NeuroD1/BETA2, PAX4and KCNQ1Gene Polymorphisms Are Associated With The Susceptibility Of Type2Diabetes Mellitus And Repaglinide Efficacy In Patients With Type2Diabetes Mellitus

Pharmacogenetics refers to drug metabolism, effective group and individual difference abnormality which mainly caused by genetic variance and disfunction of drug-metabolizing enzyme, drug transport or target proteins. Pharmacogenetics aims to explain the basic mechanisms of drug therapeutic efficacy individual difference and adverse reaction from point of view of genetic polymorphisms. From molecular level to clinical level subjects, it combines pharmacology, physiology, hereditism, genomics, clinical medicine, epidemiology, statistics, bioinformatics and biocomputer to elucidate medicine functions and its mechanisms. Individual difference of drug reaction is a common phenomenon in clinical drug use. The reasons include gender, age, weight and accompanied diseases and so on, among them, genetic factors is very important. Pharmacogenetics studies indicate that activity change of drug-metabolizing enzymes, receptors and transporter is the major mechanism for individual differences in drug response, and inherited variation in activities of drug-metabolizing enzymes, receptors and transporter results in inter-individual differences in drug metabolism, disposition and efficacy.Type2diabetes mellitus (T2DM), also called noninsulin-dependent diabetes mellitus, is a complex metabolic disease. Type2diabetes mellitus accounts90%of all diabetes and rapidly increasing prevalence year by year. Now more than170million subjects worldwide are type2diabetes mellitus patients. The world healthy organization estimates that the number of type2diabetes mellitus patients will be more than3billions in2025and age of onset shows make more youthful tendency. The pathogenesy of type2diabetes includes hereditary susceptibility, fi-cell disfunction in pancreas islet and insulin resistance. NeuroD1 (neurogenic differentiation1), also called β-cell E-box transactivator2, it very important for pancreas β-cell differentiation and normal function as positive regulation protein. It has been reported that NeuroDl/BETA2gene had a polymorphism in211nucleotide position (G>A), which caused Ala substituted by Thr. This polymorphism locates in function domain and may influence the gene transcription activity and the differentiation and rebuild ability of pancreas B-cell. The association between NeuroD1/BETA2gene Ala45Thr and type2diabetes mellitus in Chinese is not clear until now.The paired box gene4plays very important role in pancreas B-cell differentiation and development which as a transcript inhibition factor. PAX4gene knock-out mouse showed insulin secretion cells and growth hormone release inhibiting hormone secretion cells absolutely absence in full-blown pancreas, but glicentin secreted a-cell were proliferation. PAX4gene located in chromatosome7q32combined9exons and8introns. It has been reported PAX4gene R121W polymorphism associated with type2diabetes in Japanese and effected on pancreas B-cell function. Another study results showed patients with mutate homozygote121W was short of the first phase of insulin secretion. We don’t know the association of PAX4gene R121W polymorphism and Chinese type2diabetes mellitus.Genome-wide association studies (GWASs) and meta-analyses identified several new susceptibility gene polymorphisms of type2diabetes mellitus. These gene polymorphisms play important roles in insulin secretion and pancreas B-cell function. KCNQ1(potassium voltage-gated channel, KQT-like subfamily, member1) gene rs2237892and rs2237895polymorphisms associated with type2diabetes mellitus in several populations. It belongs to potassium voltage-gated channel family and expressing in heart, pancreatic gland, prostate, kidney, small intestine and peripheral blood leucocyte. The KCNQ1gene polymorphisms affect the function and insulin secretion of β-cell.Repaglinide is an insulin secretagogue agent, also called Dietary glucose regulator. It is widely used in type2diabetes patients who have higher blood glucose after alimentary control, body weight control and exercise. Repaglinide binds with sulfonylurea receptor, then blocks potassium voltage-gated channel and open calcium voltage-gated channel, causing increasing insulin secretion. Repaglinide is mainly used in control postprandial hyperglycemia and improve the first phase insulin secretion. Repaglinide therapeutic efficacy shows individual differences.This study investigated whether NeuroDl/BETA2gene Ala45Thr polymorphism, PAX4gene R121W polymorphism and KCNQ1gene rs2237892and rs2237895polymorphisms are associated with type2diabetes and repaglinide efficacy in Chinese T2DM patients.The present series of studies have found that:1. NeuroD1/BETA2gene Ala45Thr polymorphism was associated with the development of type2diabetes mellitus.2. Patients with mutated NeuroDl/BETA2gene Ala45Thr polymorphism showed higher FINS and PINS levels than that in A/T+T/T individuals.3. NeuroD1/BETA2gene Ala45Thr polymorphism affects repaglinide therapeutic efficacy. Patients with A/A genotypic NeuroDl/BETA2gene showed higher FPG DV and PPG DV values than that in A/T+T/T individuals.4. The genotypic and allelic frequencies of PAX4gene R121W polymorphism shows no differences between type2diabetes group and healthy controls.5. Patients with PAX4gene R/R polymorphism showed higher PINS levels than that in R/W+W/W individuals. 6. PAX4gene R121W polymorphism affects repaglinide therapeutic efficacy. T2DM Patients with R/R genotypic PAX4gene showed higher PPG DV values than that in R/W+W/W individuals.7. KCNQ1gene rs2237892and rs2237895polymorphisms were associated with type2diabetes and showed gene dosage effect.8. KCNQ1gene rs2237892polymorphism was associated with the values of FINS and HOMA-IR and KCNQ1gene rs2237895polymorphism affected markedly the values of PPG and HOMA-IR in T2DM patients.9. KCNQ1gene rs2237892and rs2237895polymorphisms affected repaglinide therapeutic efficacy and showed gene dosage effect in T2DM patients.The present study has provided novels susceptibility gene locus for type2diabetes mellitus. We try to explain the possible mechanism of individual differences in repaglinide therapeutic efficacy.