Fogarty D G, Zychma M J, Scott L J, Warram J H, Krolewski A S
Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
Diabetologia. 1998 Nov;41(11):1304-8. doi: 10.1007/s001250051069.
In Type I (insulin-dependent) diabetes mellitus a genetic predisposition exists to nephropathy and is related to parental hypertension. Enhanced G-protein activation, a cellular phenotype observed in cultured cells from patients with essential hypertension, was recently documented in Type I diabetic subjects with nephropathy. This enhanced G-protein activation has been associated with a genetic variant in the G-protein beta3 subunit, GNB3. A C-->T polymorphism at position 825 in exon 10 is associated with G-protein activation, the T allele associated with enhanced activity. Furthermore the T allele was observed more frequently in a group with essential hypertension. In this report we have analysed the role of the C825T polymorphism in the predisposition to diabetic nephropathy in Type I diabetes. We have investigated the frequency of this polymorphism in a large case-control study and found no association of the T allele with diabetic nephropathy. Specifically carriage of the T allele as CT or TT was observed in 49% of 200 Type I diabetic control subjects with normoalbuminuria (diabetes duration 24 years) compared with 53% of 216 Type I diabetic subjects with nephropathy (overt proteinuria or end-stage renal failure). Within this group we have also examined the inheritance of C825T alleles in a family study and found no evidence for excess transmission of the T allele to Type I diabetic offspring with nephropathy (T allele transmitted to 51% of nephropathy offspring, C allele transmitted to 49% of nephropathy offspring, p = 0.79). In none of the Type I diabetic datasets examined was there any effect of genotype on variation in systolic or diastolic blood pressure. In conclusion we can find no evidence for the C825T polymorphism of the beta3 G-protein subunit as a major gene in the susceptibility to diabetic nephropathy in Type I diabetes.
在Ⅰ型（胰岛素依赖型）糖尿病中，存在肾病的遗传易感性，且与父母的高血压有关。增强的G蛋白激活是原发性高血压患者培养细胞中观察到的一种细胞表型，最近在患有肾病的Ⅰ型糖尿病患者中也有记录。这种增强的G蛋白激活与G蛋白β3亚基（GNB3）的一个基因变异有关。外显子10第825位的C→T多态性与G蛋白激活有关，T等位基因与增强的活性相关。此外，在原发性高血压组中更频繁地观察到T等位基因。在本报告中，我们分析了C825T多态性在Ⅰ型糖尿病肾病易感性中的作用。我们在一项大型病例对照研究中调查了这种多态性的频率，发现T等位基因与糖尿病肾病无关联。具体而言，在200例尿白蛋白正常（糖尿病病程24年）的Ⅰ型糖尿病对照受试者中，49%观察到携带CT或TT形式的T等位基因，而在216例患有肾病（显性蛋白尿或终末期肾衰竭）的Ⅰ型糖尿病受试者中这一比例为53%。在该组中，我们还在一项家系研究中检查了C825T等位基因的遗传情况，未发现T等位基因过度传递给患有肾病的Ⅰ型糖尿病后代的证据（T等位基因传递给51%的肾病后代，C等位基因传递给49%的肾病后代，p = 0.79）。在所检查的任何Ⅰ型糖尿病数据集中，基因型对收缩压或舒张压的变化均无影响。总之，我们没有发现β3 G蛋白亚基的C825T多态性作为Ⅰ型糖尿病肾病易感性主要基因的证据。
