Linkage disequilibrium with HLA-DRB1-DQB1 haplotypes explains the association of TNF-308G>A variant with type 1 diabetes in a Brazilian cohort (original) (raw)
Related papers
Human Immunology, 2012
Tumor necrosis factor-␣ (TNF-␣) 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-␣ single nucleotide polymorphisms at positions Ϫ308G/A and Ϫ238G/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, Ϫ308A, and Ϫ238G were determined to be significantly increased among patients compared with controls. Although the observed positive association of Ϫ238G was caused by its presence on all 3 DR3 ϩ groups, namely, B8-DR3-DQ2, B50-DR3-DQ2, and B58-DR3-DQ2 haplotypes associated with T1D in this population, the increase of the Ϫ308A allele was caused by its association with the latter 2 haplotypes. On the other hand, TNF Ϫ308G occurred on B8-DR3 haplotypes along with Ϫ238G and TNFa5 alleles, particularly in T1D patients with late disease onset (at Ͼ20 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., Ϫ308A), they retain crucial immunological significance in the development of T1D and its management.
Is the Association Between TNF-α-308 A Allele and DMT1 Independent of HLA-DRB1, DQB1 Alleles?
Mediators of Inflammation, 2006
The aim of the study was to assess chosen factors of genetic susceptibility to DMT1: DRB1, DQB1, and TNF-α polymorphisms-308 (G/A) in children with DMT1 and their up-to-now healthy siblings. Then we tested whether the association between TNF-α genes and DMT1 is independent of HLA. 87 diabetic children, their 78 siblings, and 85 persons from healthy control group were followed up. The highest risk of DMT1 was connected with alleles: DRB1 * 0401 (OR = 3.39; CI: 1.55-7.41), DRB1 * 0301 (OR = 2.72; CI: 1.48-5.01), DQB1 * 0201 (OR = 4.04; CI: 2.17-7.52), DQB1 * 0302 (OR = 5.08; CI: 2.54-10.14), and TNF-α-308 A allele (OR = 2.59; CI: 1.23-5.44). Moreover linkage disequilibrium for TNF-α-308 A allele with DRB1 * 0301 and DQB1 * 0201 was observed in both diabetic children and their siblings. Diabetic children and their siblings present similar genetic risk factors for DMT1. The association between TNF-α-308 A allele and DMT1 is dependent of HLA-DRB1 and DQB1 alleles.
TNF-? gene polymorphisms in Type 1 (insulin-dependent) diabetes mellitus
Diabetologia, 1989
Type I (insulin-dependent) diabetes mellitus, like some other autoimmune diseases, is linked to certain alleles coded by genes in the HLA-D region. Sequence analysis of DQ ['i chains indicates that aspartic acid at codon 57 confers resistance to the development of Type I diabetes. However, a full explanation for the HLA-association of Type 1 diabetes, particularly the increased susceptibility of DR3/4 heterozygotes is still awaited. The localisation of tumour necrosis factor genes on the short arm of chromosome 6 between HLA-B and the complement genes (Class III) prompted us to investigate a possible polymorphism of TNF-cx at the genomic level in relation to Type 1 diabetes susceptibility. A dialleleic TNF-c~ restriction fragment length polymorphism was found with Ncol and its segregation with HLA-haplotypes analysed in diabetic families. We describe here a strong linkage of TNF-a alleles with certain DR haplotypes. For example, the common extended haplotype HLA AI-B8-DR3 was almost exclusively associated with the 5.5 kb TNF-(~ allele whereas Bw62-DR4 with the 10.5 kb allele. Thus both alleles segregate to diabetic patients. DR matched haplotypes of affected family members differed significantly from those of the non-affected at the TNF alpha locus. All affected sibling pairs in 11 multiplex affected families were identical for TNF-c~ alleles, even if they were only haploidentical for HLA-B-DR haplotypes. In addition, heterozygosity for the TNF-ct alleles was significantly more frequent in the patients. This tight linkage of TNF-ct alleles with some extended haplotypes could help to explain the H LA-association of Type 1 diabetes as well as some other autoimmune diseases. Key wor&s: Type 1 (insulin-dependent) diabetes, major histocompatibility complex, HLA-DR, extended haplotypes, tumour necrosis factor alpha, restriction fragment length polymorphism.
