Genetic variant in the promoter of connective tissue growth factor gene confers susceptibility to nephropathy in type 1 diabetes.
Genetic variant in the promoter of connective tissue growth factor gene confers susceptibility to nephropathy in type 1 diabetes.
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DOI：
10.1136/jmg.2009.073098
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发表时间：
2010-06
影响因子：
4
通讯作者：
DCCT/EDIC Study Group
中科院分区：
文献类型：
--
作者：
Wang B;Carter RE;Jaffa MA;Nakerakanti S;Lackland D;Lopes-Virella M;Trojanowska M;Luttrell LM;Jaffa AA;DCCT/EDIC Study Group
糖尿病肾病的发病机制中遗传易感性的证据是公认的，但涉及的基因仍有待确定。假设编码结缔组织生长因子（CTGF/CCN 2）的基因内的突变将增加糖尿病受试者发展肾病的倾向。对来自DCCT/EDIC队列的862名1型糖尿病受试者进行CTGF基因内单核苷酸多态性（SNP）的基因组筛查。在启动子区发现了一种新的SNP，它改变了-20位的C-G。微量白蛋白尿患者（白蛋白排泄率（AER）>40 mg/24 h）GG基因型频率显著高于AER <40 mg/24 h的糖尿病患者，p<0.0001。具有该多态性的糖尿病受试者发生微量白蛋白尿的相对风险（RR）是不具有该多态性的糖尿病受试者的3倍（RR 3.142，95% CI 1.9238至5.1249; p<0.05）。Kaplan-Meier生存曲线显示GG基因型组发生微量白蛋白尿和大量白蛋白尿的速度比GC或CC基因型组更快。功能研究表明，取代的等位基因/启动子（-20 GG等位基因）的基础活性显著高于野生型启动子（-20 CC基因型）。在抑制Smad 1水平后，取代的等位基因CTGF/CCN 2启动子的这种较高水平的基础活性被废除，表明CTGF/CCN 2启动子中的SNP区域在基因表达中起着至关重要的作用。这些发现提供了CTGF/CCN 2基因启动子区域内的变体使糖尿病受试者易患白蛋白尿的第一个证据，并证明Samd 1通过该区域控制CTGF/CCN 2启动子的表达。
The evidence for genetic susceptibility in the pathogenesis of diabetic nephropathy is well recognised, but the genes involved remain to be identified. It is hypothesised that mutations within the gene encoding connective tissue growth factor (CTGF/CCN2) will increase the propensity of diabetic subjects to develop nephropathy. Genomic screening was performed for single nucleotide polymorphisms (SNPs) within the CTGF gene in 862 subjects from the DCCT/EDIC cohort of type 1 diabetes. A novel SNP was identified in the promoter region that changes a C-G at the position −20. The frequency of GG genotype in microalbuminuric patients (albumin excretion rate (AER) >40 mg/24 h) is significantly greater than diabetics with AER <40 mg/24 h, p<0.0001. The relative risk (RR) to develop microalbuminuria in diabetic subjects with the polymorphism is 3X higher than diabetic subjects without the polymorphism (RR 3.142, 95% CI 1.9238 to 5.1249; p<0.05). Kaplan–Meier survival curves demonstrated that the GG genotype group developed microalbuminuria and macroalbuminuria at a more rapid rate than the GC or CC genotypes. Functional studies demonstrated that the basal activity of the substituted allele/promoter (−20 GG allele) was significantly greater than that of the wild type promoter (−20 CC genotype). This higher level of basal activity of substituted allele CTGF/CCN2 promoter was abrogated upon suppression of Smad1 levels, indicating that SNP region in the CTGF/CCN2 promoter plays a vital role in the gene expression. These findings provide the first evidence that variants within the promoter region of the CTGF/CCN2 gene predisposes diabetic subjects to develop albuminuria and demonstrate that Samd1 controls the expression of CTGF/CCN2 promoter through this region.
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影响因子：
4.8
作者：
Pannu, Jaspreet;Nakerakanti, Sashidhar;Trojanowska, Maria
通讯作者：
Trojanowska, Maria
影响因子：
4.8
作者：
Nakerakanti, Sashidhar S.;Kapanadze, Bagrat;Trojanowska, Maria
通讯作者：
Trojanowska, Maria
影响因子：
19.6
作者：
Krolewski, M;Eggers, PW;Warram, JH
通讯作者：
Warram, JH
DOI：
10.1083/jcb.114.6.1285
发表时间：
1991-09
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bradham DM;Igarashi A;Potter RL;Grotendorst GR
通讯作者：
Grotendorst GR
影响因子：
5.8
作者：
Jaffa, Ayad A.;Usinger, William R.;Wilson, Peter W. F.
通讯作者：
Wilson, Peter W. F.