NEW YORK (GenomeWeb) – Using several large cohorts of rheumatoid arthritis patients, researchers have shown for the first time that variations in the HLA-DRB1 gene that are known to confer increased susceptibility to the disease are also associated with more severe symptoms, and potentially with overall outcome and better response to anti-TNF drugs.
Sebastien Viatte, the study's first author and member of the Arthritis Research UK epidemiology unit at the University of Manchester, told GenomeWeb that his group's results, published today in JAMA, offer very strong evidence that HLA-DRB1 variations are associated with more severe disease as measured by radiologic joint imaging.
However, the other connections — between these markers and mortality, as well as their ability to anticipate patients' response to anti-TNF therapy — are only suggested by the data so far and will have to be borne out in additional replication and validation studies in order to be clinically useful, Viatte said.
In the study, Viatte and his colleagues focused on three amino acid positions within HLA-DRB1, which have been found in previous research to be the sites with the strongest association with RA susceptibility.
According to the authors, these three positions define 16 different HLA-DRB1 haplotypes that together make up a hierarchy of risk for developing RA.
To try to establish whether the same haplotypes might also be associated with disease severity, risk of death, and with responsiveness to anti-TNF drugs, the researchers collected data from several cohorts ofUKpatients, including 2,112 patients to evaluate disease severity; 2,432 patients to assess mortality; and 1,846 patients to examine treatment response to TNF inhibitor therapy.
Viatte said that though the association of variations in HLA-DRB1 with RA susceptibility has been known for decades, there weren’t ever large enough cohorts to tease out these additional associations.
But with several thousands of subjects, theManchesterteam was able to see for the first time that the HLA-DRB1 haplotypes do indeed appear to confer not only risk of developing RA, but also risk of more severe disease, risk of death, and a higher-responsiveness to anti-TNF therapy.
On the question of disease severity risk, there were enough patients available to perform an independent replication of these initial findings, which Viatte said makes a stronger case for the solidity of this association and its potential clinical utility.
"No studies had been powered enough to show [previously] that the same markers associated with susceptibility were associated with severity as well, but with this study we were able to show that there is a perfect correlation between susceptibility and severity," Viatte said.
According to the study authors, one haplotype — in which the nucleic acid valine is present at one of the three positions studied, position 11 — had the strongest correlation, and conferred a clinically relevant increase in disease severity.
The potential clinical relevance of the team's other two findings — that the same HLA-DRB1 variants also appeared to mark greater risk of death and greater responsiveness to therapy — is less definitive, Viatte said, because the researchers were not able to independently validate them as they did with their disease severity finding.
"We had data only for one cohort, so we couldn't perform any replication," Viatte said. "Also, among those 16 haplotypes, only the strongest one was actually associated with treatment response. The others did not reach statistical significance."
Additionally, Viatte said, "The effect size for this haplotype was unfortunately quite small, so it's not clear yet whether this could influence clinical practice in the future."
Viatte noted that he and his group already have plans for recruiting additional independent cohorts to validate and refine this finding. If these efforts are successful, the group would hope to eventually demonstrate that testing for HLA-DRB1 haplotypes, and using that information to guide treatment, could improve outcomes compared to current clinical practice.
An interesting aspect of the group's initial findings is that the same HLA-DRB1 variations associated with disease susceptibility and severity appear to predict a better, rather than a poorer response to anti-TNF treatment. This could mean that this treatment is affecting the same pathway through which the HLA-DRB1 markers influence a more severe disease course, Viatte said, adding that future studies may focus on whether the association is limited to anti-TNF drugs, in particular, or whether it also predicts sensitivity to different treatments.
In addition, the team plans to look into how combining HLA-DRB1 variation with clinical factors, and potentially also with other molecular risk prediction markers from the proteomic or transcriptomic space, could help improve the ability to predict outcome with enough sensitivity and specificity to be clinically useful.
"What we've done already is we have combined genetics with clinical measures of disease activity or disability, and we can explain about 15 percent of the variation in treatment response cumulatively by including genetic markers and clinical markers," Viatte said. "The next step is to add more factors, which could be transcriptomics or proteomics or other types of markers, into the model in order to increase the proportion of variability we explain and to get a better predictive accuracy."