title: Tumor necrosis factor-associated susceptibility to type 1 diabetes is caused by linkage disequilibrium with HLA-DR3 haplotypes.
abstract: Tumor necrosis factor-α (TNF-α) is an important proinflammatory cytokine involved in the pathogenesis of autoimmune type 1 diabetes (T1D). The TNF gene locus is located in the major histocompatibility complex (MHC) class III region and its genetic polymorphisms have been reported to be associated with T1D. However, it is not clear whether these associations are primary or caused by their linkage disequilibrium with other predisposing genes within the MHC. We have tested 2 TNF-α single nucleotide polymorphisms at positions -308G/A and -238G/A in the 5' untranslated region and a (GT)n microsatellite TNFa in the North Indian healthy population and T1D patients with known HLA-A-B-DR-DQ haplotypes. The allele frequencies of TNFa5, -308A, and -238G were determined to be significantly increased among patients compared with controls. Although the observed positive association of -238G was caused by its presence on all 3 DR3(+) groups, namely, B8-DR3-DQ2, B50-DR3-DQ2, and B58-DR3-DQ2 haplotypes associated with T1D in this population, the increase of the -308A allele was caused by its association with the latter 2 haplotypes. On the other hand, TNF -308G occurred on B8-DR3 haplotypes along with -238G and TNFa5 alleles, particularly in T1D patients with late disease onset (at >20 years of age). These results indicate that TNF associations with T1D are caused by their linkage disequilibrium with specific HLA-DR3-DQ2 haplotypes in the Indian population. Because polymorphisms in the promoter region regulate TNF expression levels (e.g., -308A), they retain crucial immunological significance in the development of T1D and its management.
authors.affiliation: Department of Transplant Immunology and Immunogenetics, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Kumar
authors.forename: Gurvinder
authors.initials: G
authors.lastname: Kaur
authors.forename: Nikhil
authors.initials: N
authors.lastname: Tandon
authors.forename: Narinder
authors.initials: N
authors.lastname: Mehra
mesh_terms: D020121:5' Untranslated Regions; D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000483:Alleles; D016022:Case-Control Studies; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D005260:Female; D005787:Gene Frequency; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D015803:HLA-DR3 Antigen / Q000235:genetics* / Q000276:immunology; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000276:immunology
chemical_list: D020121:5' Untranslated Regions; D015803:HLA-DR3 Antigen; D014409:Tumor Necrosis Factor-alpha