Identification of Specific Tumor Necrosis Factor-α-susceptible and -protective Haplotypes Associated with the Risk of Type 1 Diabetes

Aim: We investigated the association of tumor necrosis factor (TNF)α gene polymorphism with type 1 diabetes (T1D).

Methods: TNF-α -1031T/C, -863C/A, -857C/T, -376G/A, -308G/A, -238G/A, and +488G/A single nucleotide polymorphisms (SNPs) were assessed in 198 T1DM patients and 180 age-and gender-matched, normoglycemic control subjects using PCR-restriction fragment length polymorphism (RFLP).

Results: Higher frequencies of -863A (p = 8.0 × 10-6), -857T (p = 1.4 × 10-4), and -238A (p = 0.002) alleles were seen in T1D patients than in the control group. Significant differences were noted in the distribution of -863T/C, -857C/T, -376G/A, -308G/A, and -238G/A genotypes between patients and controls. Haploview analysis revealed high linkage disequilibrium (LD) between the -376G/A and -308G/A SNPs, but this was lower between the other polymorphisms. Five-locus TNFα haplotypes were constructed based on the prevalence of individual SNPs and the LD between them. An increased frequency of CTGGG, CCGAG, and ACGGG haplotypes, and a reduced frequency of the CCGGG haplotype was seen in patients. When the Bonferroni correction was applied, differences were significant for the CTGGG (Pc = 1.4 × 10-3), CCGAG (Pc = 0.023), and ACGGG (Pc = 1.2 × 10-3) haplotypes which were greater, and the CCGGG haplotype (Pc = 3.8 × 10-5) which was smaller, among T1D patients, thereby conferring susceptibility to and protection from T1D, respectively.

Conclusion: These results demonstrate that TNF-α polymorphisms, in particular -863C/A, -857C/T, and -238G/A, are significantly associated with T1D. Additional studies, on other racial groups, are needed to confirm our findings.