Annals of the New York Academy of Sciences, 2006
TNF microsatellite and HLA class II polymorphisms were studied in 28 recently diagnosed Brazilian patients presenting type 1 diabetes mellitus (T1DM) and in 120 healthy controls. TNFa-e and HLA-DRB1/DQB1 alleles were identified using sets of sequence-specific primers. Compared to controls, the DRB1 * 03 and DQB1 * 02 allele groups, TNFa1 allele, and the TNFa4-b5-c1-d4-e3 and TNFa10-b5-c1-d4-e3 haplotypes were overrepresented in patients. TNF microsatellite together with HLA polymorphisms is associated with type 1 diabetes in Brazilian patients, corroborating the participation of the MHC genes in disease susceptibility.
1994
Insulin-dependent diabetes mellitus (IDDM) is associated with class II molecules of the MHC on chromosome 6, in particular HLA-DR and-DQ alleles, but a pathogenic role for TNF-o~ in the class III region of the MHC has also been implied. We therefore tested whether there was any independent association between a biallelic TNF polymorphism and IDDM. The TNF2 allele was present in 61 of 114 (54 %) IDDM patients compared to 101 of 253 (40 %) control subjects (odds ratio 1.73; p < 0.02). Stratification analysis in individuals matched for HLA-DR3 revealed, however, that this association was not independent of HLA-DR3 and is most likely to be a result of linkage disequilibrium between these alleles. [Diabetologia (1994) 37: 500-503] Key wards IDDM, MHC, tumour necrosis factor alpha, polymorphism.
Human Immunology, 2010
A case-control study was performed to establish a potential association of two TNF-␣ gene promoter SNPs (Ϫ238GϾA and Ϫ308GϾA) with occurrence of type 1 Diabetes mellitus (T1DM) in Croatian population (174 patients and 193 healthy controls). Genotypes (obtained by polymerase chain reaction-restriction fragment length polymorphism), and the clinical parameters of T1DM patients were statistically evaluated by SPSS 13 and Arlequin software, G*Power 3.0.10 program, and calculator for Hardy-Weinberg equilibrium. The frequency of the risk (A) allele, as well as the distribution of high-expression (GA, AA) genotypes were significantly higher (p Ͻ 0.0001) in T1DM patients only at locus Ϫ308. The distribution of the Ϫ238G/Ϫ308A haplotype was also significantly higher in patients compared with controls (27.6% vs 9.6%, p Ͻ 0.0001). Gender-dependent analysis revealed that female T1DM Ϫ308GA genotype carriers exhibit considerably stronger association with T1DM (odds ratio ϭ 6.37, 95% confidence interval ϭ 3.16 -12.85) than male Ϫ308GA patients (odds ratio ϭ 2.71, 95% confidence interval ϭ 1.31-5.59). Clinical parameter analysis of T1DM patients revealed significantly decreased level of hemoglobin A 1 c (HbA 1 c) in Ϫ238A allele carriers compared with Ϫ238G allele carriers (6.55% vs 7.17%, p ϭ 0.022), as well as the tendency of the risk allele carriers at Ϫ238 or Ϫ308 locus to develop T1DM earlier in life compared with non-risk allele carriers. In conclusion, susceptibility to T1DM in the Croatian population is strongly associated with the TNF-␣ Ϫ308GϾA polymorphism, especially in women. In addition, significantly lower HbA 1c levels found in T1DM Ϫ238A allele carriers might indicate better glycemic control in these patients. ᭧
TNFB gene polymorphism in insulin-dependent diabetes mellitus: association with HLA-DR alleles
European Journal of Immunogenetics, 1998
A polymorphism of the TNF-beta gene can be detected by restriction digestion of a PCR product with NcoI. In this study we look at the risk associated with this polymorphism in a study of 69 insulin-dependent diabetes patients and 119 healthy controls. The risk was further characterized by comparison to the HLA type of the individual, since the TNF polymorphism is in linkage disequilibrium with HLA genes.