KCNJ11 Polymorphisms Research Articles

Association of KCNJ11 gene (rs5219) polymorphism with HOMA-IR & HOMA B values in type 2 diabetes mellitus in India: A case-control study

Objectives Type 2 diabetes mellitus (T2DM) is a complex illness that results from either insulin resistance or insufficient insulin, which raises blood sugar levels. Numerous genes interact to influence the secretion of insulin. A gene of great interest is KCNJ11 of subfamily-J, member 11, which functions as an inwardly rectifying ATP-sensitive potassium (KATP) channel in pancreatic beta cells and is involved in glucose-stimulated insulin release. Material & Methods The present case-control study attempts to delineate the genetic impact of KCNJ11 (rs5219) gene polymorphism on the risk of T2DM in the Indian population. It involves 55 patients with type 2 diabetes (fasting plasma glucose of >126 mg/dl, 2-h glucose of >200 mg/dl, or HbA1c level of >6.4%) and 55 healthy controls (fasting plasma glucose of <100 mg/dl, 2-h glucose of <140 mg/dl, or HbA1c level of <6.4%). polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) was used to study KCNJ11 polymorphism through a standard protocol. Enzyme Linked Immunosorbent Assay (ELISA) was used to estimate serum Insulin levels. HOMA-IR & HOMA-β values were calculated. Statistical analysis was done using t-test, Chi-Square test, and One-way analysis of variance (ANOVA) test. Results Serum insulin levels and HOMA-IR values were significantly decreased in cases than in the control group. Logistic regression analysis showed that the frequency of KK genotype in T2DM individuals (21.8%) was higher than the control group (9%) (p = 0.01). Frequency of K allele (38%) in patients was higher than the control group (18%) (p = 0.001). The K allele risk in diabetic patients was 9.9 times higher as compared to controls (p = 0.001, OR 9.9, 95%Cl 0.036–0.36). Homeostatic model assessment β (HOMA-β) values of KK genotype (59.9±27.8315) were lower than that of EK (76.8±33.23) and EE (127.9±44.59) genotypes (p < 0.001). Conclusion The presence of KCNJ11 (rs 5219) gene polymorphism shows a noteworthy correlation with the likelihood of developing T2DM among the North Indian population. K allele is more likely to be present in individuals with T2DM than the control group. Moreover, HOMA-β values of those with the KK genotype were found to be lower than the individuals having EK and EE genotypes.

Comprehensive data on the relationship between KCNJ11 polymorphisms and gestational diabetes mellitus predisposition: a meta-analysis.

The genetic aspect of gestational diabetes mellitus (GDM) is influenced by multiple causal genetic variants, each with different effect sizes. The KCNJ11 gene is particularly noteworthy as a potential contributor to the risk of GDM due to its role in regulating glucose-induced insulin secretion. To evaluate the association between KCNJ11 polymorphisms and GDM, a comprehensive meta-analysis was conducted to review the existing literature and quantitatively assess the correlation. A thorough search was performed on the PubMed, EMBASE, Scopus, and CNKI databases until December 25, 2023, using precise terms and keywords related to Gestational Diabetes, KCNJ11 gene, and polymorphism. Odds ratios and 95% confidence intervals were used to evaluate the relationships. The statistical analysis was conducted using Comprehensive Meta-Analysis software, and the Cochrane risk of bias assessment tool was used to determine bias presence. The meta-analysis comprised 9 studies with 3108 GDM cases and 5374 controls for the rs5219 polymorphism, and 3 studies with 1209 GDM cases and 1438 controls for the rs5210 polymorphism. The pooled data indicated a noteworthy link between the rs5219 polymorphism and GDM globally and among various ethnic groups, notably in Caucasian and Asian populations. However, no substantial association was observed between the rs5210 polymorphism and GDM. Pooled data showed a correlation between the KCNJ11 rs5219 polymorphism and GDM susceptibility, but no association was found for the rs5210 polymorphism. Future research with larger sample sizes and more diverse populations is needed to improve result generalizability. The online version contains supplementary material available at 10.1007/s40200-024-01428-0.

Association of SLC22A1, SLC47A1, and KCNJ11 polymorphisms with efficacy and safety of metformin and sulfonylurea combination therapy in Egyptian patients with type 2 diabetes.

