TNF-238A promoter polymorphism contributes to susceptibility to ankylosingspondylitis in HLA-B27 negative patients

Objective. To investigate the relative contribution of MHC loci in their su sceptibility to primary ankylosing spondylitis (AS) in HLA-B27 negative pat ients and to compare the clinical features and genetic factors with those o f HLA-B27 positive AS. Methods. DNA from patients with B27 negative primary AS (n = 28), B27 posit ive primary AS (n = 77), and matched healthy controls (B27-, n = 100; B27+, n = 70) were analyzed to investigate whether HLA genes determine the disea se susceptibility, or whether other closely linked loci might play a role i n disease development. HLA typing was carried out by serology and PCR/SSP ( HLA-B, -DR), MICA-TM polymorphism in the transmembrane region by radioactiv e PCR, and tumor necrosis factor-alpha (TNF-alpha) promoter polymorphism at positions -238 and -308 by PCR-RFLP. Results. Subtle clinical differences were found for primary AS, the B27 neg ative patients being less frequently complicated by acute anterior uveitis and more associated with peripheral arthritis than B27 positive. Difference s were found in the distribution of TNF-alpha -238 genotypes among patients with primary AS (B27- vs B27+). The TNF-alpha -238(A) polymorphism was pre sent in 50% of the B27 negative patients carrying the -238 G/A and A/A geno types and was significantly increased compared with B27 positive AS (odds r atio 4.3) and with the B27 negative control group (OR 5.9), The TNF-alpha g enotypes were equally prevalent in B27 positive AS and healthy matched B27 positive controls. No significant HLA and MICA typing differences were foun d between the populations under study. Conclusion. Our results indicate that the polymorphism variation in the TNF -alpha promoter -238.2(A) influences disease susceptibility in B27 negative primary AS but had no effect in our B27 positive AS population.