Mapping the HLA association in Behçet's disease: a role for tumor necrosis factor polymorphisms?
OBJECTIVE
Experimental evidence suggests that inappropriate regulation of tumor necrosis factor alpha (TNF alpha) may play a role in the pathogenesis of Behçet's disease (BD). This is supported by recent reports highlighting the efficacy of anti-TNF alpha agents in the treatment of this disease. The TNF gene is encoded in the class III region of the HLA complex adjacent to HLA-B. This genetic proximity to a gene that is already widely implicated in disease susceptibility led us to investigate the association between TNF promoter polymorphisms and susceptibility to BD.


METHODS
We studied 133 UK white Caucasoid patients with BD and 354 healthy controls. We attempted to dissect the contribution of individual polymorphisms in this gene-dense region by linkage disequilibrium mapping across 6 adjacent genes.


RESULTS
We report a novel association with the TNF promoter allele TNF-1031C. Subsequent analysis identified 2 extended HLA haplotypes associated with BD. One of them contained the previously recognized susceptibility gene HLA-B*51, while the other was defined by HLA-B*5701. Both of these haplotypes contained the TNF promoter polymorphism -1031C, an allele that was associated with disease even in individuals who did not carry either HLA-B*51 or HLA-B*5701.


CONCLUSIONS
The TNF-1031C allele is independently associated with susceptibility to BD in Caucasoid patients. Further studies will be required to determine the functional effects of this polymorphism, its influence in disease pathogenesis, and its role in other ethnic groups.
Ahmad
Tariq
T
Gastroenterology Unit, Gibson laboratories, University of Oxford, Radcliffe Infirmary, Oxford, UK. tariq.ahmad@ndm.ox.ac.uk
Wallace
Graham R
GR
James
Teifi
T
Neville
Matt
M
Bunce
Mike
M
Mulcahy-Hawes
Kim
K
Armuzzi
Alessandro
A
Crawshaw
Jonathan
J
Fortune
Farida
F
Walton
Robert
R
Stanford
Miles R
MR
Welsh
Ken I
KI
Marshall
Sara E
SE
Jewell
Derek P
DP
D001528:Behcet Syndrome / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006680:HLA Antigens / Q000235:genetics*; D006239:Haplotypes; D006650:Histocompatibility Testing; D006801:Humans; D017720:Molecular Epidemiology; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D006113:United Kingdom / Q000453:epidemiology
D006680:HLA Antigens; D014409:Tumor Necrosis Factor-alpha