Multidrug and toxin extrusion transporter 1 (MATE1), encoded by the SLC47A1 gene and single nucleotide polymorphisms of organic cation transport 1, may impact metformin's responsiveness and side effects. Inward-rectifier potassium channel 6.2 (Kir 6.2) subunits encoded by KCNJ11 may affect the response to sulfonylurea. This study aimed to evaluate the association between SLC22A1 rs72552763 and rs628031, SLC47A1 rs2289669 and KCNJ11 rs5219 genetic variations with sulfonylurea and metformin combination therapy efficacy and safety in Egyptian type 2 diabetes mellitus patients. This study was conducted on 100 cases taking at least one year of sulfonylurea and metformin combination therapy. Patients were genotyped via the polymerase chain reaction-restriction fragment length polymorphism technique. Then, according to their glycated hemoglobin level, cases were subdivided into non-responders or responders. Depending on metformin-induced gastrointestinal tract side effects incidence, patients are classified as tolerant or intolerant. KCNJ11 rs5219 heterozygous and homozygous mutant genotypes, SLC47A1 rs2289669 heterozygous and homozygous mutant genotypes (AA and AG), and mutant alleles of both polymorphisms were significantly related with increased response to combined therapy. Individuals with the SLC22A1 (rs72552763) GAT/del genotype and the SLC22A1 (rs628031) AG and AA genotypes were at a higher risk for metformin-induced gastrointestinal tract adverse effects. The results implied a role for SLC47A1 rs2289669 and KCNJ11 rs5219 in the responsiveness to combined therapy. SLC22A1 (rs628031) and (rs72552763) polymorphisms may be associated with increased metformin adverse effects in type 2 diabetes mellitus patients.

Correlating the role of KCNJ11 polymorphism (rs5219) and T2DM: A case control study

Correlating the role of KCNJ11 polymorphism (rs5219) and T2DM: A case control study

Association of KCNJ11 and ABCC8 single-nucleotide polymorphisms with type 2 diabetes mellitus in a Kinh Vietnamese population.

Type 2 diabetes mellitus (T2DM) is a genetically influenced disease, but few studies have been performed to investigate the genetic basis of T2DM in Vietnamese subjects. Thus, the potential associations of KCNJ11 and ABCC8 single nucleotide polymorphisms (SNPs) with T2DM were investigated in a Kinh Vietnamese population. A cross-sectional study consisting of 404 subjects including 202 T2DM cases and 202 non-T2DM controls was designed to examine the potential associations of 4 KCNJ11 and ABCC8 SNPs (rs5219, rs2285676, rs1799859, and rs757110) with T2DM. Genotypes were identified based on restriction fragment length polymorphism and tetra-primer amplification refractory mutation system polymerase chain reaction. After statistically adjusting for age, sex, and BMI, rs5219 was found to be associated with an increased risk of T2DM under 2 inheritance models: codominant (OR = 2.15, 95% confidence intervals [CI] = 1.09-4.22) and recessive (OR = 2.08, 95%CI = 1.09-3.94). On the other hand, rs2285676, rs1799859, and rs757110 were not associated with an increased risk of T2DM. Haplotype analysis elucidated a strong linkage disequilibrium between the 3 SNPs, rs5219, rs2285676, and rs757110. The haplotype rs5219(A)/rs2285676(T)/rs757110(G) was associated with an increased risk of T2DM (OR = 1.42, 95%CI = 1.01-1.99). The results show that rs5219 is a lead candidate SNP associated with an increased risk of developing T2DM in the Kinh Vietnamese population. Further functional characterization is needed to uncover the mechanism underlying the potential genotype-phenotype associations.

