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The rs2304256 Polymorphism in TYK2 Gene Is Associated with Protection for Type 1 Diabetes Mellitus.

ABSTRACT: Tyrosine kinase 2 (TYK2) is a candidate gene for type 1 diabetes mellitus (T1DM) since it plays an important role in regulating apoptotic and pro-inflammatory pathways in pancreatic β-cells through modulation of the type I interferon signaling pathway. The rs2304256 single nucleotide polymorphism (SNP) in TYK2 gene has been associated with protection for different autoimmune diseases. However, to date, only two studies have evaluated the association between this SNP and T1DM, with discordant results. This study thus aimed to investigate the association between the TYK2 rs2304256 SNP and T1DM in a Southern Brazilian population. This case-control study comprised 478 patients with T1DM and 518 non-diabetic subjects. The rs2304256 (C/A) SNP was genotyped by real-time polymerase chain reaction technique using TaqMan minor groove binder (MGB) probes. Genotype and allele frequencies of the rs2304256 SNP differed between T1DM patients and non-diabetic subjects (P<0.0001 and P=0.001, respectively). Furthermore, the A allele was associated with protection against T1DM under recessive (odds ratio [OR], 0.482; 95% confidence interval [CI], 0.288 to 0.806) and additive (OR, 0.470; 95% CI, 0.278 to 0.794) inheritance models, adjusting for human leukocyte antigen (HLA) DR/DQ genotypes, gender, and ethnicity. The A/A genotype of TYK2 rs2304256 SNP is associated with protection against T1DM in a Southern Brazilian population.

SUBMITTER: Pellenz FM

PROVIDER: S-EPMC8640150 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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The rs2304256 Polymorphism in TYK2 Gene Is Associated with Protection for Type 1 Diabetes Mellitus.

Pellenz Felipe Mateus FM Dieter Cristine C Duarte Guilherme Coutinho Kullmann GCK Canani Luís Henrique LH de Souza Bianca Marmontel BM Crispim Daisy D

Diabetes & metabolism journal 20210524 6

<h4>Background</h4>Tyrosine kinase 2 (TYK2) is a candidate gene for type 1 diabetes mellitus (T1DM) since it plays an important role in regulating apoptotic and pro-inflammatory pathways in pancreatic β-cells through modulation of the type I interferon signaling pathway. The rs2304256 single nucleotide polymorphism (SNP) in TYK2 gene has been associated with protection for different autoimmune diseases. However, to date, only two studies have evaluated the association between this SNP and T1DM, ...[more]

PMID: 34225445

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Project description:Background and Objectives: Nowadays, every tenth adult in the world suffers from diabetes mellitus (DM). Diabetic retinopathy (DR) is the most common microvascular complication of type 2 DM (T2DM) and a leading cause of acquired blindness in middle-aged individuals in many countries. Previous studies have identified associations of several gene polymorphisms with susceptibility to microvascular complications of DM in various worldwide populations. In our study, we aimed to test the hypothesis of the associations of single nucleotide polymorphisms (SNP) of the VEGF (-2549I/D), RAGE (-429T/C and -374T/A), TCF7L2 (rs7903146), and ITGA2 (BglII) genes with a predisposition to DR among T2DM patients in the Kazakhstan population. Materials and Methods: We conducted a case-control study comparing the genotype distribution and allele frequencies between groups of DR patients (N = 94), diabetic patients without DR (N = 94), and healthy controls (N = 51). Genotypes were identified using the PCR-RFLP method. Results: In all cases, the genotype distribution corresponded to the Hardy-Weinberg equilibrium. The groups of diabetic patients with and without DR did not significantly differ in the genotype distribution of the SNPs studied. Differences between both groups of diabetic patients and healthy controls in four out of five SNPs were also not significant. At the same time, both groups of diabetic patients differed significantly from healthy controls in genotype distribution (p = 0.042 and 0.005, respectively) and allele frequencies (p = 0.021 and 0.002, respectively) of the BglII polymorphism in the ITGA2 gene. After adjusting for multiple comparisons, the differences between the group of diabetic patients without DR and the control group remained significant (pBonf = 0.027 for genotypes and pBonf = 0.009 for alleles). The BglII- allele was associated with diabetes: OR = 1.81 [1.09-2.99] for DR patients, and OR = 2.24 [1.34-3.75] for diabetic patients without DR. The association was also observed in the subset of Kazakhs. Conclusions: This study shows that the BglII polymorphism in the ITGA2 gene can be associated with T2DM but not with DR. According to our data, the risk allele for diabetes is the wild BglII- allele, and not the minor BglII+, which is considered as risky for DR.

