Major Finding: TNF
Data Source: A study of 2,224 individuals.
Disclosures: The study was supported by a research grant from the Italian Association for the Defense of Psoriatic Patients, the Interdisciplinary Centre for Clinical Research at the University of Erlangen-Nuremberg (Germany), and the Bath (England) Institute for Rheumatic Diseases. Two researchers were received grants from Wyeth-Pharm GmbH (Germany).
European researchers have confirmed a new independent susceptibility allele for psoriatic arthritis that could possibly represent a new candidate pharmacogenetic marker for the disease.
“In this collaborative work, we replicated the association of TNF*-857T as a susceptibility allele for [psoriatic arthritis (PsA)] independent of the main PSORS1 risk allele,” wrote Emiliano Giardina, Ph.D., of the University of Rome, and his colleagues in an article published online in the journal (doi:10.1002/art.30591).
It's long been known that the strongest and most replicated susceptibility region for psoriatic vulgaris – and by extension PsA – is within the major histocompatibility complex (MHC) region (PSORS1-psoriasis susceptibility region). “This locus maps to chromosome 6p21.3, comprising many different class I antigens associated with disease expression. Human leukocyte antigen (HLA)-C was repetitively reported as the PSORS1 gene and HLA-Cw*06:02 as the susceptibility allele,” they noted.
In this study, the researchers attempted to confirm this finding by assessing allele and genotype frequencies of TNF*-857 in three independent cohorts. They included a German cohort (374 cases and 561 controls), an Italian cohort (400 cases and 400 controls), and a British cohort (135 cases and 354 controls.
The overall cohort of 2,224 individuals of European ancestry was assessed for distribution of HLA-Cw*06:02/PSORS1 risk allele and also was typed for TNF*-857T. The overall allele frequency of TNF*-857T was significantly higher in individuals with PsA (27%) than in control individuals (20%).
The researchers calculated the genotype frequencies of TNF*-857T in samples that were positive and negative for the PSORS1 risk allele, in order to verify the existence of an association independent of the PSORS1 risk allele.
“Overall, the frequency of heterozygous or homozygous carriers of TNF*-857T (TT/CT) in individuals negative for the PSORS1/HLA-C risk allele was significantly higher in PsA patients (30%) than in control subjects (21%),” they reported. This yielded an odds ratio of 1.35
“As expected, the haplotype analysis confirmed TNF*-857T as a susceptibility factor independent of the PSORS1/HLA-C risk allele,” they wrote. Association of PsA to TNF*-857T was significant in individuals not carrying the PSORS1/HLA-C risk allele, with an odds ratio of 1.27.
“Although the functional role of TNF*-857T remains to be determined, previous data could show that the allele T increases the transcription of TNF-alpha.”
In addition, tumor necrosis factor–alpha is known to play a pivotal role in both the activation and extravasation of T cells in the highly vascularized synovium, as well as in subchondral osteoclastogenesis promoting bone erosions. Genes encoding for TNF-alpha, along with other cytokines, could be candidate pharmacogenetic markers.
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Findings Confrims Earlier Research
A most intriguing aspect of psoriasis epidemiology is that about a quarter of these patients will develop psoriatic arthritis, and this disease clusters in families with remarkably high heritability. Despite evidence for genetic factors in this disease, the search for genes associated with arthritis and not psoriasis has been challenging because almost all PsA patients also have psoriasis. PSORS-1, the MHC region that contains Cw6, the allele with the strongest association with psoriasis, is characterized by long linkage disequilibrium. One report noted an association of PsA with the TNF*-857T allele that was independent of PSORS1. In this multinational study of 909 patients and 1,315 healthy controls, the TNF*-857T allele was found at significantly higher frequency in PsA patients negative for the PSORS1 allele (30%), compared with controls (21%). This study replicates findings in the previous study and is also of note because the TNF*-867T allele increases the transcription of TNF, a pivotal cytokine in the pathogenesis of PsA. Also of possible relevance is that this allele is associated with response to etanercept in RA. The replication of this important association should catalyze additional genetic and pharmacogenetic studies to better understand the diagnostic and functional significance of this allele in psoriatic disease.
CHRISTOPHER T. RITCHLIN, M.D., is professor of medicine, allergy/immunology, and rheumatology at the University of Rochester (N.Y.) He reported having no conflicts of interest that are relevant to this piece.
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