The E23K Polymorphism of KCNJ11 and Diabetic Retinopathy in Northern Iran

Background: Diabetic Retinopathy (DR) is one of the most severe micro-vascular complications of diabetes mellitus (DM), involving interactions between environmental and genetic risk factors. KCNJ11 gene has a key role in insulin secretion and is of substantial interest in various populations. Methods: A population-based association of 524 T2DM patients was performed to delineate the genetic influence of KCNJ11 polymorphisms (rs5219, c.67A>G or E23K) on the risk of DR in an Iranian population. Genotyping was performed using TaqMan assay. Univariate and MLR analysis controlling for confounders was conducted to evaluate the association between rs5219 and DR. Results: No significant difference was observed in either genotypes distribution (p = 0.83) or allele frequency (p = 0.66) between T2DM individuals with and without DR in any models of inheritance. Genotype-phenotype association showed that DR group carrying GA genotypes, a significantly higher mean age was observed compared with two other genotypes (p = 0.04). MLR analysis indicated that HbAlc with adjusted OR of 1.84 (95% CI, 1.46–2.33, p = 0.00) and first-degree relatives of family history with adjusted OR of 2.85 (95% CI, 1.45–5.58, p = 0.002) were significantly associated with DR, but the c.67A>G genotype is not an independent predictor of retinopathy. Conclusion: Collectively, rs5219 was not associated with DR among Iranians with T2DM.

Risk of type 2 diabetes mellitus and cardiovascular complications in KCNJ11, HHEX and SLC30A8 genetic polymorphisms carriers: A case-control study

BackgroundType 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) are two deadly diseases caused by the complex interaction of multiple genetic loci, lifestyle and environmental factors. Genome-wide association studies described hundreds of susceptibility loci for T2DM and T2DM-related CVD, but it remains uncertain due to geographic and ethnic variations. The objective of this study was to evaluate the associations of KCNJ11 rs5219, SLC30A8 rs13266634 and HHEX rs1111875 polymorphisms with T2DM and related CVD. MethodsGenotyping of all three polymorphisms was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method on 250 T2DM cases and 246 healthy controls. Both descriptive and inferential statistical methods were applied using MedCalc and IBM SPSS software programs for statistical analyses. ResultsA significantly increased association of KCNJ11 rs5219 (p<0.05) with T2DM was found in dominant, recessive, heterozygote, homozygote, and allele model (aOR = 2.23, 2.03, 1.90, 3.09, and 1.80, respectively). For SLC30A8 rs13266634, only dominant, heterozygote, and allele model (aOR = 3.37, 3.59, and 1.79, respectively) showed significantly increased association with T2DM. SNP rs1111875 (HHEX) also revealed 2.08, 4.18, 5.93, and 2.08-times significant association in dominant, recessive, homozygote, and allele models. Besides, a significantly reduced correlation of KCNJ11 rs5219 was found with T2DM-related CVD in the recessive and allele model (aOR = 0.40 and 0.65, respectively). Again, a significant difference was observed between T2DM-related CVD and non-CVD patients in terms of gender distribution, fasting blood glucose (FBG), systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), and triglycerides (TG). ConclusionsOur investigation indicates that KCNJ11 rs5219, SLC30A8 rs13266634 and HHEX rs1111875 polymorphisms are associated with T2DM. Moreover, KCNJ11 rs5219 polymorphism is correlated with the risk of T2DM-related CVD.

Association of eNOS (G894T, rs1799983) and KCNJ11 (E23K, rs5219) gene polymorphism with coronary artery disease in North Indian population.

Endothelial nitric oxide synthase (eNOS) and potassium voltage-gated channel subfamily J member 11 (KCNJ11) could be the candidate genes for coronary artery disease (CAD). This study investigated the relationship of the eNOS (rs1799983) and KCNJ11 (rs5219) polymorphisms with the presence and severity of CAD in the North Indian population. This study included 300 subjects, 150 CAD cases and 150 healthy controls. Single nucleotide polymorphism was evaluated by Polymerase chain reaction and Restriction fragment length polymorphism (PCR-RFLP). Analysis was performed by SPSS (version 21.0). We observed that KK genotype of KCNJ11E23K (rs5219) polymorphism (P=0.0001) genotypes and K allele (P=0.0001) was found to be a positive risk factor and strongly associated with CAD. In the case of eNOSG894T (rs1799983) there was no association found with CAD. These results illustrate the probability of associations between SNPs and CAD although specific genetic polymorphisms affecting ion channel function and expression have still to be clarified by further investigations involving larger cohorts.

