Genetics of Type 1 Diabetes

Noble, Janelle A.; Erlich, Henry A.

doi:10.1101/cshperspect.a007732

Cited by 258 publications

(176 citation statements)

References 112 publications

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“…We analyzed the frequency of HLA‐A, ‐B, and ‐DR alleles associated with T1D risk 33. HG‐T1DR patients had increased frequency of the high‐risk DR3/DR4 genotype (52.9%) compared to NGT patients (24.4%, p = 0.02, odds ratio [OR] = 3.5, Figure 7A).…”

Section: Resultsmentioning

confidence: 99%

“…In contrast, we found associations with HLA genes. Given the well‐known associations of certain HLA types with T1D 33, we analyzed the frequency of HLA‐A, ‐B, and ‐DR alleles in the SPK recipients as well as HLA sharing with their respective donors. The high‐risk HLA‐DR3/DR4 heterozygous genotype was associated with T1D recurrence; HG‐T1DR SPK patients carried this genotype twice as often as NGT recipients.…”

Section: Discussionmentioning

confidence: 99%

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Risk Factors for Type 1 Diabetes Recurrence in Immunosuppressed Recipients of Simultaneous Pancreas–Kidney Transplants

Vendrame

Hopfner

Diamantopoulos

et al. 2016

American Journal of Transplantation

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Patients with type 1 diabetes (T1D) who are recipients of pancreas transplants are believed to rarely develop T1D recurrence in the allograft if effectively immunosuppressed. We evaluated a cohort of 223 recipients of simultaneous pancreas–kidney allografts for T1D recurrence and its risk factors. With long‐term follow‐up, recurrence was observed in approximately 7% of patients. Comparing the therapeutic regimens employed in this cohort over time, lack of induction therapy was associated with recurrence, but this occurs even with the current regimen, which includes induction; there was no influence of maintenance regimens. Longitudinal testing for T1D‐associated autoantibodies identified autoantibody positivity, number of autoantibodies, and autoantibody conversion after transplantation as critical risk factors. Autoantibodies to the zinc transporter 8 had the strongest and closest temporal association with recurrence, which was not explained by genetically encoded amino acid sequence donor–recipient mismatches for this autoantigen. Genetic risk factors included the presence of the T1D‐predisposing HLA‐DR3/DR4 genotype in the recipient and donor–recipient sharing of HLA‐DR alleles, especially HLA‐DR3. Thus, T1D recurrence is not uncommon and is developing in patients treated with current immunosuppression. The risk factors identified in this study can be assessed in the transplant clinic to identify recurrent T1D and may lead to therapeutic advances.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Risk Factors for Type 1 Diabetes Recurrence in Immunosuppressed Recipients of Simultaneous Pancreas–Kidney Transplants

Vendrame

Hopfner

Diamantopoulos

et al. 2016

American Journal of Transplantation

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“…ANO1 is located within a previously reported type 1 diabetes susceptibility locus more than 68 Mb away from the INS gene (38)(39)(40)(41)(42), although recent genome-wide association studies (GWAS) have not confirmed this association (43). Nonetheless, we note that ANO1 (TMEM16A) overexpression has been shown to suppress proinflammatory cytokine expression in human cystic fibrosis bronchial epithelia (44).…”

Section: Discussionmentioning

confidence: 95%

Mapping of long-range INS promoter interactions reveals a role for calcium-activated chloride channel ANO1 in insulin secretion

Lefèvre

Гаврилова

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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We used circular chromatin conformation capture (4C) to identify a physical contact in human pancreatic islets between the region near the insulin (INS) promoter and the ANO1 gene, lying 68 Mb away on human chromosome 11, which encodes a Ca 2+ -dependent chloride ion channel. In response to glucose, this contact was strengthened and ANO1 expression increased, whereas inhibition of INS gene transcription by INS promoter targeting siRNA decreased ANO1 expression, revealing a regulatory effect of INS promoter on ANO1 expression. Knockdown of ANO1 expression caused decreased insulin secretion in human islets, establishing a physical proximity-dependent feedback loop involving INS transcription, ANO1 expression, and insulin secretion. To explore a possible role of ANO1 in insulin metabolism, we carried out experiments in Ano1 +/− mice. We observed reduced serum insulin levels and insulin-to-glucose ratios in high-fat diet-fed Ano1 +/− mice relative to Ano1 +/+ mice fed the same diet. Our results show that determination of long-range contacts within the nucleus can be used to detect novel and physiologically relevant mechanisms. They also show that networks of long-range physical contacts are important to the regulation of insulin metabolism.chloride channel | diabetes | insulin secretion

