Tumor necrosis factor gene and microsatellite polymorphism in chronic inflammatory bowel diseases.

Objectives. - Multiplex family studies have excluded chromosome 6 as a candidate gene of susceptibility to inflammatory bowel disease. However one recent study suggested that a gene involved in the pathogenesis of Crohn's disease is located on chromosome 6 confering to a microsatellite allelic combination (a2, b1, c2, d4, e1) a strong genetic risk factor in Crohn's disease. The aim of our study was to determine simultaneously the polymorphisms of the TNF microsatellites and of the the genes coding for TNF synthesis in patients with inflammatory bowel disease. Patients and methods. - Sixty patients with ulcerative colitis, 100 patients with Crohn's disease were compared to 64 healthy ethnically matched controls. Five TNF microsatellite loci (a, b, c, d, e) were typed using polymerase chain reaction PCR, and two dimorphisms of TNF alpha and TNF beta (intron 1) were studied by restriction fragment length polymorphism (RFLP). Results. - Allelic frequencies of TNF microsatellites and of TNF alpha and beta genes were similar in Crohn's disease, ulcerative colitis and controls. Five loci microsatellite haplotypes, especially a2 b1 c2 d4 e1 allelic combination, were not more frequent in Crohn's disease (25 %) compared to ulcerative colitis (27 %) or controls (20 %). Subgroups stratification according to clinical characteristics did not modify haplotype frequencies. Analysis of our data taking simultaneously into account the MHC alleles (DRB1*01 or DRB1*04) did not modify our data ; however it suggested that extended haplotype on short arm of chromosome 6 differed between patients and controls. Linkage disequilibrium (Delta = -360.10(-4); P < 0.01) between a2, b1, c2, d4, e1 allelic combination and DRB1*04 allele was observed only in Crohn's disease. Conclusion. - Percentages of patients with Crohn's disease or ulcerative colitis carrying TNF microsatellite or TNF alpha and beta gene haplotypes were similar to those of healthy controls. These data argue against involvement of the TNF locus without exclusion of short arm of chromosome 6 implication in Crohn's disease pathogenesis.