Modulation of Type 1 Diabetes Susceptibility by Tumor Necrosis Factor Alpha -308 G/A and Lymphotoxin Alpha +249 A/G Haplotypes and Lack of Linkage Disequilibrium with Predisposing DQB1-DRB1 Haplotypes in Bahraini Patients (original) (raw)
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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.
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.
Association of Lymphotoxin Alpha Polymorphism with Type 1 Diabetes in a Tunisian Population
Biochemical Genetics, 2014
We investigated the association of the lymphotoxin (LT)-a gene polymorphism ?249A/G with type 1 diabetes. The distribution of genotypes of the LT-a ?249A/G single nucleotide polymorphism (SNP) was assessed in 115 diabetic patients and 123 normoglycemic control subjects, using PCR-restriction fragment length polymorphism analysis. Among unselected patients, the SNP was significantly associated with increased risk of diabetes (v 2 = 8.44, p = 0.014) and was found to be more pronounced among female (v 2 = 8.37, p = 0.02) than male (v 2 = 6.11, p = 0.047) patients. A significant association was detected between LTa ?249A/G and increased risk of diabetes, in particular for young-onset patients (v 2 = 6.92, p = 0.031). Moreover, we reported significant differences in levels of HbA1c, triglycerides, alanine transaminase, and anti-glutamic acid decarboxylase-65 among alleles. Additional studies with extended patient age groups and different ethnicities are needed to confirm our findings.
TNF-α Gene G308A Polymorphism: Frequency in Patients with Type 2 Diabetes Mellitus
International Journal of Current Research and Review
Introduction: Tumour necrosis factor-alpha (TNF-α), a pro-inflammation cytokine, plays a critical role in the pathogenesis of type 2 diabetes mellitus due to involving into the regulation of insulin signalling. Overproduction of this cytokine in metabolic syndrome is linked to TNF-α promoter gene G-308A polymorphism. Objective: The work was initiated to measure the serum TNF-α concentrations and to determine the frequency of the Tumour necrosis factor-alpha (TNF-α) gene G308A polymorphism in Uzbek patients with type 2 diabetes mellitus. Methods: Healthy and type 2 diabetes mellitus Uzbek patients were observed. Results: In the group with diabetes fasting blood glucose and the glycated haemoglobin (HbA1c) levels were 2.7 and 1.6 times higher respectively (both p<0.01). HDL cholesterol was reduced, while LDL cholesterol, total cholesterol and triglycerides were higher in diabetic group. There was a significant difference between the serum TNF-α concentration in people with and without DM. As to TNF-α gene G308A polymorphism in the sample under study, it was represented mostly by GG homozygous genotype to be registered among persons without diabetes (90.2%) and patients with type 2 DM (83.3%). GA heterozygous genotype occurred in 9.8% and 16.7% of non-diabetics and diabetics, respectively. In our study, pathological AA homozygous genotype was found neither among the diabetics nor in the controls. There were no significant differences in frequencies of alleles and genotypes of TNFα gene G308A polymorphism. In the diabetics, frequencies of A allele and GA genotype is insignificantly higher than those in the controls. Conclusion: In compare to non-diabetic controls, patients with type 2 diabetes mellitus had higher serum concentrations of TNF-α. However, in that small group association of A allele and GA genotype of TNF-α gene with a higher risk of DM2 were insignificant.
