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Valine 11 on the HLA-DRB1 gene may be an indicator of radiographic damage in RA
VBCR - August 2014, Volume 3, No 4 - Personalized Medicine in Rheumatology
Phoebe Starr

Paris, France—Progress in genotyping patients with rheumatoid arthritis (RA) suggests that the amino acid valine at position 11 of the HLA-DRB1 gene appears to be the strongest independent genetic determinant of radiographic damage in this disease.

In addition, positions 71 and 74 on the HLA-DRB1 gene were independent predictors of radiographic damage. All 3 positions together were strongly associated with disease severity, treatment outcomes, and mortality in a study presented at the 2014 Euro­pean League Against Rheumatism (EULAR) Congress.

Although the study is preliminary, the authors are enthusiastic about the promise of this research. “This major advance in genetics might allow stratification of RA patients at the onset of disease to identify those at risk of joint damage and early death, and also those who are more likely to respond to anti-TNF [tumor necrosis factor] biological therapy,” stated lead author Sebastien Viatte, MD, Arthritis Research UK Centre for Genetics and Genomics, Manchester.

Genotype Has a Strong Influence in the Epidemiology of RA
The exact cause of RA is unknown. Environmental factors contribute to approximately 30% of disease susceptibility, and genetic factors contribute to the remainder. The geographic distribution of the prevalence of RA can provide some genetic indications, according to Dr Viatte.

For example, in most countries the prevalence of RA ranges from 0.5% to 1%, but in Native Americans the prevalence is higher, whereas it is very low in populations in China and Japan.

“This supports the strong influence of genotype on the epidemiology of RA,” Dr Viatte stated.

It has previously been shown that a group of alleles on the HLA-DRB1 gene (ie, shared epitope) accounted for the strongest susceptibility to RA. A group of researchers then found that position 11 outside this epitope was a stronger predictor than the shared epitope. The multicenter study presented at EULAR by Dr Viatte and colleagues adds to the growing body of evidence for position 11, implicating positions 71 and 74.

The study was based on patients from 3 multicenter prospective cohort studies: the Norfolk Arthritis Register, the Early Rheumatoid Arthritis Study, and a cohort from 57 centers in the United Kingdom totaling 1691 patients with 2811 x-rays, 421 patients with 3758 x-rays, and 1846 patients with treatment response, respectively.

These cohorts were used to assess whether HLA-DRB1 positions 11, 71, and 74 could predict radiologic outcome, anti-TNF response, and mortality in patients with RA. ImmunoChip array was used to perform the human leukocyte antigen (HLA) typing.

On the Way to Tailoring Therapy
The findings were replicated in all 3 cohorts. Fifty-two percent of all patients carried the HLA-DRB1 haplotype. The 3 positions were strongly associated with disease outcome, and the hierarchy of these 3 positions was correlated with disease susceptibility. These 3 positions were also predictors of good treatment response from anti-TNF therapy and predicted both all-cause and cardiovascular mortality.

“If these susceptibility markers can predict disease severity, treatment response, and mortality, this will allow us to tailor therapy so that every patient gets the right treatment,” Dr Viatte noted.

EULAR President Gerd Burmester, MD, said that, at present, the findings of the study by Dr Viatte and colleagues are not clinically applicable. If future studies validate this work, then risk stratification of patients will be possible based on the genetic polymorphisms within the HLA gene.

“This is a first step toward classification of patients into different categories based on genetic predisposition to identify those at risk of disease progression and early death,” Dr Bur­mester said.

“The study needs to be replicated in independent cohorts, and we may need more markers to add to this. But I would expect to see genotyping in the clinical arena within 5 to 10 years,” Dr Burmester said. “Cancer is way ahead of us, but rheumatology is on its way.”

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