The Interaction between KCNJ11 Gene Polymorphism and Refined Carbohydrates Intake on Obesity in Indonesian Adolescents

Background: Obesity has been associated with genetic and environmental factors. Although carbohydrate intake was previously shown to be associated with a high risk of obesity and insulin resistance, some studies reported that genetic factors also have a role in this association. KCNJ11 is a gene involved in protein K-ATP channels of pancreatic beta cells and previously associated with obesity. Objective: The objective of this study was to determine the interaction between KCNJ11 polymorphism with a high intake of refined carbohydrates in relation to the incidence of obesity in adolescents. Method: This was an observational study with a case-control design. The subjects of this study were male and female adolescents from 10 high schools in Yogyakarta. Dietary intake, body weight, and height were collected. KCNJ11 gene polymorphism was detected by polymerase Chain Reaction- Restriction Fragment Length Polymorphism (PCR-RFLP) method. Result: There is a significant association between KCNJ11 polymorphism with a high intake of refined carbohydrates in the incidence of obesity in adolescents (OR = 2.35, p =0.036). Conclusion: There is a significant association between the KCNJ11 polymorphism with a high intake of refined carbohydrates in adolescent obesity.

KCNJ11 polymorphism is associated with type 2 diabetes mellitus in Iraqi patients

BackgroundDiabetes mellitus (DM) is a polygenic metabolic disorder associated with hyperglycemia and reduced metabolism rate caused by impaired insulin secretion or function or both. Various genetic factors are reported to be associated with type 2 diabetes mellitus (T2DM) including single nucleotide polymorphism (SNP) in various designated genes. This study was conducted to evaluate the role of KCNJ11 SNP, E23K; rs5219, in T2DM. MethodsForty blood samples were collected from T2DM patients (22 males and 18 Females) with age ranged between 48 and 57 year and other 20 blood samples of healthy subjects served as a controls. Genomic DNA was isolated from the samples then polymerase chain reaction (PCR) was used to amplify one DNA fragment concerning E23K; rs5219 SNP in KCNJ11 gene. The E23K polymorphism was followed up using the restriction fragment length polymorphism (RFLP) technique. Glucose, urea, creatinine and lipid profile were estimated as DM associated biochemical parameters using routine work techniques. ResultsThe distribution of E23K alleles was 25% of E/E and 75% of E/K in patients and 70% of E/E and 30% of E/K in controls (X2 = 11.25, OR = 7.0 and p = 0.0014) with absence of K/K allele in both the two groups. There were no significant variations in each of urea, creatinine and lipid profile parameters between the patients and the controls, while glucose and BMI were significantly elevated in patients compared to controls (243.682 ± 106.029 mg/dl for patients vs. 94.1 ± 10.311 mg/dl for controls and 30.175 ± 5.161 kg/m2 for patients vs. 25.684 ± 2.903 kg/m2 for controls respectively). There was no significant statistical association between E23K; rs5219 distribution and the levels of biochemical parameters. ConclusionThe E23K; rs5219 SNP is associated with T2DM, however, further investigations are needed to assess the accurate association between E23K; rs5219 of KCNJ11 and T2DM.

Association of KCNJ11 rs5219 gene polymorphism with type 2 diabetes mellitus in a population of Syria: a case-control study

BackgroundType 2 diabetes mellitus is believed to be a polygenic disorder that develops as a result of a complex interaction between multiple genes and environmental factors. KCNJ11 gene encodes a Kir6.2 protein which forms the inner section of the potassium channels in pancreatic beta cells. Several studies found that KCNJ11 polymorphism increases T2DM risk. Our study aimed to investigate the association between rs5219 polymorphism of the KCNJ11 gene and T2DM in Syrian patients.MethodsThis case-control study involved 75 T2DM patients and 63 healthy controls. The KCNJ11 rs5219 polymorphism was genotyped by Restriction Fragment Length Polymorphism (RFLP).ResultsThe frequency of the risk allele K was similar between the two groups (38.7% vs. 38.1%, P = 0.132). The frequency of the KK genotype was higher among the patients’ group (16% vs. 4.8%), and the frequency of the EK genotype was higher among the control group (45.3% vs. 66.6%); however, the differences were statistically insignificant. The KK genotype was significantly associated with T2DM in the recessive model with an OR of 3.81 (95% CI 1.024–14.17, P = 0.035).ConclusionsThis study showed that rs5219 polymorphism of the KCNJ11 gene is an important risk factor for type 2 diabetes mellitus in a sample of the Syrian population.

Changes of the echocardiographic parameters in chronic heart failure patients with Ile337val, Glu23lys, and Ser1369ala polymorphisms of genes encoding the ATP-sensitive potassium channels subunits in the Ukrainian population.

