TNFA–TNFB haplotypes modify susceptibility to type I diabetes mellitus independently of HLA class II in a Moroccan population

Abstract

The contribution of single nucleotide polymorphisms in tumor necrosis factors (TNF) alpha and beta to autoimmune diseases, and to type 1 diabetes mellitus (T1DM) in particular, is not well established, and may be confounded by linkage disequilibrium to class II HLA genes. At least two polymorphisms seem to have functional relevance in the respective genes: TNFA-307 and TNFB+252. We have typed these two polymporphisms in samples of Moroccan T1DM patients and controls for which class II HLA genes had already been typed. Tumor necrosis factors and compound TNF-class II HLA haplotypes were inferred; it was the first time that such a design had been implemented. Independent of linkage disequilibrium with class II HLA, TNF haplotype TNFA-307*2 - TNFB+252*2 showed a significant protective effect (OR = 0.031), partly exacerbated by partial linkage to protective class II haplotypes. Such effect could be detected because Morocco shows the highest frequency of the TNFA-307*2 allele yet reported. This highlights the possible population differences in alleles contributing to autoimmune diseases.

Family-based analysis of tumor necrosis factor and lymphotoxin-α tag polymorphisms with type 1 diabetes in the population of South Croatia

“…However, several other studies found an independent effect of TNF/LTA with T1DM [17][18][19][20]. TNF involvement in the destruction of pancreatic β-cells [10,11] and multiple inflammatory activities of TNF and LTA cytokines make them plausible targets for revealing molecular susceptibility to T1DM.…”

“…TNF involvement in the destruction of pancreatic β-cells [10,11] and multiple inflammatory activities of TNF and LTA cytokines make them plausible targets for revealing molecular susceptibility to T1DM. The joint analysis of TNF and LTA genes may be more informative in defining the risk/protection to T1DM susceptibility [7,18].…”

“…According to Makhatadze there is a localization of TNF and LTA genes within the HLA complex, as shown in Figure 1 [8]. Two TNF gene promoter single nucleotide polymorphisms (SNPs), G-238A (rs361525) and G-308A (rs1800629), have frequently been studied [6,[16][17][18][19][20][21][22]. However, inconsistencies in SNP designation through various LTA gene studies makes difficult to distinguish and differentiate investigated SNPs [6,7,18,22].…”

“…Two TNF gene promoter single nucleotide polymorphisms (SNPs), G-238A (rs361525) and G-308A (rs1800629), have frequently been studied [6,[16][17][18][19][20][21][22]. However, inconsistencies in SNP designation through various LTA gene studies makes difficult to distinguish and differentiate investigated SNPs [6,7,18,22]. Studies in North Indian, Hungarian, Bahraini, and Moroccan populations observed associations of TNF -308 SNP and TNF/LTA haplotypes with T1DM independently of HLA loci [17][18][19][20]22].…”

“…However, inconsistencies in SNP designation through various LTA gene studies makes difficult to distinguish and differentiate investigated SNPs [6,7,18,22]. Studies in North Indian, Hungarian, Bahraini, and Moroccan populations observed associations of TNF -308 SNP and TNF/LTA haplotypes with T1DM independently of HLA loci [17][18][19][20]22]. On the other hand, TNF/LTA T1DM associations in Chinese, Caucasian, and Polish populations were explained by dependence on HLA alleles [6,16,21].…”