Canadian researchers have taken an important step in the long-running process of identifying genetic causes of psoriatic arthritis.
The analysis, which targeted polymorphisms in the tumor necrosis factor-α (TNF-α) gene in two psoriatic arthritis populations, suggests that the −238(A) variant is a significant risk factor for this disease (Ann. Rheum. Dis. 2006;65:919–23).
The study involved 237 psoriatic arthritis patients and 103 controls from Newfoundland and 203 patients and 101 controls from Toronto. The mean age of patients in both groups was 50 years. With respect to the subtype of psoriatic arthritis in the two populations, 61% had the polyarticular pattern, 27% had the oligoarticular pattern, 5% had isolated spondyloarthropathy, and 7% had assorted other patterns, explained Dr. Proton Rahman and colleagues at St. Clare's Mercy Hospital in St. Johns, Newfoundland.
“Before our study, a significant association for TNF-α and psoriatic arthritis was noted only in German populations. We examined five common variants with the TNF-α promoter gene, including −238 and −308. We noted a significant association between −238 variant and psoriatic arthritis,” explained the investigators, who took the additional step of conducting a pooled analysis of nine cohorts from eight studies (including their own two Canadian cohorts). Again, the −238(A) gene polymorphism was a significant risk factor, though the six outside studies each used fewer than 150 probands and may have been underpowered.
“We acknowledge that population stratification was not entirely avoided as family-based controls were not used in these studies,” the authors said, adding that publication bias may exist in the metaanalysis, because small, negative association studies often are not published. “As demonstrated in our study, because metaanalysis of association studies in complex diseases [is] helpful in estimating population-wide genetic effects, further efforts must be made to track all association data for a given polymorphism,” they wrote.
The targeting of the TNF-α gene is supported by studies noting significantly higher serum, synovial fluid, and synovial membrane levels of TNF-α in patients with psoriatic arthritis, compared with either patients with osteoarthritis or healthy controls, the investigators point out. “The importance of TNF-α in psoriatic arthritis is further strengthened by the marked clinical response of TNF-α blockade.”
However, genetic studies have produced conflicting results, with inconsistencies that may reflect insufficient sample sizes, differences in populations, the presence of linkage disequilibrium, or multiple testing, the authors said.