Young R P, Chan J C, Critchley J A, Poon E, Nicholls G, Cockram C S
Department of Clinical Pharmacology, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.
Diabetes Care. 1998 Mar;21(3):431-7. doi: 10.2337/diacare.21.3.431.
Genetic polymorphisms of the renin-angiotensin system (RAS) have been implicated in the pathogenesis of diabetic proteinuria. Ethnic differences in the frequencies of these genotypes have also been reported. To date, most of these studies have been performed in white and Japanese populations. In this study, we examined the associations between albuminuria and RAS genetic polymorphisms in Chinese patients with type 2 diabetes.
In a case-control study, the ACE insertion/deletion (I/D) gene, the angiotensinogen (AGT) gene (M235T), and the angiotensin II (AII) type 1 receptor gene (AT1 A1166C) were examined in 110 Chinese type 2 diabetic patients. Increased urinary albumin excretion (UAE) was defined as > or = 30 mg/day on at least two occasions during a 6-week study period.
Compared with whites, there were high frequencies of the AGT TT genotype in Chinese control subjects (120/183 = 70%) and type 2 diabetic patients (74/110 = 67%). The frequencies of the MM genotype were 5 and 3%, respectively, and those of the ACE DD genotype were 13 and 10%, respectively. Although 9% of subjects carried the C allele, the AT1 CC genotype was not found in either group. Chinese type 2 diabetic patients with increased albuminuria (n = 56) had higher systolic blood pressure (160 +/- 26 mmHg vs 145 +/- 27 mmHg, P < 0.001) than the normoalbuminuric patients (n = 54). Both the AGT TT genotype (78.6% [44/56] vs. 55.6% [30/54], odds ratio [OR]: 3.0 [1.3-6.8]) and the T allele (88% [99/112] vs. 77% [83/108], OR: 2.5 [1.3-5.4]) were associated with an increased risk of albuminuria. Patients with the AGT TT genotype (n = 74) had higher 24-h UAE than those with the MT or MM genotypes (n = 36) (median: 37.8 mg/day vs. 17.8 mg/day, P < 0.01). This association remained significant in patients with normotension (56 mg/day [n = 19] for patients with the TT genotype vs. 22 mg/day [n = 14] for those with the MT/MM genotype, P = 0.03). The D allele carriers (DD or DI, n = 61) had higher serum ACE activities (75.5 +/- 29 U/l vs. 60.5 +/- 36.3 U/l, P < 0.01) than the noncarriers (II genotype). The median 24-h UAE also tended to be higher in the D allele carriers (38.9 mg/day vs. 21.4 mg/day, P = 0.07). The lowest UAE was observed in patients with the MM/MT/II genotype (16.3 mg/day [n = 18]) and the highest, in patients with the TT/DD/DI genotype (52.3 mg/day [n = 43]). No association was found between the TT genotype or D allele and hypertension.
The high frequencies of the TT genotype and T allele in Chinese populations may contribute to the high prevalence of albuminuria in patients with type 2 diabetes. The possibility of synergism between the AGT TT genotype and the ACE D allele should also be explored.
肾素 - 血管紧张素系统（RAS）的基因多态性与糖尿病蛋白尿的发病机制有关。这些基因型频率的种族差异也有报道。迄今为止，大多数此类研究是在白人和日本人群中进行的。在本研究中，我们检测了中国2型糖尿病患者蛋白尿与RAS基因多态性之间的关联。
在一项病例对照研究中，对110例中国2型糖尿病患者检测了ACE插入/缺失（I/D）基因、血管紧张素原（AGT）基因（M235T）和血管紧张素II（AII）1型受体基因（AT1 A1166C）。在为期6周的研究期间，至少两次尿白蛋白排泄量（UAE）增加定义为≥30mg/天。
与白人相比，中国对照受试者（120/183 = 70%）和2型糖尿病患者（74/110 = 67%）中AGT TT基因型频率较高。MM基因型频率分别为5%和3%，ACE DD基因型频率分别为13%和10%。虽然9%的受试者携带C等位基因，但两组均未发现AT1 CC基因型。白蛋白尿增加的中国2型糖尿病患者（n = 56）的收缩压（160±26mmHg对145±27mmHg，P<0.001）高于正常白蛋白尿患者（n = 54）。AGT TT基因型（78.6%[44/56]对55.6%[30/54]，优势比[OR]：3.0[1.3 - 6.8]）和T等位基因（88%[99/112]对77%[83/108]，OR：2.5[1.3 - 5.4]）均与蛋白尿风险增加相关。AGT TT基因型患者（n = 74）的24小时UAE高于MT或MM基因型患者（n = 36）（中位数：37.8mg/天对17.8mg/天，P<0.01）。在血压正常的患者中，这种关联仍然显著（TT基因型患者为56mg/天[n = 19]，MT/MM基因型患者为22mg/天[n = 14]，P = 0.03）。D等位基因携带者（DD或DI，n = 61）的血清ACE活性（75.5±29U/L对60.5±36.3U/L，P<0.01）高于非携带者（II基因型）。D等位基因携带者的24小时UAE中位数也往往更高（38.9mg/天对21.4mg/天，P = 0.07）。MM/MT/II基因型患者（16.3mg/天[n = 18]）的UAE最低，TT/DD/DI基因型患者（52.3mg/天[n = 43]）的UAE最高。未发现TT基因型或D等位基因与高血压之间存在关联。
中国人群中TT基因型和T等位基因的高频率可能导致2型糖尿病患者蛋白尿的高患病率。还应探讨AGT TT基因型与ACE D等位基因之间协同作用的可能性。
