The association of rs4646994 ACE and rs1799983 eNOS gene polymorphisms with metabolic effects of dapagliflozin in patients with diabetic nephropathy and essential hypertension
Authors: Chernyshov V. A. , Nesen A. O. , Semenovykh P. S. , Savicheva K. O. 
Published: December 2023

Objective — to establish possible associations of rs4646994 ACE and rs1799983 eNOS gene polymorphisms with metabolic effects of dapagliflozin in patients (pts) with diabetic nephropathy (DN) and essential hypertension (EH).
Materials and methods. Clinical investigation and examinations involved 171 pts, from them 85 (49.7%) females and 86 (50.3%) males with DN of I—IV stages and EH of II—III stages, aged 31 to 82 years old (an average age was 59.38±1.58 years). They were also genotyped for rs4646994 (I/D) ACE and for rs1799983 (G894T) eNOS gene polymorphisms with the use of polymerase chain reaction. Among the patients with I/D polymorphism of ACE gene there were 24 (14.0%) pts with genotype II, 32 (18.7%) pts with genotype ID and 26 (15.2%) subjects with genotype DD. Among the participants with G894T eNOS gene polymorphism GG genotype was revealed in 29 (16.9%) pts, GT genotype was found in 33 (19.3%) cases and 27 (15.8%) examined persons had TT genotype. Standard parameters of lipid profile were measured in all included pts with a use of an immune enzyme method. Glucose oxidase and immune enzyme methods were used to define serum glucose and insulin levels; level of glycosylated hemoglobin (HbA1C) was detected by fluid chromatography method. Insulin resistance (IR) indices such as HOMA‑IR, triglyceride‑glucose index (TGGI), METS‑IR (metabolic score for insulin resistance) index were calculated by known formulas. Cardiometabolic risk (CMR) of the pts was estimated by ­METS‑IR index. Body mass index (BMI), body fat percentage (BFP), total fat mass (TFM) and fat mass index (FMI) in all the pts were calculated by standard known formulas. Serum uric acid concentration was measured with phosphovolframic method. Dapagliflozin 10 mg/daily was added for 24 weeks to the basic standard antidiabetic therapy including gliclazide or glimepiride and metformin combined with lipid lowering therapy containing atorvastatin. The standard therapy was not changed during the whole period of observation.
Results. No association has been revealed between I/D ACE and G894T eNOS gene polymorphisms in pts with DN and EH, with a noted improvement of lipid blood spectrum due to administration of dapagliflozin in a dose of 10 mg/daily for 24 weeks. It has been established that allele D was associated with a reduction of dapagliflozin efficacy in the correction of carbohydrate metabolism disorders in pts with DN and EH. At presence of allele D (ID and DD) in genotype, the levels of glycemia, insulinemia, HbA1C, IR indices such as HOMA‑IR, TGGI, METS‑IR decreased less effective than in the case of allele D absence (genotype II). In pts with DN and EH who had G894T eNOS gene polymorphism, dapagliflozin 10 mg/daily improved muscle sensitivity to insulin and decreased CMR depended on genotype in the following order: GT >TT >GG, whereas the intensity of glycemia, insulinemia, HbA1C and HOMA‑IR index reduction was found to be associated with genotype as follows: GG >GT >TT. Allele I compared with allele D of I/D ACE gene polymorphism in pts with DN and EH was revealed to be associated with more significant reduction of BFP, TFM and FMI due to dapagliflozin administration. In pts with DN and EH who had G894T eNOS gene polymorphism dapagliflozin 10 mg/daily reduced a body mass due to its influence on fat accumulation but not on muscle tissue both in phenotype of visceral obesity (genotype GG) and in phenotype of sarcopenic obesity (genotype GT). In the realization of hypouricemic effects of dapagliflozin in patients with DN and EH, both genetic factors (D and T alleles of I/D ACE and G894T eNOS gene polymorphisms correspondingly), and metabolic factors (initial levels of HbA1C and UA together with anthropometric parameters characterized visceral obesity phenotype such as BMI, TFM and FMI) were involved.
Conclusions. In pts with DN and EH, the association of I/D ACE (rs4646994) and G894T eNOS (rs1799983) gene polymorphisms with metabolic effects of dapagliflozin 10 mg/daily has been established. A presence of allele D of I/D ACE and allele T of G894T eNOS gene polymorphisms in genotype was concluded to be associated with less significant metabolic effects of dapagliflozin compared with an absence of these alleles in genotype.