ACE Variants Interact with the RAS Pathway to Confer Risk and Protection against Type 2 Diabetic Nephropathy
ACE Variants Interact with the RAS Pathway to Confer Risk and Protection against Type 2 Diabetic Nephropathy
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DOI：
10.1089/dna.2008.0810
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发表时间：
2009-03-01
影响因子：
3.1
通讯作者：
Khullar, Madhu
中科院分区：
文献类型：
--
作者：
Ahluwalia, Tarunveer Singh;Ahuja, Monica;Khullar, Madhu
遗传易感性被认为是糖尿病肾脏并发症发生的主要决定因素。血管紧张素转换酶（ACE）基因是糖尿病肾病易感性的候选基因之一，与糖尿病肾病的发生、发展密切相关。然而，其他的肾素-血管紧张素系统（RAS）多态性的作用及其可能的相互作用与不同的ACE I/D基因型不太清楚。最近的研究还表明，ACE单倍型可能是更好的疾病易感性的预测。因此，在本研究中，我们评估了亚洲印度人ACE单倍型和ACE、血管紧张素原（AGT）和血管紧张素II受体I型（AGTR 1）基因多态性与DNP的相互作用。我们使用等位基因特异性寡核苷酸-PCR和PCR-限制性片段长度多态性分析，对无肾病（DM）和有肾病（DNP）的2型糖尿病队列中RAS通路基因（ACE、AGT和AGTR 1）的7种变体进行基因分型。我们研究了这些变异之间的相互作用和ACE I/D多态性。DNP患者ACE D等位基因和DD基因型频率（ACE I/D）显著增高（p < 0.005），并与肾病风险增加相关。T等位基因、MT/TT基因型（AGT：M235 T）和C等位基因1166 CC基因型（AGTR 1：A1166 C）的频率较高，与DNP风险增加相关（235 T，p < 0.0001; 235 TT/MT，p < 0.01; 1166 C，p < 0.007; 1166 CC，p < 0.0001）。ACE基因座显示DNP患者T-D-G风险单倍型的患病率（比值比，1.76）（0.13）与DM患者（0.08; p < 0.02）相比几乎加倍。携带I等位基因的ACE单倍型与DNP风险较低相关（C-I-A，p < 0.04; C-I-G，p < 0.008）。ACE ID/DD基因型与ACE rs 4311、rs 4343和AGT rs699突变基因型组合使DNP发生的风险增加4倍（p < 0.01）。这项研究提供了第一个证据DNP在亚洲印度人的ACE基因座的疾病单倍型。该研究进一步表明，ACE D等位基因单独和与其他RAS单核苷酸多态性的相互作用显着增加亚洲印度裔2型糖尿病患者的肾病风险。
Genetic predisposition has been proposed to be a major determinant in the development of renal complications of diabetes. Among candidate genes examined for susceptibility to diabetic nephropathy, angiotensin-converting enzyme (ACE) gene has been found to be associated with pathogenesis and progression of diabetic nephropathy. However, the role of other renin-angiotensin system (RAS) polymorphisms and their possible interactions with different ACE I/D genotypes are less clearly defined. Recent studies also show that ACE haplotypes may be better predictors to disease susceptibility. Thus, in the present study, we evaluated the association of ACE haplotypes and the interactions of ACE, angiotensinogen (AGT), and angiotensin II receptor type I (AGTR1) gene polymorphisms with DNP in Asian Indians. We genotyped seven variants of the RAS pathway genes (ACE, AGT, and AGTR1) in type 2 diabetic cohorts without nephropathy (DM) and with nephropathy (DNP), using allele-specific oligonucleotide-PCR, and PCR-restriction fragment length polymorphism assays. We studied the interaction of these variants with each other and ACE I/D polymorphism. Frequency of ACE D allele and DD genotype (ACE I/D) was significantly higher in DNP (p < 0.005) and was associated with increased risk of nephropathy. The frequency of T allele, MT/TT genotypes (AGT: M235T), and C allele 1166CC genotype (AGTR1: A1166C) was higher and associated with increased risk of DNP (235T, p < 0.0001; 235TT/MT, p < 0.01; 1166C, p < 0.007; 1166CC, p < 0.0001). The ACE locus revealed a near doubling in the prevalence of T-D-G risk haplotype (odds ratio, 1.76) in DNP (0.13) compared to DM (0.08; p < 0.02). ACE haplotypes carrying the I allele were associated with a lower risk of DNP (C-I-A, p < 0.04; C-I-G, p < 0.008). ACE ID/DD genotypes in combination with ACE rs4311, rs4343, and AGT rs699 mutant genotypes increased the risk of DNP development fourfold (p < 0.01). This study provides the first evidence for a disease haplotype for DNP at the ACE locus in Asian Indians. The study further indicates that ACE D allele individually and in interaction with other RAS single-nucleotide polymorphisms significantly increases the risk of nephropathy in type 2 diabetic patients of Asian Indian origin.