No association between the −1031 polymorphism in the TNF-α promoter region and type 1 diabetes
Human Immunology, 2003
Tumor necrosis factor alpha (TNF-␣) is an important immunomodulator and is believed to be involved in the development or progression of type 1 diabetes. In the following study, we evaluated TNF-␣ promoter polymorphisms at positions Ϫ863 and Ϫ1031 and their association with type 1 diabetes in a group of 210 diabetic patients from Lebanon. Our results show that in our population, the C allele is predominant at position Ϫ863, whereas the A allele is very rare (2%). At position Ϫ1031, however, the C and T allele distribution was similar in both the patient (17.8% vs 82.2%, respectively) and the control (21.4% vs 79.6%) groups. No association of TNF-␣ genotype at position 1031 with type 1 diabetes was found as demonstrated by the family-based associa-tion test and the transmission disequilibrium test. However, when patient genotypes were compared, the recessive CC genotype was only found in type 1 diabetic males but not in type 1 diabetic females. This observation, however, requires further investigation in a larger sample before conclusive association to gender is suggested. In conclusion, our results demonstrate that no association between TNF-␣ polymorphism and type 1 diabetes seems to exist in our population. Human Immunology 64, 633-638 (2003).
Human Immunology, 2003
The human leukocyte antigen (HLA) class III region, located on chromosome 6p21, has been regarded as one of the susceptible loci for type 1 diabetes. Because it contains many genes related to inflammatory and immune responses, including tumor necrosis factor (TNF), lymphotoxin-␣ (LT-␣), and allograft inflammatory factor 1 (AIF-1) genes, it is unclear which gene within the class III region is responsible for the susceptibility to the disease. We sequenced the AIF-1 gene region and detected three novel polymorphisms, all of which were diallelic and localized at introns. Then, we investigated AIF-1, TNF, and LT-␣ gene polymorphisms in 165 patients with type 1 diabetes, consisting of 90 patients with young-onset type 1 diabetes, 75 patients with adult-onset type 1 diabetes, and 200 control patients. We also analyzed TNF receptors type 1 (TNFR1) and type 2 (TNFR2) gene polymorphisms, located on chromosome 12p13 and 1p36, respectively. Although there were significant differences between type 1 diabetes patients and controls in the distributions of TNF promoter poly-morphisms at position Ϫ1031 and Ϫ857, and LT-␣ gene NcoI polymorphism, none of them was independently associated with the disease after two-locus analysis with HLA class II alleles. We detected the significantly increased frequency of the Ϫ383C allele, located in the TNFR-1 promoter region, in both young-onset and adult-onset diabetes patients compared with controls. In addition, the Ϫ383C allele was found to be associated with higher expression of the TNFR1 gene than that of Ϫ383A allele in in vitro expression. These results suggest that the TNFR1 gene region might be a susceptible locus to type 1 diabetes in Japanese.
European Journal of Immunology, 1993
We have investigated the correlation between different tumor necrosis factor (TNF) and class I1 major histocompatibility complex alleles in the lipopolysaccharideor phytohemagglutinin-induced secretion of TNF-a and TNF-b by human monocytes and peripheral blood mononuclear cells in 87 unrelated Danish male individuals. Significant differences in TNF-a secretory capacity between TNF NcoI restriction fragment length polymorphisms, TNFa and TNFc microsatellite alleles and DR alleles were identified. No correlation with TNF-fi secretory capacity was found for any of the markers studied. TNF genotyping allowed us to define four extended HLA haplotypes which correlate withTNF-a secretory capacity.Two of these are DR4 positive: DQw8, DR4,"3*1,TNFa6, B44, A2 and DQw8, DR4, TNFB"2, TNFa2, B15, A2. Individuals carrying the TNFB*2, TNFa2 haplotype had a higher TNF-a secretory capacity than those carrying the TNFB*l, TNFa6 haplotype. In a group of DR3/DR4 heterozygous patients with insulin-dependent diabetes mellitus (IDDM), the frequency of the TNFa2 allele was higher than in HLA-DR matched controls, whereas theTNFa6 allele was more frequent in control individuals. In the DR3DR4 heterozygous diabetic group 12/26 had the alleles combination DQw8, DR4 ( D w~) , C4A3, TNFB"2, TNFa2, B15, whereas only 1/18 controls had this haplotype. This diabetogenic haplotype is identical to the DR4 haplotype which correlates with a higher TNF-a response.These observations suggest a direct role for theTNF locus in the pathogenesis of IDDM.