Project description:Introduction Periodontitis is a multifactorial disease caused by periodontopathic bacteria and influenced by both genetic and environmental factors. Genetic predispositions are found to play a crucial part in the onset and progression of periodontal disease. There is a two-way relationship between diabetes and periodontitis with severe periodontal tissue destruction seen in diabetic patients. Antimicrobial peptide, β-defensin-1 (DEFB1 gene), plays an important role in the innate immune responses and forms the first line of host defense against periodontal pathogens. Single nucleotide polymorphisms (SNPs) in the specific genetic loci of the DEFB1 gene and its expression level could confer a degree of risk or protection from periodontitis associated with diabetes. The present study determined the association between SNPs at the 5' untranslated region (UTR) in the DEFB1 gene and susceptibility to periodontitis associated with type 2 diabetes mellitus (T2DM) and analyzed the effect of 5' UTR polymorphisms on DEFB1 gene expression. Methods SNPs in the 5' UTR of the DEFB1 gene (-20G>A (rs11362), -44C>G (rs1800972), and -52G>A (rs1799946)) were genotyped by polymerase chain reaction (PCR) followed by Sanger sequencing. The study group included periodontitis (n = 40), periodontitis with T2DM (n = 20), and periodontally and systemically healthy as controls (n = 40). DEFB1 gene expression was determined by real-time PCR in the study group comprising periodontitis (n = 20), periodontitis with T2DM (n = 15), and healthy controls (n = 20). The effect of 5' UTR polymorphisms on the expression was analyzed by statistical tools. Results Statistically significant higher prevalence of the variant AA genotype of rs11362 was observed in periodontitis (odds ratio (OR) = 3.64, 95% confidence Interval (CI) = 1.16-11.43, p = 0.04) and periodontitis with T2DM (OR = 5.14, 95% CI = 1.29-20.5, p = 0.03) in comparison with healthy controls. Moreover, there was a significant increase of the variant AA genotype of rs1799946 in periodontitis (OR = 3.88, 95% CI = 1.19-12.68, p = 0.04) compared to healthy controls. DEFB1 gene expression was downregulated in periodontitis and upregulated in periodontitis with T2DM patients when compared to healthy controls but was not statistically significant. No significant association was found for the effect of SNPs of the DEFB1 gene on its expression. Conclusion From the SNP analysis, it can be inferred that the presence of SNPs at the 5' UTR (rs11362 and rs1799946) in the DEFB1 gene may be an important predictive factor for periodontitis.

Project description:This study aims to investigate the relationship between single nucleotide polymorphisms (SNPs) of sex hormone binding globulin (SHBG) and type 2 diabetes mellitus (T2DM) in an Uighur population. One hundred and fourteen T2DM male patients (with a history of diabetes or diagnosed as diabetic by the oral glucose tolerance test) and 173 healthy males from the Uighur ethnic group were included in the study to test the following SNPs of SHBG: rs727428, rs1799941, rs6259, rs6257, rs858521, rs858518, rs3760213, and rs11078701. The body mass index (BMI), blood pressure, and waist circumference, and lipid, glucose, HbA1c, insulin, HOMA-IR, testosterone, and SHBG levels of enrolled individuals were measured. We used the t-test or rank sum test and Chi-square test to analyze the difference and compare numeration data, respectively, between the case and control groups. Comparisons among multiple groups were carried out using analysis of variance, and the correlation between variables was determined by nonparametric Spearman rank correlation analysis; multivariate logistic regression analysis was used to assess the risk of abnormal glucose in the two groups. There was a significant difference (P < 0.05) in BMI, blood pressure, and waist circumference, and lipid, glucose, HbA1c, insulin, and HOMA-IR levels between the case and control groups. The risk factors for diabetes included testosterone (P = 0.042) and SHBG (P = 0.001). The distribution of rs858521 (P = 0.001), rs1799941 (2.3%, P = 0.032), rs6259 (2.5%, P = 0.040), and rs727428 (3.4%, P = 0.016) was significantly different between the case and control groups (P < 0.05). In the control group, there was linkage disequilibrium (LD) between rs727428 and rs6259, while in the case group LD was found among rs858518, rs3760213, rs1799941, and rs6257. The frequency of rs858518-rs3760213-rs1799941-rs6257 haplotype TCGC was significantly different between the two groups (P = 0.033). Both testosterone and SHBGwere found to be risk factors of diabetes in the Uighur population, and SNPs of SHBG may contribute to T2DM.

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The rs2304256 Polymorphism in TYK2 Gene Is Associated with Protection for Type 1 Diabetes Mellitus.

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The rs2304256 Polymorphism in TYK2 Gene Is Associated with Protection for Type 1 Diabetes Mellitus.

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