title: Secretion of tumour necrosis factor alpha and lymphotoxin alpha in relation to polymorphisms in the TNF genes and HLA-DR alleles. Relevance for inflammatory bowel disease.
abstract: The genes for tumour necrosis factor alpha (TNF alpha) and lymphotoxin alpha (LT alpha; TNF beta) are tandemly arranged in the central region of the MHC. They may, therefore, be of importance for the aetiology of MHC-associated diseases. The authors have prospectively studied the secretion of TNF alpha and LT alpha in relation to polymorphisms at positions -308 and -238 in the TNF alpha gene (TNFA), and two polymorphisms in the first intron of the LT alpha gene (LTA), as well as HLA-DR in 30 patients with chronic inflammatory bowel diseases (IBD) and 12 healthy controls. In the Dutch population, the alleles of these four polymorphisms are present in only five combinations, called TNF-haplotypes: TNF-C, -E, -H, -I, and -P. Significant associations between TNF haplotypes and TNF alpha and LT alpha secretion were found when PBMC were cultured with T-cell activators, irrespective of disease. Mean TNF alpha secretion of individuals carrying the HLA-DR3 associated TNF-E haplotype was significantly higher, as compared to individuals without this haplotype (26 441 pg/ml versus 19 629 pg/ml; P = 0.014). Individuals carrying the TNF-C haplotype produced the lowest amount of TNF alpha (17 408 pg/ml; P=0.022). The TNF-C and TNF-E haplotypes differ only at position -308 in the promoter of TNFA. Individuals carrying the HLA-DR1 associated TNF-I haplotype produced significantly less LT alpha when compared to those who lack this haplotype (1979 pg/ml versus 3462 pg/ml; P = 0.006). As the TNF-I haplotype is also associated with low TNF alpha secretion, this haplotype thus defines a 'low secretor phenotype'. In conclusion, this is the first study to show associations between TNF haplotypes and TNF alpha and LT alpha secretion when T-cell stimulators are used. These findings will contribute to define disease heterogeneity in IBD and may be of relevance for understanding the pathogenesis of autoimmune diseases.
authors.affiliation: Department of Gastroenterology, Free University Hospital Amsterdam, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: Bouma
authors.forename: J B
authors.initials: JB
authors.lastname: Crusius
authors.forename: M
authors.initials: M
authors.lastname: Oudkerk Pool
authors.forename: J J
authors.initials: JJ
authors.lastname: Kolkman
authors.forename: B M
authors.initials: BM
authors.lastname: von Blomberg
authors.forename: P J
authors.initials: PJ
authors.lastname: Kostense
authors.forename: M J
authors.initials: MJ
authors.lastname: Giphart
authors.forename: G M
authors.initials: GM
authors.lastname: Schreuder
authors.forename: S G
authors.initials: SG
authors.lastname: Meuwissen
authors.forename: A S
authors.initials: AS
authors.lastname: Peña
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D001483:Base Sequence; D005260:Female; D006684:HLA-DR Antigens / Q000235:genetics*; D006239:Haplotypes / Q000276:immunology; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000276:immunology*; D008233:Lymphotoxin-alpha / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*
chemical_list: D006684:HLA-DR Antigens; D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha