Identification of specific tumor necrosis factor-α-susceptible and -protective haplotypes associated with the risk of type 1 diabetes

Mouna Stayoussef; Jihen Benmansour; Fayza A Al-Jenaidi; Mansoor H Rajab; Hichem B Said; Mohamed Ourtani; Chiheb B Rayana; Touhami Mahjoub; Wassim Y Almawi

doi:10.1684/ecn.2010.0215



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Identification of specific tumor necrosis factor-α-susceptible and -protective haplotypes associated with the risk of type 1 diabetes
European Cytokine Network. Volume 21, Number 4, 285-91, December 2010, Research article
Free Article
Author(s) : Mouna Stayoussef, Jihen Benmansour, Fayza A Al-Jenaidi, Mansoor H Rajab, Hichem B Said, Mohamed Ourtani, Chiheb B Rayana, Touhami Mahjoub, Wassim Y Almawi
Summary : 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.
Keywords : tumor necrosis factor, polymorphisms, type 1 diabetes