Polymorphisms of the KCNQ1 gene are associated with the therapeutic responses of sulfonylureas in Chinese patients with type 2 diabetes

Abstract

KCNQ1 channel is a member of the voltage-gated potassium channel KQT-like subfamily. The KCNQ1 gene has recently been identified as a susceptibility locus for type 2 diabetes mellitus (T2DM). In the present study, we examined the effects of KCNQ1 variants on the therapeutic response to modified-release gliclazide (gliclazide MR) treatment in Chinese patients newly diagnosed with T2DM. A total of 100 newly diagnosed T2DM patients without a history of any anti-diabetic medications were treated with gliclazide MR for 16 weeks, but 91 patients completed the entire study. The anthropometric parameters were determined at baseline and at the final visit, while clinical laboratory tests were performed at baseline and on weeks 2, 4, 6, 12, 16. Two SNPs, rs2237892 and rs2237895, in the region of the KCNQ1 gene were genotyped in all the participants. All calculations and statistical analyses were conducted using SPSS. The rs2237892 TT homozygotes exhibited significantly higher 2-h glucose levels at baseline (P<0.05) and a lower cumulative attainment rate of the target 2-h glucose level (P log-rank =0.020) than the C allele carriers. Patients with greater numbers of rs2237892 T alleles exhibited larger augmentations (Δ) in the 2-h glucose levels (P=0.027); and patients with the rs2237892 TT genotype exhibited a higher Δ homeostasis model assessment of β-cell function (HOMA-β) than CC and CT genotype carriers (P=0.021 and P=0.043, respectively). Moreover, the rs2237895 C allele was associated with a greater decrement in Δ glycated hemoglobin (HbA1c) (P=0.024); and patients with the CC genotype exhibited greater variance than those with the AA and AC genotypes (P=0.005 and 0.021, respectively). Compared with the C allele, the odds ratio for treatment success among carriers of the rs2237892 T allele was 2.533 (P=0.007); and the rs2237895 C allele was associated with a 2.360-fold decrease in HbA1c compared with the A allele (P=0.009). KCNQ1 polymorphisms are associated with gliclazide MR efficacy in Chinese patients with type 2 diabetes.

Pharmacogenomics of Insulin Secretagogues in Pharmacodynamics, Pharmacokinetics and Adverse Reactions

“…∆FPG was significantly higher in TT+TG group than in GG group (P=0.016). Li et al [14] expounded the association between rs2237892/rs2237895 and modified-release gliclazide effect in Chinese T2DM patients. In rs2237892 variant, carriers of TT genotype exhibited higher 2-h glucose levels after 16 weeks of sulfonylureas gliclazide MR (modified-release gliclazide) treatment (P=0.044).…”

Pharmacogenomic Studies of Current Antidiabetic Agents and Potential New Drug Targets for Precision Medicine of Diabetes

“…The KCNQ1 rs163184 variant was found to markedly reduce FPG in patients with diabetes on sulfonylurea treatment [ 58 ]. Two studies from China revealed that KCNQ1 polymorphisms are associated with response to sulfonylurea therapy in patients with newly diagnosed T2D [ 59 , 60 ].…”

Advances and potential of gene therapy for type 2 diabetes mellitus

“…A large number of genetic polymorphisms affect the response to oral anti-diabetic drugs. Genes encoding SLC2A2 and organic cation transporters (OCT1, OCT2, and OCT3) are associated with glycemic response to metformin [17][18][19], while SLCO1B3 and KCNQ are associated with sulfonylureas response [20,21]. However, these genes have little applicability in therapy due to the different polymorphisms among different populations.…”