Personalized Medicine Comes to RA: 3 DNA Codons Show Prognosis

Three specific positions on the HLA-DRB1 gene are strong independent predictors of radiological damage, early death, and response to anti-tumor necrosis factor (TNF) therapy in rheumatoid arthritis (RA), researchers from the UK report.

Sebastien Viatte MD PhD of the Arthritis Research UK Centre for Genetics and Genomics in Manchester described the research at the 2014 annual meeting of the European Union League Against Rheumatism meeting in Paris.

The study amassed X-rays from altogether 2,112 patients with RA and treatment response for another 1,846, drawing the data from 3 independent prospective UK registries. Gene-chip analysis probed their HLA-DRB1 DNA sequences.

HLA-DRB1 has been the subject of intense study in RA research for many years. The "shared epitope" hypothesis holds that many people with RA share similar genotypes at five positions (70-74) in HLA-DRB1. This region of the gene shapes an antigen important in generating antibodies that target citrullinated proteins (ACPA), which are implicated in autoimmune responses and strongly associated with RA risk.

Firmly forging the link between smoking and RA, a study from Sweden found that current smokers with 2 copies of the shared epitope had a 21-fold increased risk for ACPA-positive RA. 

Recently an outsider has challenged the shared epitope dogma:  Position 11 in the HLA-DRB1 gene, well away from the group at positions 70-74, has also been linked to RA prognosis. The new UK analysis favors the outsider: Possessing the code for the amino acid valine at position 11 is the strongest independent determinant of radiological damage in RA.

However, the shared epitope still holds its place: Positions 71 and 74 add independent predictors of risk in their own right. Together, the three positions in HLA-DRB1 gene define 16 haplotypes (gene-code combinations) that are strongly associated with RA prognosis, including cardiovascular risk and all-cause mortality. The 52% of RA patients whose genes specify the amino acids valine at 11, lysine at 71, and alanine at 74 have particularly good treatment responses, as judged by EULAR criteria.

Together the 3 positions  "might allow the stratification of RA patients at the onset of their disease to identify those at risk," declared Viatt, as well as those best suited for anti-TNF treatment. 

The study is a good example of the importance of including biologic samples when creating disease registries in rheumatology, which is the plea of many researchers in the field. 

It is hardly the end of our story, however. Other gene regions, some outside the HLA system, are also implicated in RA risk.