Different allelic variants of genes that encode ATP-sensitive potassium (KATP ) channels' subunits may contribute to the development of heart failure. The purpose of the work to investigate SNPs in genes that encode KATP channels in relation to echocardiographic parameters in chronic heart failure (CHF) patients. Ninety-nine people with CHF of ischemic origin with left ventricular systolic dysfunction were examined. The control group is represented by 108 clinically healthy subjects. KCNJ11 polymorphisms Ile337Val and Glu23Lys, and ABCC8 polymorphism Ser1369Ala were genotyped using polymerase chain reaction. In CHF patients, the frequency of the Ile337Val genotype was: Ile/Ile, 40.4%; Ile/Val, 45.5%; and Val/Val, 14.1%. The patients with the Val/Val genotype had left ventricular (LV) mass that was 334.15g, which was 27.3% (P < 0.05) lower versus Ile/Val patients (425.48g). The index of this parameter was also significantly lower (28.4%, P < 0.05). In CHF patients, the frequency of Glu23Lys and Ser1369Ala was: Glu/Glu and Ser/Ser, 43.4%; heterozygote, 44.4%; Lys/Lys and Ala/Ala, 12.2%. The patients with the Lys/Lys and Ala/Ala genotypes had a significantly lower LV mass index and LV end-diastolic volume (22.9% and 26.8%, P < 0.05) versus heterozygotes. Thus, the greatest LV mass and LV end-diastolic volume values are associated with heterozygotes, while the smallest are associated with minor homozygotes.

Genetic polymorphisms in KCNJ11 (E23K, rs5219) and SDF-1β (G801A, rs1801157) genes are associated with the risk of type 2 diabetes mellitus

BackgroundType 2 diabetes mellitus (T2DM) is a global major health problem resulting from interaction of environmental and genetic factors, examples of the latter being KCNJ11 (coding for part of the ATP-sensitive potassium channel) and SDF-1β (coding for chemokine CXCL12). Our case-control study was conducted to assess whether recessive, dominant or additive genotype model associations of KCNJ11 (E23K, rs5219) and SDF-1β (G801A, rs1801157) were more strongly linked to type 2 diabetes.Subjects & MethodsGenetic polymorphism analysis was performed by polymerase chain reaction-restriction fragment length polymorphism. Alleles and genotype frequencies between 200 cases and 200 controls were determined and compared.ResultsThe dominant (EE v EK + KK, p = 0.022) and additive (EK v EE + KK, p = 0.021) models, but not the recessive model (KK v EE + EK, p = 0.727) of KCNJ11 were linked to diabetes. Similarly, the dominant (GG v GA + AA, p < 0.001) and additive (AG v GG + AA, p=<0.001) models, but not the recessive model (AA v AG + GG, p = 0.430) of SDF-1β were linked to diabetes. The A allele (p = 0.006) of SDF-1β was protective against the risk of T2DM.ConclusionBoth dominant and additive models in both KCNJ11 (E23K, rs5219) and SDF-1β (G801A, rs1801157) genetic polymorphisms are significantly associated with type 2 diabetes.

Polymorphism Genes Sulfonylurea Receptpr-1 and Potassium InwardlyRectifying Channel Subfamily J Member 11 as a Risk Factor for Type 2 Diabetes Mellitus in Ethnic of Ternate

Background: Sulfonylurea Receptor-1 (SUR1) and Potassium Inwardly-Rectifying Channel Sub Family J Member 11 (KCNJ11) is the gene at canal its activity of ATP sensitive potassium (KATP). Canal KATP ATP acts as a sensor on the settings of the secretion of insulin. Polymorphism R1273R E23K genes SUR1 and KCNJ11 cause interference with the activity of the Canal KATP, affect the secretion of insulin causing hyperglycemia and Impaired Glucose Tolerance (IGT) are at risk of type 2 DM occurs.Purpose: Examine the interconnectedness of Polymorphism R1273R E23K genes SUR1 and KCNJ11 as risk factors of type 2 DM on Ternate Ethnic.Methods: The case-control Design to the subject research of sufferers of type 2 DM (n=52) as Group cases and subject to the Non-DM (n=52) as a control group. Genotyping gene is done by the method of PCR-RFLP. Compare the subject case and control groups with the test t-test are not paired. Test of chi-square and the odds ratio (OR) to analyze the relationship of polymorphism R1273R E23K genes SUR1 and KCNJ11 with risk of incident type 2 DM.Results: The frequency of Genotype GA genes SUR1 group cases (9.6%) while genotype GA in the control group (3.8%) (p=0.256; Or=2.660). Combination genotype GG genes SUR1 and genotype GA genes KCNJ11 compared to genotype GG genes SUR1 and KCNJ11 is a protective factor for DM (p=0.000; Or=0.083). Genotype GG genes SUR1 and AA genotype genes KCNJ11 compared to genotype GG genes SUR1 and KCNJ11 (p=0.975; Or=1.031).Conclusion: The individual carrier genotype GA polymorphism R1273R genes SUR1 statistically not different but has a significant risk of developing type 2 DM. Genotype GA E23K genes KCNJ11 polymorphism as protective factors in type 2 DM on Ternate ethnic.

