Phenotypic heterogeneity and associations of two aldose reductase gene polymorphisms with nephropathy and retinopathy in type 2 diabetes.
OBJECTIVE
We investigated the phenotypic features of diabetic microvascular complications and their association with a (CA)(n) microsatellite and a C/T polymorphism at the 5' region of the aldose reductase gene (ALR2) in a consecutive cohort of 738 Chinese type 2 diabetic patients.


METHODS
Of the entire patient cohort, 392 were free of diabetes complications, or uncomplicated, 159 had diabetic nephropathy, 66 had diabetic retinopathy, and 121 had both diabetic nephropathy and retinopathy. Nephropathy was defined as urinary albumin excretion rate (AER) >or=20 micro g/min and albumin-to-creatinine ratio >or=3.5 mg/mmol in two urine collections. Retinopathy was defined by the presence of hemorrhages, exudates, laser marks, and fibrous proliferation or by a history of vitrectomy. (CA)(n) and C/T polymorphisms were examined by PCR followed by capillary electrophoresis and digestion with BfaI, respectively.


RESULTS
In the whole cohort, patients with diabetic retinopathy (n = 187) had higher blood pressure and lower BMI, while those with diabetic nephropathy (n = 280) had higher blood pressure, waist-to-hip ratio, and lipid profile than those without the respective complications. The z+6 carriers of the (CA)(n) polymorphism were less common in patients with diabetic retinopathy than those without diabetic retinopathy (n = 551) (4.3 vs. 9.3%, P = 0.04). The CT/TT carriers had a higher AER than the CC carriers (30.2 x/divided by 7.2 vs. 21.9 x/divided by 6.9 micro g/min, P = 0.03). Further subgroup analysis was performed after excluding uncomplicated patients with <5 years disease duration. The group with both diabetic nephropathy and retinopathy had higher frequencies of the z-2 allele (25.7 vs. 16.9%, P = 0.03) and T allele (26.4 vs. 18.5%, P = 0.04) and a lower frequency of the z+6 allele (1.7 vs. 5.5%, P = 0.054) than the uncomplicated group. Multiple logistic regression analysis confirmed that z-2 carrying (odds ratio 2.6, 95% CI 1.20-5.83, P = 0.02) and CT/TT genotypes (OR 2.5, 95% CI 1.19-5.19, P = 0.02) were independent predictors for both diabetic nephropathy and retinopathy.


CONCLUSIONS
Chinese type 2 diabetic patients exhibited phenotypic differences in terms of risk factors for both diabetic nephropathy and diabetic retinopathy. Both the z-2 allele of (CA)(n) polymorphism and T allele of ALR2 were independently associated with severe diabetic microvascular complications.
Wang
Ying
Y
Division of Clinical Pharmacology, Department of Medicine and Therapeutics, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong SAR.
Ng
Maggie C Y
MC
Lee
Shao-Chin
SC
So
Wing-Yee
WY
Tong
Peter C Y
PC
Cockram
Clive S
CS
Critchley
Julian A J H
JA
Chan
Juliana C N
JC
D000328:Adult; D000368:Aged; D000449:Aldehyde Reductase / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D003928:Diabetic Nephropathies / Q000235:genetics*; D003930:Diabetic Retinopathy / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006723:Hong Kong; D006801:Humans; D008297:Male; D008833:Microcirculation; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic
D000449:Aldehyde Reductase