Correlation between polymorphisms of SIRT2 gene and renal injury in patients with type 2 diabetes mellitus

Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2024 Jul 28;49(7):1005-1014. doi: 10.11817/j.issn.1672-7347.2024.240186.
[Article in English, Chinese]

Abstract

Objectives: Genetic factors play an important role in the pathogenesis of diabetic kidney disease (DKD). Studies have shown that SIRT2 gene polymorphism is associated with the pathogenesis of type 2 diabetes mellitus (T2DM), but its role in DKD remains unclear. This study aims to analyze the distribution of alleles and genotypes of SIRT2 gene in patients with T2DM, and investigate the association between SIRT2 genetic polymorphism and DKD susceptibility in T2DM patients, which may provide new ideas for the pathogenesis of DKD.

Methods: A toal of 205 T2DM patients who receiving treatment in the Third Xiangya Hospital of Central South University were divided into a DKD group (n=100) and a DM group (n=105) according to the presence of kidney injury, and 100 healthy volunteers were selected as NC group. Clinical data of the subjects were collected and estimated glomerular filtration rate (eGFR) were calculated. Genomic DNA was extracted and the genotypes of single nucleotide polymorphism (SNP) loci (rs11879029, rs11879010, and rs2241703) were determined using Sanger chain termination method. The genotype/allele frequencies among the 3 groups were compared. Logistic regression was used to analyze the correlation between SNP locus genotype of SIRT2 gene and risk of DKD in T2DM patients. According to the genotypes of rs11879029/rs11879010, T2DM patients were divided into a GG1/GG2 group, a GA1/GA2 group, and an AA1/AA2 group, and the clinical data were compared. Linkage disequilibrium analysis and haplotype analysis were performed.

Results: The genotype distribution and allele frequencies of the rs11879029 and rs11879010 loci in the DKD group were significantly different in comparison with the NC and DM groups (all P<0.05). For rs2241703, there were no differences in genotype and allele frequencies (all P>0.05). After correcting by age, gender, systolic blood pressure, duration of diabetes, glycosylated hemoglobin, and serum albumin, rs11879029 and rs11879010 genotype were associated with DKD susceptibility in T2DM patients. Carriers of rs11879029 genotype AA were 6.27 times more likely to have DKD than carriers of genotype GG. And carriers of rs11879010 genotype AA were 4.72 times more likely to have DKD than carriers of genotype GG. The eGFR levels in the AA1/AA2 groups were significantly lower than those in the GG1/GG2 groups (both P<0.05). Analysis of linkage disequilibrium showed complete linkage disequilibrium existed between SIRT2 rs11879029 and rs11879010, and the 2 SNPs (rs11879029 and rs11879010) were in strong linkage disequilibrium with rs2241703. Monotype GGG reduced the risk of DKD in T2DM patients (OR=0.53, 95% CI 0.35 to 0.81, P=0.003), while haplotype AAG increased the risk of DKD in patients (OR=1.80, 95% CI 1.16 to 2.80, P=0.008).

Conclusions: The genetic polymorphisms rs11879029 and rs11879010 of SIRT2 gene are potential contributors to the susceptibility of DKD in patients with T2DM, and allele A significantly increases the risk of DKD compared with allele G. The AA genotype might be a genetic risk factor for DKD.

目的: 遗传因素在糖尿病肾病(diabetic kidney disease,DKD)发病中发挥重要作用。研究表明SIRT2基因多态性与2型糖尿病(type 2 diabetes mellitus,T2DM)发病相关,但其在DKD中的作用尚不清楚。本研究旨在探讨SIRT2基因多态性与T2DM患者发生肾损伤风险的相关性,为DKD的发病机制的研究提供新思路。方法: 纳入2019至2021年在中南大学湘雅三医院就诊的T2DM患者205例,根据是否有肾损伤将其分为DKD组(n=100)和DM组(n=105),同时选取100名健康志愿者作为NC组。收集研究对象的临床资料,计算估算肾小球滤过率(estimated glomerular filtration rate,eGFR);提取基因组DNA,采用Sanger双脱氧末端终止法进行SIRT2基因单核苷酸多态性(single nucleotide polymorphism,SNP)位点(rs11879029、rs11879010和rs2241703)基因型的检测。比较3组间基因型/等位基因频率。采用Logistic回归分析SIRT2基因SNP位点基因型与2型糖尿病患者发生DKD风险的相关性。根据SIRT2基因rs11879029/rs11879010的基因型,分别将T2DM患者分为GG1/GG2组、GA1/GA2组、AA1/AA2组,比较不同基因型T2DM患者的临床资料。进行连锁不平衡分析和单体型分析。结果: 与NC组和DM组比较,DKD组rs11879029、rs11879010位点的基因型分布和等位基因频率差异均有统计学意义(均P<0.05)。3组间rs2241703位点的基因型和等位基因频率差异均无统计学意义(均P>0.05)。在校正年龄、性别、收缩压、糖尿病病程、糖化血红蛋白、血清白蛋白后,rs11879029、rs11879010位点基因型仍与T2DM患者发生DKD的风险显著相关,rs11879029位点AA基因型患者发生DKD风险是GG基因型的6.27倍,rs11879010位点AA基因型患者发生DKD风险是GG基因型的4.72倍。AA1/AA2组eGFR水平均显著低于GG1/GG2组(均P<0.05)。连锁不平衡分析显示SIRT2基因rs11879029与rs11879010位点存在完全连锁不平衡,rs11879029、rs11879010分别与rs2241703之间存在较强连锁不平衡。单体型GGG可能降低T2DM患者发生DKD的风险(OR=0.53,95% CI 0.35~0.81,P=0.003),单体型AAG可能增加患者DKD风险(OR=1.80,95% CI 1.16~2.80,P=0.008)。结论: SIRT2基因rs11879029和rs11879010位点与T2DM患者DKD易感性相关,携带A等位基因能增加DKD的患病风险,AA基因型是DKD的遗传危险因素。.

Keywords: SIRT2; diabetic kidney disease; genotype; single nucleotide polymorphisms; susceptibility; type 2 diabetes mellitus.

MeSH terms

  • Case-Control Studies
  • Diabetes Mellitus, Type 2* / complications
  • Diabetes Mellitus, Type 2* / genetics
  • Diabetic Nephropathies* / etiology
  • Diabetic Nephropathies* / genetics
  • Female
  • Gene Frequency*
  • Genetic Predisposition to Disease
  • Genotype*
  • Glomerular Filtration Rate
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Risk Factors
  • Sirtuin 2* / genetics

Substances

  • Sirtuin 2
  • SIRT2 protein, human