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“…Therefore, we propose to add the usage of a molecular marker (HLA) to the international standard criteria According to the ADA type 1 diabetes is strongly associated with specific HLA groups while in type 2 diabetes does not exist this association [14] . Of all of the type 1 diabetes associated genes and regions revealed by different studies, the HLA association remains the strongest by far, with reported ORs ranging from 0.02 to .11 for specific DR-DQ haplotypes [15,16] . The presence of these genetic variants in patients diagnosed as type 2 let us assign them the "atypical" label.…”

Section: Introductionmentioning

confidence: 99%

HLA alleles may serve as a tool to discriminate atypical type 2 diabetic patients

Fernández

Fabregat

Javiel

et al. 2014

WJD

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AIM:To investigate whether the presence of human leukocyte antigen (HLA) marker could add new information to discriminated atypical diabetic type 2 patients. METHODS:We analyzed 199 patients initially diagnosed as type 2 diabetes who are treated in special care diabetes clinics (3 rd level). This population was classified in "atypical" (sample A) and "classic" (sample B) according to HLA typing. We consider "classic patient" when has absence of type 1 diabetes associated HLA alleles and no difficulties in their diagnosis and treatments. By the other hand, we considered "atypical patient" when show type 1 diabetes associated HLA alleles and difficulties in their diagnosis and treatments. The standard protocol Asociacion Latinoamericana de Diabetes 2006 was used for patients follow up. To analyze differences between both populations in paraclinical parameters we used unpaired t tests and contingence tables. Bivariate and multivariate analyses were carried out using the SPSS software program. In all studies we assume differences statistically significant, with a P -value < 0.05 corrected and 95%CI. RESULTS:The typing HLA in the "atypical" populations show that 92.47% patients presented at list one type 1 diabetes associated HLA alleles (DQB1*0201-0302 and DR 3-4) and 7.53% had two of its. The results showed for categorical variables (family history, presence or absence of hypertension and/or dyslipidemia, reason for initial consultation) the only difference found was at dyslipidemia (OR = 0.45, 0.243 < OD < 0.822 (P < 0.001). In relation to continuous variables we found significant differences between atypical vs classic only in cholesterol (5.07 ± 1.1 vs 5.56 ± 1.5, P < 0.05), high density lipoproteins (1.23 ± 0.3 vs 1.33 ± 0.3, P < 0.05) and low density lipoproteins (2.86 ± 0.9 vs 3.38 ± 1.7, P < 0.01). None of the variables had discriminating power when logistic regression was done. CONCLUSION:We propose an algorithm including HLA genotyping as a tool to discriminate atypical patients, complementing international treatment guidelines for complex patients. Key words: Atypical diabetes; Clinical algorithm; Immunity molecular marker Core tip: There are evidences that exists a lot of patients who were diagnosed as type 2 diabetics but present difficult management, don't have good responses to treatment and don't achieve the metabolic goals. We include the study of human leukocyte antigen markers typically associated whit type 1 diabetes to characterize these patients. This paper provides information about the possibility of incorporate a standardized molecular

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Genetics of Type 1 Diabetes

Cited by 258 publications

References 112 publications

Risk Factors for Type 1 Diabetes Recurrence in Immunosuppressed Recipients of Simultaneous Pancreas–Kidney Transplants

Risk Factors for Type 1 Diabetes Recurrence in Immunosuppressed Recipients of Simultaneous Pancreas–Kidney Transplants

Mapping of long-range INS promoter interactions reveals a role for calcium-activated chloride channel ANO1 in insulin secretion

HLA alleles may serve as a tool to discriminate atypical type 2 diabetic patients

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