Association of ABCC8 and KCNJ11 gene variants with type 1 diabetes in south Indians

Abstract Background Type 1 diabetes mellitus (TIDM) is a polygenic disorder with the involvement of several genetic and environmental risk factors. Mutation in genes namely ABCC8 and KCNJ11 disrupt the potentiality of KATP channel and regulates the secretion of insulin by detecting a change in the blood glucose level and consequently maintains glucose homeostasis. The present study was designed to investigate the association of ABCC8 and KCNJ11gene polymorphisms with type 1 diabetes. A case-control study was conducted enrolling 60 cases suffering from T1DM and 60 healthy controls of comparable age and sex. Gene variations were determined by PCR-RFLP and ARMS-PCR method. Results The ABCC8-3C > T (rs1799854) variation was found to be significantly associated with T1DM (p<0.01) and “CT” genotype was found to be predominant in T1DM with a threefold increased risk to diabetes and the association was statistically significant. However, we did not find any significant association of C>T (rs1801261) polymorphism of ABCC8 with T1DM. A significant association was observed for genetic variation at rs5219 C>T polymorphism and the frequency of TT genotype was found to be significantly higher in patients (46.7%) than in controls (21.7%), indicating the significant role of the KCNJ11 rs5219 variant in T1DM susceptibility (p<0.001), but we did not observe any significant association of G>A (rs5215) polymorphism of KCNJ11 with T1DM. In addition, haplotype analysis of the two genes revealed four haplotypes such as T-C-G-T, T-C-A-T, C-C-G-T, and T-T-G-T as risk haplotypes for type 1 diabetes (p<0.02) potentially making individual effects of these variants on the disease susceptibility, thereby indicating the synergistic role of these genes in the regulation of glucose homeostasis. Conclusions The present study highlights the importance of personalized medicine based on individual genetic profile.

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Diabetic Retinopathy May Indicate an Increased Risk of Cardiovascular Disease in Patients With Type 1 Diabetes—A Nested Case-Control Study in Brazil

Frontiers in Endocrinology ◽

10.3389/fendo.2019.00689 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 1

Author(s):

Laura Gomes Nunes Melo ◽

Paulo Henrique Morales ◽

Karla Rezende Guerra Drummond ◽

Deborah Conte Santos ◽

Marcela Haas Pizarro ◽

...

Keyword(s):

Cardiovascular Disease ◽

Type 1 Diabetes ◽

Diabetic Retinopathy ◽

Case Control Study ◽

Case Control ◽

Increased Risk ◽

Nested Case Control ◽

Control Study

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The Role of Autoantibodies to Zinc Transporter 8 in Prediction of Type 1 Diabetes in Relatives: Lessons from the European Nicotinamide Diabetes Intervention Trial (ENDIT) Cohort

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2011-1952 ◽

2012 ◽

Vol 97 (2) ◽

pp. 632-637 ◽

Cited By ~ 18

Author(s):

Anna E. Long ◽

A. Talia Gooneratne ◽

Saba Rokni ◽

Alistair J. K. Williams ◽

Polly J. Bingley

Keyword(s):

Type 1 Diabetes ◽

Genetic Risk ◽

Zinc Transporter ◽

Intervention Trial ◽

First Degree Relatives ◽

Zinc Transporter 8 ◽

Increased Risk ◽

Diabetes Intervention

Context: Antibodies to islet autoantigens are detectable many years before clinical onset of type 1 diabetes and can be used to identify individuals at increased risk of diabetes. Zinc transporter 8 is a recently identified islet autoantigen. Objective: Our aim was to determine whether addition of zinc transporter 8 autoantibodies (ZnT8A) improved prediction of type 1 diabetes in a well-characterized cohort of islet cell antibody (ICA)-positive first-degree relatives. We were particularly interested in the role of ZnT8A in prediction in antibody-positive relatives with intermediate and low overall risk of diabetes. Participants and Methods: ZnT8A were assayed in baseline samples from 526 ICA-positive first-degree relatives randomized in the European Nicotinamide Diabetes Intervention Trial. Antibodies to insulin, glutamate decarboxylase, islet antigen-2 (IA-2A) and IA-2β (IA-2βA), and human leukocyte antigen type had been previously determined. Risk of diabetes was assessed by survival analysis. Results: Of 221 ZnT8A-positive individuals, 113 developed diabetes during follow-up (5-yr cumulative risk, 55%). In multivariate models based on other autoantibodies, ZnT8A improved prediction in relatives at low genetic risk of diabetes (P = 0.030) and over age 20 yr (P = 0.026), but not in those with ICA alone or with one additional autoantibody (P = 0.696), IA-2A-negative relatives (P = 0.361), those at high or intermediate genetic risk, or younger relatives. Conclusions: ZnT8A are useful additional risk markers in relatives at low genetic risk of diabetes and older individuals, but they add relatively little in younger populations because of the precise prediction possible with current autoantibody combinations.

