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. 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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Young
R P
RP
Department of Clinical Pharmacology, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.
Chan
J C
JC
Critchley
J A
JA
Poon
E
E
Nicholls
G
G
Cockram
C S
CS
D000328:Adult; D000367:Age Factors; D000368:Aged; D000419:Albuminuria / Q000150:complications / Q000208:ethnology* / Q000235:genetics*; D000483:Alleles; D019943:Amino Acid Substitution; D000808:Angiotensinogen / Q000235:genetics*; D015415:Biomarkers / Q000097:blood / Q000652:urine; D001794:Blood Pressure / Q000502:physiology; D015992:Body Mass Index; D016022:Case-Control Studies; D002681:China / Q000208:ethnology; D002784:Cholesterol / Q000097:blood; D004251:DNA Transposable Elements; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000208:ethnology* / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D011905:Genes, ras / Q000235:genetics; D005838:Genotype; D006442:Glycated Hemoglobin / Q000378:metabolism; D006723:Hong Kong / Q000453:epidemiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D007703:Peptidyl-Dipeptidase A / Q000235:genetics*; D011110:Polymorphism, Genetic; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000235:genetics; D012044:Regression Analysis; D012084:Renin-Angiotensin System / Q000235:genetics; D012307:Risk Factors; D017384:Sequence Deletion; D012737:Sex Factors; D013997:Time Factors
D000808:Angiotensinogen; D015415:Biomarkers; D002784:Cholesterol; D004251:DNA Transposable Elements; D006442:Glycated Hemoglobin; D007703:Peptidyl-Dipeptidase A; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin