Tumor necrosis factor–associated susceptibility to type 1 diabetes is caused by linkage disequilibrium with HLA-DR3 haplotypes

Kumar, Neeraj; Kaur, Gurvinder; Tandon, Nikhil; Mehra, N. K.

doi:10.1016/j.humimm.2012.01.012

Cited by 16 publications

(8 citation statements)

References 66 publications

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“…In the current study, we have found almost similar TNF-α -238G/A and -308G/A allele frequencies as reported earlier from North Indian population in studies related to Mycobacterium tuberculosis infection and Type-1 Diabetes [24] [25]. It seems therefore that -238A is a rare allele in Indian population (with frequency varying between 2 to 5%) as compared to European population which has been reported to be more than 8% [19].…”

Section: Discussionsupporting

confidence: 88%

High Producer Haplotype (CAG) of -863C/A, -308G/A and -238G/A Polymorphisms in the Promoter Region of TNF-α Gene Associate with Enhanced Apoptosis of Lymphocytes in HIV-1 Subtype C Infected Individuals from North India

2014

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IntroductionThe natural history of HIV-1 infection and its progression towards AIDS vary considerably among individuals. Host genetic factors may be one of the possible reasons for variable HIV-1 disease progression. Single nucleotide polymorphisms (SNPs) in the promoter region of TNF-α gene can influence its production. The aim of the present study was to determine the association of functional TNF-α SNPs and its associated parameters related to apoptosis that may influence the rate of HIV-1 disease progression.MethodsTherapy naive, 100 HIV slow progressors (SPs), 100 HIV fast progressors (FPs), 50 HIV exposed but seronegative individuals (ESNs) and 260 healthy controls from same ethnic origin were recruited. Genotyping of TNF-α variants (−863C/A, -308G/A and -238G/A) was done using PCR-RFLP. CD4 counts were determined by flow cytometry. Plasma viral load was estimated by COBAS AMPLICOR HIV-1 monitor test. Plasma TNF-α concentration was estimated by Human CBA Th1/Th2 cytokine kit. The lymphocyte mitochondrial membrane potential was measured by JC-1 dye by flow cytometry.ResultsGenotype and allele frequency of TNF-α -238G/A and -863C/A was not significantly different in HIV-1-infected patients when compared to controls, while that of TNF-α -308G/A variant (high TNF-α producer) was significantly higher in FPs compared to SPs (p<0.01, OR = 3.43). Haplotype analyses also showed that carriers of high TNF-α producing haplotype CAG was significantly more common among FPs compared to SPs (p<0.01, OR = 3). The circulating TNF-α levels in blood also correlated well with genotypes. The lymphocyte mitochondrial membrane potential of FPs having CAG haplotype was significantly low as compared to wild type (CGG) haplotype (417±22 vs 571±28, p<0.01).ConclusionHigh producer haplotype, CAG of TNF-α gene associates with enhanced apoptosis of lymphocytes in HIV-1 infected individuals, hence faster progression to AIDS. However, further functional studies are needed to confirm this association and this knowledge may help clinicians to better understand the disease outcome.

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Section: Discussionsupporting

confidence: 88%

High Producer Haplotype (CAG) of -863C/A, -308G/A and -238G/A Polymorphisms in the Promoter Region of TNF-α Gene Associate with Enhanced Apoptosis of Lymphocytes in HIV-1 Subtype C Infected Individuals from North India

2014

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“…Therefore, the contribution of HLA Class I alleles (A and B) also modifies the disease association or protection contributed by HLA Class II alleles (DRB1, DQA1, and DQB1) on an HLA haplotype, and should not be neglected. In addition, other candidate genes within the MHC Class III region, like the MHC Class I polypeptide‐related sequence A ( MICA ), tumor necrosis factor ( TNF ), and complement factor B ( BF ) genes, may contribute to the susceptibility to or protection against T1D …”

Section: Discussionmentioning

confidence: 99%

Diverse human leukocyte antigen association of type 1 diabetes in north India

Kumar

Mehra

Kanga

et al. 2019

Journal of Diabetes

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Highlights• Type 1 diabetes (T1D) in north India is strongly associated with HLA-DRB1*03 haplotypes. • The association between HLA-DRB1*04 and T1D in north India differs from that in south India and in Caucasians. AbstractBackground: Type 1 diabetes (T1D) is a complex disease, with involvement of various susceptibility genes. Human leukocyte antigen (HLA) on chromosome 6p21 is major susceptibility region. This study examined genetic association of HLA genes with T1D.Methods: The study recruited 259 T1D patients and 706 controls from north India. PCR-SSP and LiPA were used to type HLA Class I and II alleles. Results: At HLA Class I locus, HLA-A*02, A*26, B*08 and B*50 were significantly increased in patients vs controls (39.8% vs 28.9% [Bonferroni-corrected P {P c } = 0.032], 24.7% vs 9.6% [P c = 4.83 × 10 −8 ], 37.2% vs 15.7% [P c = 1.92 × 10 −9 ], and 19.4% vs 5.5% [P c = 4.62 × 10 −9 ], respectively). Similarly, in Class II region, DRB1*03 showed a strong positive association with T1D (78.7% vs 17.5% in controls; P = 1.02 × 10 −9 ). Association of DRB1*04 with T1D (28.3% vs 15.5% in controls; P c = 3.86 × 10 −4 ) was not independent of DRB1*03. Negative associations were found between T1D and DRB1*07, *11, *13, and *15 (13.8% vs 26.1% in controls [P c = 0.00175], 3.9% vs 16.9% in controls [P c = 6.55× 10 −6 ], 5.5% vs 21.6% in controls [P c = 2.51 × 10 −7 ], and 16.9% vs 43.9% in controls [P c = 9.94× 10 −10 ], respectively). Compared with controls, patients had significantly higher haplotype frequencies of A

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“…However, in insulin-resistant states (obesity, prediabetes, and T2D), hepatic production of glucose and lipid synthesis are heightened in concert, implying that insulin deficiency and insulin excess coexists in this setting24. TNFα is an important proinflammatory cytokine involved in the pathogenesis of autoimmune T1D2526. Adiponectin, which is secreted by the white adipose tissue, is a protein with insulin-sensitivity and anti-atherogenic effects27.…”

Section: Discussionmentioning

confidence: 99%

Environmental exposure to BDE47 is associated with increased diabetes prevalence: Evidence from community-based case-control studies and an animal experiment

Zhang

Liu

et al. 2016

Sci Rep

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Brominated flame retardants exposure has been associated with increasing trends of diabetes and metabolic disease. Thus, the purpose of this study was to provide evidence of polybrominated diphenyl ethers (PBDEs) exposure in relation to diabetes prevalence and to reveal the potential underlying mechanism in epidemiological and animal studies. All the participants received a questionnaire, health examination, and the detection of 7 PBDE congeners in serum in two independent community-based studies from 2011 to 2012 in China. Male rats were exposed to 2,2’4,4’-tetrabromodiphenyl ether (BDE47) for 8 weeks to explore its effects on glucose homeostasis and potential mechanisms using high-throughput genomic analysis. Among the 7 congeners, BDE47 showed significant high detection rate and concentration in cases in Study I and Study II. Every tertile of BDE47 exposure significantly increased the risk of diabetes prevalence in Study I (Ptrend = 0.001) and Study II (Ptrend < 0.001). Additionally, BDE47 treatments induced hyperglycemia in rats. Furthermore, gene microarray analysis showed that diabetes pathway and three gene ontology terms involved in glucose transport were enriched. The results indicated that environmental exposure to BDE47 was associated with increased diabetes prevalence. However, further prospective and mechanistic studies are needed to the causation of diabetes in relation to BDE47.

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Tumor necrosis factor–associated susceptibility to type 1 diabetes is caused by linkage disequilibrium with HLA-DR3 haplotypes

Cited by 16 publications

References 66 publications

High Producer Haplotype (CAG) of -863C/A, -308G/A and -238G/A Polymorphisms in the Promoter Region of TNF-α Gene Associate with Enhanced Apoptosis of Lymphocytes in HIV-1 Subtype C Infected Individuals from North India

High Producer Haplotype (CAG) of -863C/A, -308G/A and -238G/A Polymorphisms in the Promoter Region of TNF-α Gene Associate with Enhanced Apoptosis of Lymphocytes in HIV-1 Subtype C Infected Individuals from North India

Diverse human leukocyte antigen association of type 1 diabetes in north India

Environmental exposure to BDE47 is associated with increased diabetes prevalence: Evidence from community-based case-control studies and an animal experiment

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