TNF-238A promoter polymorphism contributes to susceptibility to ankylosing spondylitis in HLA-B27 negative patients.
OBJECTIVE
To investigate the relative contribution of MHC loci in their susceptibility to primary ankylosing spondylitis (AS) in HLA-B27 negative patients and to compare the clinical features and genetic factors with those of HLA-B27 positive AS.


METHODS
DNA from patients with B27 negative primary AS (n = 28), B27 positive primary AS (n = 77), and matched healthy controls (B27-, n = 100; B27+, n = 70) were analyzed to investigate whether HLA genes determine the disease susceptibility, or whether other closely linked loci might play a role in disease development. HLA typing was carried out by serology and PCR/SSP (HLA-B, -DR), MICA-TM polymorphism in the transmembrane region by radioactive 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 negative patients being less frequently complicated by acute anterior uveitis and more associated with peripheral arthritis than B27 positive. Differences 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 present in 50% of the B27 negative patients carrying the -238 G/A and A/A genotypes and was significantly increased compared with B27 positive AS (odds ratio 4.3) and with the B27 negative control group (OR 5.9). The TNF-alpha genotypes were equally prevalent in B27 positive AS and healthy matched B27 positive controls. No significant HLA and MICA typing differences were found between the populations under study.


CONCLUSIONS
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.
González
S
S
Department of Immunology, Hospital Central de Asturias, E-33006 Oviedo, Spain.
Torre-Alonso
J C
JC
Martínez-Borra
J
J
Fernández Sánchez
J A
JA
López-Vazquez
A
A
Rodríguez Pérez
A
A
López-Larrea
C
C
D000328:Adult; D005260:Female; D020022:Genetic Predisposition to Disease; D015796:HLA-B27 Antigen / Q000235:genetics*; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006650:Histocompatibility Testing; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics*; D013167:Spondylitis, Ankylosing / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D015796:HLA-B27 Antigen; D015395:Histocompatibility Antigens Class I; C099187:MHC class I-related chain A; D014409:Tumor Necrosis Factor-alpha