Risk of type 2 diabetes mellitus in the Kyrgyz population in the presence of ADIPOQ (G276T), KCNJ11 (Glu23Lys), TCF7L2 (IVS3C>T) gene polymorphisms

To analyze the association of genotype combinations of the polymorphic markers G276T in the ADIPOQ gene, Glu23Lys in the KCNJ11 gene, and IVS3C>T in the TCF7L2 gene with the development of type 2 diabetes mellitus (T2DM) in the Kyrgyz population. The investigation enrolled 23 Kyrgyz people, of whom there were 114 patients with T2DM and 109 without T2DM (a control group). T2DM was diagnosed in accordance with the WHO criteria (1999). The genotypes of ADIPOQ (G276T), KCNJ11 (Glu23Lys), and TCF7L2 (IVS3C>T) gene polymorphisms were identified using the restriction fragment length polymorphism analysis. When typing at the polymorphic loci G276T in the ADIPOQ gene, Glu23Lys in the KCNJ11 gene, and IVS3C>T in the TCF7L2 gene, the development of T2DM in the Kyrgyz population was associated with the T allele (odds ratio (OR), 1.68; p=0.025), the heterozygous G276T genotype (OR 1,8; p=0.036) in the ADIPOQ gene; the 23Lys allele (OR, 1.62; p=0.019) in the KCNJ11 gene; a two-locus genotype combination in the genes ADIPOQ/KCNJ11: G276T/Glu23Lys (OR, 4.88; p=0.0013), G276G/Lys23Lys (OR, 4.65; p=0.019), G276T/Glu23Glu (OR, 3.10; p=0.022), a two-locus genotype combination in the genes ADIPOQ/TCF7L2: G276T/СС (OR, 1.97; p=0.04); two-locus genotype combinations in the genes KCNJ11/TCF7L2: Lys23Lys/CC (ОR, 2.65; p=0.042), Glu23Lys/CT (OR, 3.88; p=0.027); and a three-locus genotype combination in the genes ADIPOQ/KCNJ11/TCF7L2: G276T/Glu23Lys/CT (OR, 14.48; p=0.02). The development of T2DM in the Kyrgyz population is genetically determined by ADIPOQ (G276T) gene, KCNJ11 (Glu23Lys), and TCF7L (IVS3C>T) gene polymorphisms with the predisposing value of the T allele of the heterozygous G276T genotype in the ADIPOQ gene; the 23Lys allele in the KCNJ1 gene; as well as by genotype combinations in the genes ADIPOQ/KCNJ11 (G276T/Glu23Lys, G276G/Lys23Lys, G276T/Glu23Glu); ADIPOQ/TCF7L2 (G276T/SS); KCNJ11/TCF7L2 (Lys23Lys/CC, Glu23Lys/CT); ADIPOQ/KCNJ11/TCF7L2 (G276T/Glu23Lys /CT). The IVS3C>T locus in the TCF7L2 gene is not independently statistically significantly associated with the development of T2DM; however, its predisposing effect has been identified in its combination with the variant genotypes of the polymorphic loci G276T in the ADIPOQ gene and Glu23Lys in the KCNJ11 gene.

