鉴定特定的血管紧张素转换酶变异体和单倍型，这些变异体和单倍型可导致 2 型糖尿病肾病的发病风险和保护作用。

Identification of specific angiotensin-converting enzyme variants and haplotypes that confer risk and protection against type 2 diabetic nephropathy.

机构信息

Research Unit of Biology and Genetics of Cancer and Haematological and Autoimmune Diseases, Faculty of Pharmacy of Monastir, Monastir University, Monastir, Tunisia.

出版信息

Diabetes Metab Res Rev. 2009 Nov;25(8):717-24. doi: 10.1002/dmrr.1006.

DOI:10.1002/dmrr.1006

PMID:19787680

Abstract

BACKGROUND

Cross-sectional and family studies identified angiotensin-converting enzyme (ACE) gene as a risk factor for diabetic nephropathy (DN). The contribution of ACE gene variants to DN development and progression is controversial and varies among different ethnic/racial groups.

METHODS

We investigated the association of three ACE gene variants with DN, rs1799752 insertion/deletion (I/D), rs1800764T/C and rs12449782A/G in 917 Tunisian type 2 diabetic (T2DM) patients: 515 with (DN) and 402 without (DWN) nephropathy. ACE genotyping was done by PCR-based assays; haplotype estimation was performed using H-Plus software (chi(2)-test based).

RESULTS

Genotype frequency distributions of the three studied variants were in Hardy-Weinberg equilibrium. Minor allele frequency of rs1800764 was higher in DN patients than DWN patients or healthy controls, and minor allele frequency of rs1799752 was higher in DN than DWN patients. Higher frequency of rs1799752 and rs1800764 homozygous mutant genotypes was seen in DN compared to DWN patients. Of the three variants, only rs1799752 deletion/deletion (D/D) genotype was associated with a significant increase in albumin to creatinine ratios levels, and D/D carriers had elevated low-density lipoprotein, total cholesterol and urea. Three locus haplotype [rs1799752(I/D)/rs1800764(T/C)/rs12449782(A/G)] analysis revealed that the frequency of DCG haplotype was higher, while that of ITG and ICA haplotypes were lower among unselected type 2 diabetic patients. Taking ITA haplotype as reference, multivariate regression analysis confirmed the negative (ITG), and positive (DCG, DTG, DCA and DTA) association of specific ACE haplotypes with DN, after adjusting for potential nephropathy-linked covariates.

CONCLUSIONS

Our results support the involvement of specific ACE variants in DN pathogenesis and demonstrate the presence of DN-specific haplotypes at the ACE locus.

摘要

背景

横断面和家系研究将血管紧张素转换酶（ACE）基因鉴定为糖尿病肾病（DN）的风险因素。ACE 基因变异对 DN 发展和进展的贡献存在争议，并且在不同的种族/人群中存在差异。

方法

我们研究了三个 ACE 基因变异与 917 例突尼斯 2 型糖尿病（T2DM）患者的 DN 的相关性，其中 515 例患有（DN）和 402 例未患有（DWN）肾病：rs1799752 插入/缺失（I/D）、rs1800764T/C 和 rs12449782A/G。ACE 基因分型采用基于 PCR 的检测方法；采用 H-Plus 软件（基于卡方检验）进行单体型估计。

结果

三个研究变异的基因型频率分布均符合 Hardy-Weinberg 平衡。与 DWN 患者或健康对照组相比，DN 患者 rs1800764 的次要等位基因频率更高，而 rs1799752 的次要等位基因频率在 DN 患者中更高。与 DWN 患者相比，DN 患者中 rs1799752 和 rs1800764 纯合突变基因型的频率更高。在这三个变异中，只有 rs1799752 缺失/缺失（D/D）基因型与白蛋白与肌酐比值水平的显著升高相关，D/D 携带者的低密度脂蛋白、总胆固醇和尿素水平升高。三个位点单体型[rs1799752（I/D）/rs1800764（T/C）/rs12449782（A/G）]分析显示，未选择的 2 型糖尿病患者中 DCG 单体型的频率更高，而 ITG 和 ICA 单体型的频率更低。以 ITA 单体型为参考，多元回归分析证实，在调整潜在的肾病相关协变量后，特定 ACE 单体型与 DN 呈负相关（ITG），呈正相关（DCG、DTG、DCA 和 DTA）。