TNF-alpha -308A promoter polymorphism is associated with enhanced TNF-alpha production and inflammatory activity in Crohn's patients with fistulizing disease.
OBJECTIVE
Tumor necrosis factor-alpha (TNF-alpha) plays a key role in the inflammatory response and pathogenesis of Crohn's disease (CD). TNF-alpha -308A polymorphism within the TNF-alpha gene promoter has been associated with enhanced TNF-alpha production in vitro. The aim of this study was to investigate the effect of TNF-alpha promoter polymorphism at -308 on the susceptibility and phenotypic expression of fistulizing CD.


METHODS
The distribution of -308 TNF-alpha genotypes was analyzed in 50 patients with fistulizing CD and 100 healthy matched controls. TNF-alpha, interleukin-1beta, and interleukin-6 serum levels were measured by ELISA. Serum amyloid-A, C-reactive protein, alpha1-antitrypsin, alpha1-acid glycoprotein, and haptoglobin were measured by nephelometry.


RESULTS
No significant differences were found in the allele frequencies of the polymorphism between patients and controls. However, compared with -308GG patients, those carrying -308AG had a significant increase of serum levels of TNF-alpha (58 +/- 79 vs 8 +/- 19 pg/ml, p < 0.001), interleukin-1beta (36 +/- 45 vs 16 +/- 20 pg/ml, p = 0.048), and acute phase proteins (APPs). -308A carriers had also a higher frequency of arthritis (66% vs 26%, p = 0.039). The logistic regression model showed that the patients carrying -308A polymorphism had a relative risk for developing arthritis of 5.45 (95% CI = 1.1-25.6). No other clinical or analytical findings were predictive for the risk of development of arthritis.


CONCLUSIONS
TNF-alpha -308A polymorphism is associated with enhanced TNF-alpha production, more intense inflammatory activity, and an increased risk for arthritis susceptibility in CD patients with fistulizing disease.
González
Segundo
S
Department of Functional Biology, University of Oviedo, Oviedo, Spain.
Rodrigo
Luis
L
Martínez-Borra
Jesús
J
López-Vázquez
Antonio
A
Fuentes
Dolores
D
Niño
Pilar
P
Cadahía
Valle
V
Saro
Cristina
C
Dieguez
M Angeles
MA
López-Larrea
Carlos
C
D000209:Acute-Phase Proteins / Q000032:analysis; D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D003424:Crohn Disease / Q000235:genetics* / Q000378:metabolism; D017577:Cutaneous Fistula / Q000235:genetics* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012003:Rectal Fistula / Q000235:genetics* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics*
D000209:Acute-Phase Proteins; D014409:Tumor Necrosis Factor-alpha