Pharmacogenomics of Type 2 Diabetes Mellitus

Diabetes mellitus is a complex metabolic disorder with multiple factors associated with its causation, outcome and response to treatment. Several researchers are working on identifying the genetic and non-genetic factors that are implicated in disease causation as well as response to therapy. It has been found that, some of the genetic factors such as ABCC8 and KCNJ11 polymorphisms are associated with disease causation as well as outcome of therapy with specific drugs. Presence of multiple associative factors have led to the realization of a much complex network of pathways that are involved in diabetes mellitus. In this review we discuss the genetic factors involved in type 2 diabetes mellitus and in its response to treatment with different classes of drugs. The genetic factors include single nucleotide polymorphisms in genes coding for drug metabolizing enzymes (e.g., CYP2C9), drug transporters (e.g., OCT1, OCT 2, MATE1, MATE2), receptors and channels such as ABCC8, KCNJ11. The net effect of all genetic variations in each individual patient determines the outcome of therapy. To translate pharmacogenetics in to clinical practice, it is needed to have evidence on the net effect of genetic polymorphisms.

Prediabetes is associated with genetic variations in the gene encoding the Kir6.2 subunit of the pancreatic ATP-sensitive potassium channel (KCNJ11): A case-control study in a Han Chinese youth population.

The E23K variant of the potassium voltage-gated channel subfamily J member 11 (KCNJ11) gene has been reported to be associated with type 2 diabetes (T2D) in many populations. However, little is known about the role of E23K in the development of prediabetes in Chinese youth. To investigate the role of E23K in the development of prediabetes, 279 subjects with prediabetes and 240 normal controls (mean [± SD] age 18.1 ± 3.2 and 17.8 ± 4.3 years, respectively) were recruited to the study. Height, weight, and hip and waist circumferences were measured by trained physicians. Genotyping of KCNJ11 polymorphisms and clinical laboratory tests to determine cholesterol, triglyceride (TG), blood glucose, and insulin levels were performed. The carrier rate of K23 allele-containing genotypes was higher for prediabetic than control subjects (P = 0.005). Logistic regression analyses revealed that higher body mass index percentiles (P = 0.013), lower insulin levels at 30 min during an oral glucose tolerance test (P = 0.001), a higher ratio of total cholesterol: high-density lipoprotein cholesterol (P = 0.001), and a K allele-containing genotype (P = 0.019) are independent risk factors for prediabetes in Chinese Han youth. Furthermore, K23 allele-containing genotypes were associated with impaired indices of insulin secretion and β-cell function in female youth with prediabetes. These effects were not seen in male youth with prediabetes. The results confirm that the common E23K polymorphism of KCNJ11 carries a higher susceptibility to the development of prediabetes in the Chinese Han population. The results suggest that E23K may have a greater effect on the development of T2D in female Chinese youth.

KCNJ11, ABCC8 and TCF7L2 polymorphisms and the response to sulfonylurea treatment in patients with type 2 diabetes: a bioinformatics assessment

BackgroundType 2 diabetes (T2D) is a worldwide epidemic with considerable health and economic consequences. Sulfonylureas are widely used drugs for the treatment of patients with T2D. KCNJ11 and ABCC8 encode the Kir6.2 (pore-forming subunit) and SUR1 (regulatory subunit that binds to sulfonylurea) of pancreatic β cell KATP channel respectively with a critical role in insulin secretion and glucose homeostasis. TCF7L2 encodes a transcription factor expressed in pancreatic β cells that regulates insulin production and processing. Because mutations of these genes could affect insulin secretion stimulated by sulfonylureas, the aim of this study is to assess associations between molecular variants of KCNJ11, ABCC8 and TCF7L2 genes and response to sulfonylurea treatment and to predict their potential functional effects.MethodsBased on a comprehensive literature search, we found 13 pharmacogenetic studies showing that single nucleotide polymorphisms (SNPs) located in KCNJ11: rs5219 (E23K), ABCC8: rs757110 (A1369S), rs1799854 (intron 15, exon 16 -3C/T), rs1799859 (R1273R), and TCF7L2: rs7903146 (intron 4) were significantly associated with responses to sulfonylureas. For in silico bioinformatics analysis, SIFT, PolyPhen-2, PANTHER, MutPred, and SNPs3D were applied for functional predictions of 36 coding (KCNJ11: 10, ABCC8: 24, and TCF7L2: 2; all are missense), and HaploReg v4.1, RegulomeDB, and Ensembl’s VEP were used to predict functions of 7 non-coding (KCNJ11: 1, ABCC8: 1, and TCF7L2: 5) SNPs, respectively.ResultsBased on various in silico tools, 8 KCNJ11 missense SNPs, 23 ABCC8 missense SNPs, and 2 TCF7L2 missense SNPs could affect protein functions. Of them, previous studies showed that mutant alleles of 4 KCNJ11 missense SNPs and 5 ABCC8 missense SNPs can be successfully rescued by sulfonylurea treatments. Further, 3 TCF7L2 non-coding SNPs (rs7903146, rs11196205 and rs12255372), can change motif(s) based on HaploReg v4.1 and are predicted as risk factors by Ensembl’s VEP.ConclusionsOur study indicates that a personalized medicine approach by tailoring sulfonylurea therapy of T2D patients according to their genotypes of KCNJ11, ABCC8, and TCF7L2 could attain an optimal treatment efficacy.

