 haplotypes.
HLA typing was determined using a reverse dot-blot method or dense genotyping of the HLA region by the ImmunoChip array, followed by imputation. Longitudinal modelling of the presence of erosions was performed with Generalized Estimating Equation (GEE) models, whilst the Larsen score was modelled with Generalized Linear Latent and Mixed Modelling (GLLAMM).
More information: 1 Viatte S et al. Personalised genetic medicine: amino acid positions 11, 71 AND 74 in HLA-DRB1 predict disease severity, treatment response and mortality in rheumatoid arthritis; multi-centre prospective cohort studies. EULAR 2014; Paris: OP0190
2 Silman AJ, Pearson JE. Epidemiology and genetics of rheumatoid arthritis. Arthritis Res. 2002; 4 (Suppl 3): S265–S272
3 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