Relations Between ACE Gene and ecNOS Gene Polymorphisms and Resistive Index in Type 2 Diabetic Patients With Nephropathy

Abstract

OBJECTIVE -ACE and endothelial cell nitric oxide synthase (ecNOS) genotypes have been reported to be related to the incidence of renal diseases and coronary artery diseases. In order to assess the effect of the gene polymorphism of both ACE and ecNOS on renal hemodynamic abnormality, we examined 155 Japanese patients with type 2 diabetes with various stages of nephropathy.RESEARCH DESIGN AND METHODS -The patients ranged in age from 40 to 72 years (92 men and 63 women). They were divided into four groups: group 1 consisted of patients with urinary albumin excretion (UAE) Ͻ30 mg/day (n ϭ 69), group 2 had 30 Յ UAE Ͻ 300 mg/day (n ϭ 44), group 3 had UAE Ն300 mg/day and serum creatinine Ͻ1.5 mg/dl (n ϭ 22), and group 4 had serum creatinine Ͼ1.5 mg/dl (n ϭ 20). Intrarenal hemodynamics were studied by duplex Doppler sonography in patients with type 2 diabetes. The ACE and ecNOS gene polymorphisms were examined by polymerase chain reaction.RESULTS -There were no significant differences in sex, BMI, and blood glucose level, but there were differences in HbA 1c and lipoprotein profiles among the four groups. There were no significant differences in the distribution of ACE genotype or in the frequency of the ecNOS 4a allele among the four groups. Resistive index (RI) values of the interlobar arteries of group 4 were significantly higher than those of groups 1, 2, and 3, whereas the RI values were not significantly different among groups 1, 2, and 3. Multiple regression analysis showed that age, duration of diabetes, systolic and diastolic blood pressure, and creatinine clearance were significantly associated with the increased RI values, but that there was no significant association between RI values and the ecNOS genotype (R 2 ϭ 0.613, P Ͻ 0.0001).CONCLUSIONS -These results suggest that intrarenal hemodynamic abnormalities are present as a feature of the progression of nephropathy in type 2 diabetes, and that they are associated with age, duration of diabetes, decreased creatinine clearance, and blood pressure, but not with the genetic factors of the ACE and ecNOS gene polymorphism in nephropathy of type 2 diabetes. Diabetes Care 24:1653-1660, 2001S everal studies have demonstrated that diabetic nephropathy occurs in familial clusters, suggesting that a genetic factor(s) may be involved (1).ACE insertion/deletion (I/D) polymorphism of intron 16 was reported to be a genetic marker for coronary artery disease in the general population (2). Accordingly, the I/D polymorphism has been investigated as a strong candidate marker for genetic predisposition to diabetic vascular complications (3,4). However, studies of the association of the ACE genotype with diabetic complications, such as nephropathy, have yielded conflicting results (5-7).It is now established that endothelialderived nitric oxide (NO) plays a major role in vascular regulation in normal and disease states (8). NO is synthesized by endothelial cell NO synthase (ecNOS) in the vascular endothelium, and it plays a key role in the regulation of blood flow and pressure....

Association of genetic variants with diabetic nephropathy

“…Three polymorphisms in this gene G894T missense mutation (rs1799983), a 27-bp repeat in intron 4, and the T786C single nucleotide polymorphism (SNP) in the promoter (rs2070744) have been found to be associated with diabetic nephropathy susceptibility [26][27][28][29][30] . The G894T variant was found to increase the risk of macroalbuminuria and progression from microalbuminuria to macroalbuminuria, with declining glomerular filtration rate as serum creatinine value rises progressively, culminating in nephropathy [31,32] However, these results have been contradictory and not all studies support this association [33][34][35] . Recent studies on different gene variants observed that there was an association between eNOS4b/a polymorphism and the risk of type 2 diabetic nephropathy [36,37] while others suggested that there was no significant association [38] .…”

Variation in the eNOS Gene Modifies the Association Between Total Energy Expenditure and Glucose Intolerance

“…A recent meta-analysis of published studies reported evidence of linkage for fasting glucose and insulin resistance to 7q36, the genomic region to which the eNOS gene maps (33). Although large population-based cohort studies examining the relationship between variation at the eNOS gene and glucose intolerance are scarce (34), several clinical studies in people with type 2 diabetes have examined the association of eNOS polymorphisms with hypertension (35), nephropathy (36,37), retinopathy (38), and ischemic heart disease (39).…”

Endothelial NO Synthase Gene Polymorphisms and Hypertension

“…Two studies 1 investigated 3 polymorphisms together: G894T, 4a/b, and T786C. The design in 24 studies was case-control,* in 7 studies was population-based cohort, 4,29,31,36,43,45 and in 4 studies was cross-sectional. 23,37,34,47 The studies were published between 1995 and 2006.…”

“…23,24,29,32,51,52 The polymorphism 4a/b was genotyped using electrophoretic differentiation. 1,25,27,28,35,36,[41][42][43][44][45][46][47][48][49] Five studies stated that the controls were age or sex matched. 29,30,38,48,53 24,33 provided data for males and females separately.…”