ANGIOTENSINOGEN T235 AND ACE INSERTION DELETION POLYMORPHISMS ASSOCIATED WITH ALBUMINURIA IN CHINESE TYPE-2 DIABETIC-PATIENTS/

OBJECTIVE- Genetic polymorphisms of the renin-angiotensin system (RAS) have been implicated in the pathogenesis of diabetic proteinuria. Eth nic differences in the frequencies of these genotypes have also been r eported. To date, most of these studies have been performed in white a nd Japanese populations. In this study, we examined the associations b etween albuminuria and RAS genetic polymorphisms in Chinese patients w ith type 2 diabetes. RESEARCH DESIGN AND METHODS- In a case-control st udy, the ACE insertion/deletion (I/D) gene, the angiotensinogen (AGT) gene (M235T), and the angiotensin II (AII) type 1 receptor gene (AT1 A 1166C) mere examined in 110 Chinese type 2 diabetic patients. Increase d urinary albumin excretion (UAE) was defined as greater than or equal to 30 mg/day on at least two occasions during a 6-week study period. RESULTS- Compared with whites, there were high frequencies of the AGT TT genotype in Chinese control subjects (120/183 = 70%) and type 2 dia betic 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 1 0%, respectively. Although 9% of subjects carried the C allele, the AT 1 CC genotype was not found in either group. Chinese type 2 diabetic p atients with increased albuminuria (n = 56) had higher systolic blood pressure (160 +/- 26 mmHg vs. 145 +/- 27 mmHg, P < 0.001) than the nor moalbuminuric patients (n = 54). Both the AGT TT genotype (78.6% [44/5 6] 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 wi th 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 associat ion remained significant in patients with normotension (56 mg/day [n = 19] for patients with the TT genotype vs. 22 mg/day [n = 14] for thos e 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 wi th the MM/MT/II genotype (16.3 mg/day [n = 18]) and the highest, in pa tients with the TT/DD/DI genotype (52.3 mg/day [n = 43]). No associati on was found between the TT genotype or D allele and hypertension. CON CLUSIONS- The high frequencies of the TT genotype and T allele in Chin ese populations may contribute to the high prevalence of albuminuria i n patients with type 2 diabetes. The possibility of synergism between the AGT TT genotype and the ACE D allele should also be explored.