Differential association of polymorphisms in the TNFalpha region with psoriatic arthritis but not psoriasis

Abstract

Objective: To investigate the potential association of tumour necrosis factor α (TNFα) microsatellite and promoter alleles with psoriatic arthritis (PsA). Methods: DNA from 89 white patients with PsA, 65 patients with psoriasis, and 99 healthy white controls was investigated for two TNFα promoter (-238 and -308) and three microsatellite polymorphisms (TNFa, c, and d). Patients had previously been studied by serology for HLA class I antigens and by sequence-specific polymerase chain reaction for DRB1* alleles. In addition, TNFα production of Ficoll separated peripheral blood mononuclear cells (PBMC) into culture supernatants after stimulation with lipopolysaccharide, αCD3 antibodies, phytohaemagglutinin, and streptococcal superantigen C was determined.Results: A significant, HLA class I independent increase of the TNFa6c1d3 haplotype was found in the group with PsA but not among patients with psoriasis (32% v 8%, pc<0.008; relative risk (RR)=5.3). In addition, patients with PsA showed a marked decrease of the TNF308A promoter allele (6% v 18%; pc<0.008; RR=3.5) compared with healthy controls, which was independent of the increased frequency of the -238A polymorphism in this group. PBMC from patients with PsA secreted significantly less TNFα than cells from patients without arthritis. In particular, the TNFa6 microsatellite was associated with decreased TNFα production. Conclusion: These data indicate that allelic variations at the TNFα locus influence susceptibility to PsA. Decreased production of TNFα is at least in part genetically determined and might be related to the development of arthritis. However, the association of the TNF308G allele with the disease also points to other disease related haplotypes with still unknown susceptibility genes.

Angiotensin-converting enzyme gene polymorphism in patients with psoriatic arthritis

“…Although, the exact gene(s) involved in genetic susceptibility have not been identiWed, some candidate genes are located on chromosome 6p [11,12,33,34]. However, these genes are too distant from the ACE gene (17q23) to explain the association observed.…”

“…It also seems reasonable to postulate that the skin and joint disease have a similar pathogenesis although the activity of these manifestations does not always change in parallel. Genetic association with PsA has been most extensively studied in human leukocyte antigen (HLA) class I and II polymorphism [5][6][7][8], immunoglobulin genes [9], CARD15 gene [10], tumor necrosis factor (TNF) genes [11,12], and SEEK I gene [13].…”

Discrimination of suballeles present at the TNFd microsatellite locus using induced heteroduplex analysis

“…Alleles d4 and d4b differ by two imperfect repeats (GA 4AA) in repeat region 1 and repeat region 3. 19,20 leading to the conclusion that the TNFd1b allele alone would be a strong marker of disease association in these studies. Further to this we have identified strong linkage disequilibrium between the TNFd4b allele and the TNF À238A allele.…”

“…As the TNFd3 allele was by far the most frequent allele, this has obvious implications for those studies that have associated this allele with given conditions. 11,[18][19][20][21] We have demonstrated this by reanalysing TNFd3 homozygotes in an identical sibling BMT cohort.…”

Tumor necrosis factor haplotype analysis amongst schizophrenia probands from four distinct populations in the Asia‐Pacific region

“…Thus, allelic variation to TNF may be relevant to schizophrenia pathology. Investigations into the functional relevance of TNF À308A , and other TNF promoter allelic variants, most notably TNF À238A , have provided mixed results, although both have been shown to increase transcription rates [Naudin et al, 1997;Wilson et al, 1997;Bayley et al, 2001;Hohler et al, 2002].…”