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Role of C1858T Polymorphism of Lymphoid Tyrosine Phosphatase in Egyptian Children and Adolescents with Type 1 Diabetes

Current Diabetes Reviews ◽

10.2174/1573399814666180709102533 ◽

2019 ◽

Vol 16 (1) ◽

pp. 73-79 ◽

Cited By ~ 2

Author(s):

Wafaa Moustafa M. Abo El Fotoh ◽

Dina Abd El Razek Midan ◽

Abeer Hamdy El Shalakany

Keyword(s):

Type 1 Diabetes ◽

Tyrosine Phosphatase ◽

Negative Regulator ◽

Egyptian Children ◽

Important Negative Regulator ◽

Different Populations ◽

1858T Allele ◽

Control Study

Background: Type 1 Diabetes Mellitus (T1DM) is a multifactorial autoimmune disease. The Protein Tyrosine Phosphatase Non-receptor 22 (PTPN22) gene is an important negative regulator of signal transduction through the T-cell Receptors (TCR). A PTPN22 polymorphism, C1858T, has been found to be a risk determinant for several autoimmune diseases, including T1DM, in different populations. Objective: The present study was aimed to analyze a possible association between the C1858T polymorphism in Egyptian children with T1DM. Methods: This case-control study included 240 children divided evenly between T1DM patients and controls. The PTPN22 C1858T polymorphism was genotyped using polymerase chain reaction with Restriction Fragment Length Polymorphism (RFLP). Results: Both the 1858CΤ and 1858ΤΤ genotypes and the 1858T allele were found more frequently in patients (32.5% and 18.7%, respectively) than in controls (10% and 5.0%, respectively), P=0.013 and P=0.007, respectively. Among females, the 1858T allele was more common in patients (18%) than in controls (2.6%), P=0.014. Conclusion: These findings suggest that the PTPN22 1858T allele could be a T1DM susceptibility factor in the Egyptian population and that it might play a different role in susceptibility to T1DM according to gender in T1DM patients.

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The Role of Age and Excess Body Mass Index in Progression to Type 1 Diabetes in At-Risk Adults

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2017-01490 ◽

2017 ◽

Vol 102 (12) ◽

pp. 4596-4603

Author(s):

Christine T Ferrara ◽

Susan M Geyer ◽

Carmella Evans-Molina ◽

Ingrid M Libman ◽

Dorothy J Becker ◽

...

Keyword(s):

Body Mass Index ◽

Type 1 Diabetes ◽

Body Mass ◽

Protective Factor ◽

Diabetes Incidence ◽

Increased Risk ◽

Diabetes Progression ◽

The Impact

Abstract Background Given the global rise in both type 1 diabetes incidence and obesity, the role of body mass index (BMI) on type 1 diabetes pathophysiology has gained great interest. Sustained excess BMI in pediatric participants of the TrialNet Pathway to Prevention (PTP) cohort increased risk for progression to type 1 diabetes, but the effects of age and obesity in adults remain largely unknown. Objective To determine the effect of age and sustained obesity on the risk for type 1 diabetes in adult participants in the TrialNet PTP cohort (i.e., nondiabetic autoantibody-positive relatives of patients with type 1 diabetes). Research Design and Methods Longitudinally accumulated BMI >25 kg/m2 was calculated to generate a cumulative excess BMI (ceBMI) for each participant, with ceBMI values ≥0 kg/m2 and ≥5 kg/m2 representing sustained overweight or obese status, respectively. Recursive partitioning analysis yielded sex- and age-specific thresholds for ceBMI that confer the greatest risk for type 1 diabetes progression. Results In this cohort of 665 adults (age 20 to 50 years; median follow-up, 3.9 years), 49 participants developed type 1 diabetes. Age was an independent protective factor for type 1 diabetes progression (hazard ratio, 0.95; P = 0.008), with a threshold of >35 years that reduced risk for type 1 diabetes. In men age >35 years and women age <35 years, sustained obesity (ceBMI ≥5 kg/m2) increased the risk for type 1 diabetes. Conclusions Age is an important factor for type 1 diabetes progression in adults and influences the impact of elevated BMI, indicating an interplay of excess weight, age, and sex in adult type 1 diabetes pathophysiology.

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Human Leukocyte Antigens class II (HLA II) gene profile from an admixed population of patients with type 1 diabetes with severe diabetic retinopathy: a nested case-control study in Brazil

Diabetology & Metabolic Syndrome ◽

10.1186/s13098-021-00702-y ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Deborah Conte Santos ◽

Luís Cristóvão Porto ◽

Marcela Haas Pizarro ◽

Laura Gomes Nunes de Melo ◽

Dayse A. Silva ◽

...

Keyword(s):

Type 1 Diabetes ◽

Diabetic Retinopathy ◽

Case Control Study ◽

Case Control ◽

P Value ◽

Admixed Population ◽

Nested Case Control ◽

Control Study

Abstract Background Although the well-established role of the HLA genes on the predisposition of type 1 diabetes (T1D), its contribution to the development and progression of diabetic retinopathy is still unclear, especially in admixed populations. We aimed to study the relationship between HLA alleles and severe diabetic retinopathy in a highly admixed population of T1D patients. Methods This was a nested case-control study based on a cross-sectional, nationwide survey conducted in Brazil. We included 117 patients with severe diabetic retinopathy and 117 random controls composed of T1D patients without retinopathy, matched for diabetes duration. HLA-class II genes (HLA-DRB1, -DQA1, and -DQB1) were genotyped using the SSO and NGS methods. Results Haplotypes HLA-DRB1*04:05 ~ DQA1*03:01 g ~ DQB1*03:02 (OR 1.75, CI 0.97–3.16, p value 0.058) and HLA-DRB1*13:02 ~ DQA1*01:02 ~ DQB1*06:04 (OR 5.18, CI 1.12–23.09, p value 0.019) were more prevalent on the severe DR group but they did not present statistically difference after Bonferroni correction. The most frequent haplotype on both groups was HLA-DRB1*03:01 ~ DQA1*05:01 g ~ DQB1*02:01 (29.6% on severe DR and 33.33% on the control group). Conclusions Our study showed no influence of HLA genes on the development of DR. Further longitudinal data is needed to better understand the role of genetic factors on this multifactorial significant microvascular complication.

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