EVALUATION OF AN ASSOCIATION BETWEEN RS5219 POLYMORPHISM OF KCNJ11 GENE AND THE RISK OF TYPE 2 DIABETES MELLITUS

Background: Type 2 diabetes mellitus (T2DM) represents from 90 to 95% of all diabetes and usually occurs in obese individuals above 40 years of age, is highly prevalent, associated with high morbidity and mortality from complications involving, first of all, the cardiovascular system. The risk of T2DM is determined by combined effects of genetic and environmental factors. Genes associated with T2DM have been identified, including the gene of ATPdependent potassium channel (KCNJ11); the prevalence of its polymorphisms may have some regional characteristics.Aim: To study an association between rs5219 KCNJ11 gene polymorphisms and the risk of T2DM in the population of the Moscow Region.Materials and methods: The study involved 1050 subjects, including 311 men and 739 women, 139 of whom (17 men and 122 women) had T2DM. Genotyping of rs5219 KCNJ11 gene polymorphisms was performed with the use of allele-specific amplification, the real-time detection and TaqMan-probes complementary to the DNA polymorphism sites.Results: The analysis of rs5219 KCNJ11 polymorphism frequencies showed that 14.2% of patients had TT genotype, 44.8 – CT genotype, and 41.1% – normal (wild) CC genotype. The prevalence of the mutant T allele was 36.6%, that of the C allele – 63.4%. The frequency of the mutant T allele in patients with obesity (body mass index≥30 kg/m²) was not significantly different from that in patients without obesity (body mass index&lt;30 kg/m²) (38.8% and 35.7%, respectively, odds ratio (OR) 1.14, 95% confidence interval (CI) 0.907–1.439, p=0.26). At the same time, energy expenditure at rest per kg of lean body mass was significantly lower in men who have rs5219 KCNJ11 gene polymorphism, both in homoand heterozygotes. The frequency of the T allele and TT genotype in diabetic patients was higher than in the control group. An association between TT genotype and the risk of T2DM was found (OR 2.35, CI 1.018–5.43, p=0.04).Conclusion: In the population of the Moscow Region, gene polymorphism rs5219 KCNJ11 contributes to the risk of developing T2DM which is most obvious and statistically significant in homozygotes.

Lack of association between KCNJ11 (rs5219) and ABCC8 (rs757110) polymorphisms and sulphonylurea treatment response in type 2 diabetes patients in Novosibirsk region

Aim. Sulfonylureas (SU) are widely used in everyday clinical practice in treatment of patients with type 2 diabetes mellitus (T2DM). There is a considerable variability in SU effects, which may be caused by psychological, social, biological and genetic factors. The aim of the study was to investigate the association between rs5219 KCNJ11 gene and rs757110 ABCC8 gene polymorphism and long-term response to SU-drugs of second and third generation in the Novosibirsk region. Materials and Methods. 326 patients with type 2 diabetes in the Novosibirsk region were examined. Patients were divided into 2 groups, depending on HbA1c level. The first group included patients with target HbA1c levels on SU monotherapy. The second group included patients who did not reach target HbA1c levels on the highest dose of SU. Genotyping of KCNJ11 (rs5219) and ABCC8 (rs757110) was performed by TaqMan real-time PCR (ICBFM SB RAS, Novosibirsk, Russia). Results. Patients with type 2 diabetes with a good response to SU-therapy compared to the group of patients with a poor response to SU-therapy were older (65.8?9.1 years vs. 61.6?7.9 years, p