MANCHESTER, UK—Genetic screening for rheumatoid arthritis (RA) risk using 5 confirmed loci is not viable right now, but it may be tested for in the near future, according to a new study published on line in Rheumatology.1 The study objective was to determine whether any of these combinations could be used to predict an individual's risk of developing RA.
The researchers measured predictive value of combinations of 5 confirmed risk loci:
The analysis did identify 8 high-risk combinations associated with elevated risk of RA. However, at present genetic screening based on these loci alone is neither sensitive nor specific enough to be used for screening.
“It may be that these high-risk SE genotypes, combined with other established RA risk loci could be used to identify a group of individuals at very high risk of RA,” conclude researchers who were led by Annie McClure, PhD, of the University of Manchester in Manchester, UK. “Such individuals could be offered lifestyle advice, or be followed closely such that early intervention could be offered as soon as symptoms or signs of inflammatory arthritis became apparent,” they write, noting that “this is particularly important as there is mounting evidence that a ‘window of opportunity’ exists during which early diagnosis and treatment of RA can reduce the extent of jointly damage, and could also help limit the involvement of extra articular tissues.”
The investigators analyzed genes from 4,238 RA patients and 1,811 controls for which genotypes were available at all 5 loci.
Overall, there are 8 high-risk combinations conferring an odds ratio >6 compared with carriage of no susceptibility variants. Moreover, 10% of the controls carried a combination conferring high risk for developing RA, the study showed.
All high-risk combinations included SE, which is known to confer the largest single effect. All but one high-risk combination contained PTPN22. A model containing only these 2 loci could achieve comparable sensitivity and specificity to a model including all 5. Furthermore, replacing SE (which requires full subtyping at the HLA-DRB1 gene) with DRB1*1/4/10 carriage resulted in little further loss of information, the study authors write.
Translating research into practice: population screening for RA risk?
Not so fast, said Peter K. Gregersen, MD, director of the Robert S. Boas center for genomics and human genetics at the Einstein Institute for Medical Research in Manhasset, New York.
“We just don’t know enough yet,” he told MSKreport.com. “Genetic screening for RA risk is nowhere near ready for clinical utility.” A well-known gene hunter, Dr. Gregersen’s work has helped to identify most of the known RA risk genes.
In the future, “if we combine genes with regular screening for biomarkers such as antibodies and cytokines, we will be able to do screening to detect people who are at higher likelihood to develop RA, but it won’t be genes alone,” he said. “That is how it will fall out, and then we can intervene early with a drug or vaccine at point where immune abnormalities suggest a smoldering something,” he said.
Reference1. McClure A, Lunt M, Eyre S, et al. Investigating the viability of genetic screening/testing for RA susceptibility using combinations of five confirmed risk loci. Rheumatology. [epub ahead of print Sept. 9, 2009].
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