Phenotypic Heterogeneity and Associations of Two Aldose Reductase Gene Polymorphisms With Nephropathy and Retinopathy in Type 2 Diabetes

Abstract

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 5Ј region of the aldose reductase gene (ALR2) in a consecutive cohort of 738 Chinese type 2 diabetic patients.RESEARCH DESIGN AND 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) Ն20 g/min and albumin-to-creatinine ratio Ն3.5 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 ϭ 187) had higher blood pressure and lower BMI, while those with diabetic nephropathy (n ϭ 280) had higher blood pressure, waist-to-hip ratio, and lipid profile than those without the respective complications. The zϩ6 carriers of the (CA) n polymorphism were less common in patients with diabetic retinopathy than those without diabetic retinopathy (n ϭ 551) (4.3 vs. 9.3%, P ϭ 0.04). The CT/TT carriers had a higher AER than the CC carriers (30.2 ϫ/Ϭ 7.2 vs. 21.9 ϫ/Ϭ 6.9 g/min, P ϭ 0.03). Further subgroup analysis was performed after excluding uncomplicated patients with Ͻ5 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 ϭ 0.03) and T allele (26.4 vs. 18.5%, P ϭ 0.04) and a lower frequency of the zϩ6 allele (1.7 vs. 5.5%, P ϭ 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 ϭ 0.02) and CT/TT genotypes (OR 2.5, 95% CI 1.19 -5.19, P ϭ 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. Diabetes Care 26:2410 -2415, 2003G lycemic control, blood pressure, and disease duration are known predictive factors for the development of diabetic microvascular complications, including nephropathy and retinopathy (1,2). However, not all diabetic patients develop microvascular complications. Family studies in Pima Indian and Caucasian populations suggest genetic influences in the development of these complications (3,4). There is also increasing evidence (5,6) showing that non-Caucasian (including Asian) diabetic patients have a higher risk of renal complications than Caucasian populations. In Hong Kong, up to 50% of type 2 diabetic patients attending ho...

Aldose reductase inhibition counteracts nitrosative stress and poly(ADP-ribose) polymerase activation in diabetic rat kidney and high-glucose-exposed human mesangial cells

“…However, this contradicts numerous reports of (1) alleviation, rather than aggravation, of oxidative-nitrosative stress by AR inhibitors in other tissues of diabetic animals as discussed above, and (2) beneficial effects of both AR inhibitors and antioxidants on experimental DN [4,5,14,15]. Furthermore, several groups demonstrated that prevalence of DN depends on (1) erythrocyte AR content, and/or (2) frequency of the z-2 allele of the AR gene, in human subjects with diabetes mellitus [4,67,68]. Homozygosity for the z-2 allele in Type 1 (insulin-dependent) diabetes is associated with an increased expression of the AR gene and DN [67].…”

“…Homozygosity for the z-2 allele in Type 1 (insulin-dependent) diabetes is associated with an increased expression of the AR gene and DN [67]. In Type 2 (non-insulin-dependent diabetes), the z-2 allele is also associated with an increased AR activity and nephro-retinopathy [68]. Furthermore, homozygosity for the z-2 allele was recently reported to be associated with classic diabetic glomerulopathy manifested by overexpression of TGF-β1, mesangial cell transdifferentiation by expression of α-smooth muscle actin, and aberrant deposition of collagen type IY, fibronectin, and laminin [69].…”

Genetic and environmental factors associated with type 2 diabetes and diabetic vascular complications

“…The prevalence of DR is doubled in patients with microalbuminuira, and 6 times higher in the presence of macroalbuminuria [112], suggesting that DN and DR may share common risk factors, including genetic susceptibility factors. Indeed, sev-eral genes have been associated with DR and DN [113][114][115].…”

“…Polymorphism in the retinoid-X receptor (RXR) gamma gene has also been associated with DR (OR = 2.388; 95% confidence interval = 1.17-4.875) in Asians with T2D [126]. Polymorphisms in the regulatory region of the aldose reductase (ALR2) gene (encoding the rate-limiting enzyme of the polyol pathway) were associated with susceptibility to DN and DR [114,127]. However, the impacts of these genetic risk factors were modest, and some studies yielded inconsistent findings [128,129].…”

Association of Glomerulopathy With the 5′-End Polymorphism of the Aldose Reductase Gene and Renal Insufficiency in Type 2 Diabetic Patients

“…Plasma creatinine was measured using the Jaffe method on a Dimension AR system (Dade Behring, Deerfield, IL; normal reference range 44 -80 mol/l) (29). Glomerular function was also estimated using the formula proposed by Cockcroft and Gault for creatinine clearance (36), expressed as ml ⅐ min Ϫ1 ⅐ 1.73 m Ϫ2 and calculated as (140 Ϫ age in years) ϫ body wt in kg ÷ 72 ÷ (plasma creatinine in mol/l ÷ 88.4) ϫ 0.85 (if patient was female), and the Modification of Diet in Renal Disease (MDRD) Study Group formula for the GFR (37), expressed as ml ⅐ min Ϫ1 ⅐ 1.73 m Ϫ2 and calculated as 170 ϫ (plasma creatinine in mg/dl) Ϫ0.999 ϫ (age in years) Ϫ0.176 ϫ 0.762 (if patient was female) ϫ (plasma urea in mg/dl) Ϫ0.170 ϫ (plasma albumin in g/dl) 0.318 .…”