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Identification of specific tumor necrosis factor-α-susceptible and -protective haplotypes associated with the risk of type 1 diabetes Volume 21, numéro 4, December 2010

Auteurs
Research unit of Hematological and Autoimmune Diseases, Faculty of Pharmacy, University of Monastir, Tunisia, Department of Pediatrics, Salmaniya Medical Complex, Manama, Bahrain, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain, Department of Endocrinology, CHU Farhat Hached, Sousse, Hospital of Kairouan, Kairouan, Tunisia

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.