Journal Article

Association of RASGRP1 polymorphism with vascular complications in Chinese diabetic patients with glycemic control and antihypertensive treatment

Xu, Bo, Liu, Zhaoqian, Zhou, Jiecan, Zhang, Wei, Chen, Xiaoping, He, Fazhong, Sun, Bao, Shu, Yan

2024

Overview

Background Studies have shown that RASGRP1 was potently associated with the onset of type 2 diabetes mellitus (T2DM), and RASGRP1 rs7403531 was significantly correlated with islet function in T2DM patients. However, the effect of RASGRP1 polymorphism on blood glucose and blood pressure in T2DM patients after continuous treatment has yet to be fully elucidated. Objective This study aimed to explore the association between RASGRP1 genetic polymorphism and cardiovascular complications in T2DM patients, so as to provide more evidence for the individualized treatment of T2DM patients. Methods We retrospectively analyzed a large-scale multicenter drug clinical study cohort that based on a 2 × 2 factorial (glucose control axis and blood pressure lowering axis) randomized controlled design, with follow-up for 5 years. The major vascular endpoint events included cardiovascular death, non-fatal stroke, coronary heart disease, new-onset or worsening renal disease, and diabetic retinopathy. RASGRP1 rs12593201, rs56254815 and rs7403531 were finally selected as candidate single nucleotide polymorphisms. Mixed linear model and Cox hazard ratio (HR) model were used for data analysis with IBM SPSS (version 20.0 for windows; Chicago, IL). Results Our study enrolled 1357 patients with high-risk diabetes, with a mean follow-up duration of 4.8 years. RASGRP1 rs7403531 was associated with vascular events in hypoglycemic and antihypertensive therapy. Specifically, compared with CC carriers, patients with CT/TT genotype had fewer major microvascular events (HR = 0.41, 95% confidence interval (CI) 0.21–0.80, P  = 0.009), and reduced the risk of major eye disease events (HR = 0.44, 95% CI 0.20–0.94, P  = 0.03). For glucose lowering axis, CT/TT carriers had a lower risk of secondary nephropathy (HR = 0.48, 95% CI 0.25–0.92, P  = 0.03) in patients with standard glycemic control. For blood pressure lowering axis, all cerebrovascular events (HR = 2.24, 95% CI 1.11–4.51, P  = 0.025) and stroke events (HR = 2.07, 95% CI 1.03–4.15, P  = 0.04) were increased in patients with CC genotype compared to those with CT/TT genotype in the placebo group, respectively. Furthermore, patients with CC genotype showed a reduced risk of major cerebrovascular events in antihypertensive group (HR = 0.36, 95% CI 0.15–0.86, P  = 0.021). For RASGRP1 rs56254815, compared with the AA genotype carriers, the systolic blood pressure of AG/GG carriers in the antihypertensive group decreased by 1.5mmhg on average ( P  = 0.04). In the placebo group, the blood pressure of AG/GG carriers was 1.7mmHg higher than that of AA carriers ( P  = 0.02). Conclusion We found that patients with G allele of RASGRP1 (rs56254815) showed a better antihypertensive therapy efficacy in T2DM patients. The rs7403531 T allele could reduce the risk of major microvascular events and major eye diseases in T2DM patients receiving either hypoglycemic or antihypertensive therapy. Our findings suggest that RASGRP1 genetic polymorphism might predict the cardiovascular complications in T2DM patients.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Aged / Alleles / Angina pectoris / Angiology / Antihypertensive Agents - adverse effects / Antihypertensive Agents - therapeutic use / Antihypertensives / Asian People - genetics / Biomarkers - blood / Blood Glucose - drug effects / Blood Glucose - metabolism / Blood pressure / Blood Pressure - drug effects / Blood Pressure - genetics / Cardiology / Cardiovascular disease / China - epidemiology / Clinical trials / Coronary artery disease / Diabetes / Diabetes mellitus (non-insulin dependent) / Diabetes Mellitus, Type 2 - blood / Diabetes Mellitus, Type 2 - complications / Diabetes Mellitus, Type 2 - diagnosis / Diabetes Mellitus, Type 2 - drug therapy / Diabetes Mellitus, Type 2 - genetics / Diabetic Angiopathies - diagnosis / Diabetic Angiopathies - genetics / Diabetic retinopathy / DNA-Binding Proteins - genetics / Drug dosages / Drug therapy / East Asian People / Eye diseases / Female / Gene polymorphism / Genetic Association Studies / Genetic Predisposition to Disease / Glucose / Glycemic Control - adverse effects / Guanine Nucleotide Exchange Factors - genetics / Heart diseases / Heart failure / Humans / Hypertension / Hypertension - diagnosis / Hypertension - drug therapy / Hypertension - genetics / Hypertension - physiopathology / Hypoglycemic Agents - adverse effects / Hypoglycemic Agents - therapeutic use / Individual drug treatment / Insulin resistance / Kidney diseases / Male / Medical treatment / Medicine / Medicine & Public Health / Metabolism / Microvasculature / Middle Aged / Nephropathy / Patients / Phenotype / Placebos / Polymorphism / Polymorphism, Single Nucleotide / Proteins / RASGRP1 / Retinopathy / Retrospective Studies / Risk Assessment / Risk Factors / rs7403531 / Signal transduction / Single-nucleotide polymorphism / Stroke / Time Factors / Treatment Outcome / Type 2 diabetes / Vascular complications