CD28 Genetic Variants Increase Susceptibility to Diabetic Kidney Disease in Chinese Patients with Type 2 Diabetes: A Cross-Sectional Case Control Study.

Yangyang Li,Jing Yan,Rong Zhang,Hong Zhang,Cheng Hu,Li Jin,Joilson O Martins

doi:10.1155/2021/5521050

Yangyang Li, Jing Yan + Show 5 more

Open Access

https://doi.org/10.1155/2021/5521050

Copy DOI

Abstract

Few studies have illuminated the genetic role of T cell costimulatory molecule CD28/CD80/CTLA4 variants in diabetic kidney disease (DKD) susceptibility. We aimed to investigate the causal role of genetic polymorphisms in CD28/CD80/CTLA4 with DKD susceptibility in patients with T2DM. A total of 3253 patients with T2DM were recruited for genotyping: including 204 DKD patients and 371 controls in stage 1 and 819 DKD patients and 563 controls in stage 2; besides, 1296 T2DM patients were selected for the analysis of association between loci and DKD-related traits. A subset of 227 T2DM patients (118 patients with DKD and 109 patients without DKD) from the total population above were selected to assess serum soluble CD28 (sCD28) levels. Then, we performed a candidate gene association study to identify single-nucleotide polymorphisms (SNPs) associated with DKD susceptibility and further used those SNPs to perform Mendelian randomization analyses of serum sCD28 level and DKD susceptibility. Under additive genetic models, CD28-rs3116494 (OR = 1.29 [95% CI 1.11, 1.51], P = 0.0011) and CD80-rs3850890 (OR = 1.16 [95% CI 1.02, 1.31], P = 0.0283) were associated with DKD susceptibility adjusted for age, gender, body mass index (BMI), duration of diabetes, and HbA1c. CD28-rs3116494 was associated with serum sCD28 level (β = 0.26 [95% CI 0.08, 0.44], P = 0.0043). The Mendelian randomization analysis showed that CD28-rs3116494 played a causal role in DKD by influencing serum sCD28 levels (β = 1.15 [95% CI 0.46, 1.83], P = 0.0010). In conclusion, we identified that two novel SNPs, CD28-rs3116494 and CD80-rs3850890, were associated with DKD susceptibility. Using the Mendelian randomization analysis, our study provided evidence for a causal relationship between serum CD28 levels and DKD with T2DM in the Chinese population.

Highlights

Diabetic kidney disease (DKD) is a major microvascular complication of diabetes mellitus (DM), which remains a leading cause of end-stage renal disease (ESRD) and an independent risk factor for all-cause mortality [1,2,3]
Associations between the 26 single-nucleotide polymorphisms (SNPs) studied in stage 1 and DKD, after adjusting for age, gender, body mass index (BMI), duration of diabetes, and HbA1c levels, are shown in Supplementary Table 1 and Figures 1(a)– 1(c)
We found a significant association of DKD with rs3116494 in the CD28 gene region (P = 0:0360) and a marginal association with rs3850890 in the CD80 gene region (P = 0:0929) in stage 1

Summary

Introduction

Diabetic kidney disease (DKD) is a major microvascular complication of diabetes mellitus (DM), which remains a leading cause of end-stage renal disease (ESRD) and an independent risk factor for all-cause mortality [1,2,3]. It is recognized that intensive glucose control reduces the risk of DKD [5]. Despite advances in glycemic control therapies, the development of ESRD remains a growing problem globally, and it has generated a substantial public health burden over the past 2 decades [2, 6]. Under similar durations of diabetes and comparable blood glucose concentrations, the occurrence, progression, and regression of DKD are highly variable in T2DM [7]. Other risk factors for DKD in diabetics should not be ignored, including gender, obesity, hypertension, inflammation, resistance to insulin, hypovitaminosis D, and dyslipidaemia [10]. A hereditary component to DKD has been recognized for a long time, and many genetic loci in specific genes have been identified to be associated with

Objectives

Methods

Results

Conclusion