SUMO4 M55V variant is associated with diabetic nephropathy in type 2 diabetes

OBJECTIVE-SUMO4 mRNA was recently found to be mainly expressed in the kidney, and the methionine-to-valine substitution at codon 55 (M55V) variant of SUMO4 may induce higher nuclear factor-kappaB (NF-kappaB) activity. Because NF-kappaB is known to mediate the development of diabetic nephropathy, we examined the association between the SUMO4 M55V variant and the severity of diabetic nephropathy. RESEARCH DESIGN AND METHODS-We recruited a total of 430 patients with type 2 diabetes. The M55V (rs237025, 163A-->G) polymorphism of SUMO4 was genotyped by real-time PCR, and urine albumin concentration was measured by radioimmunoassay. RESULTS-The frequencies of SUMO4 AA, GA, and GG were 52.6, 40.7, and 6.7%, respectively, in the normoalbuminuric group; 45.5, 47.3, and 7.1% in the microalbuminuric group; and 36.9, 46.2, and 16.9% in the macroalbuminuric group. We detected a significant linear trend for SUMO4 genotype between the macroalbuminuric and normoalbuminuric groups. The mean urine albumin-to-creatinine ratio (42.3 +/- 108.82 mg/mmol) in the GG group was significantly higher than in the AA (14.9 +/- 51.49 mg/mmol) and GA (17.0 +/- 43.74 mg/mmol) groups. Multivariate logistic regression analysis showed the SUMO4 M55V variant to be independently associated with the severity of diabetic nephropathy. CONCLUSIONS-This study indicates that the SUMO4 gene M55V variant is associated with severity of diabetic nephropathy in patients with type 2 diabetes.     

Association of the DD genotype and development of Japanese type 2 diabetic nephropathy.

We determined the insertion/deletion (I/D) polymorphism of the angiotensin-coverting enzyme (ACE) gene in a multicenter trial of ethnically homogeneous Japanese type 2 diabetes mellitus (DM) patients. All patients (n = 748) were divided into 5 groups as follows: group I (normoalbuminuric patients), group II (microalbuminuric patients), group III (overt albuminuric patients with serum creatinine (s-Cr) levels of less than 1.2 mg/dl), group IV (overt albuminuric patients with s-Cr levels of more than 1.3 mg/dl but excluding hemodialysis patients), and group V (hemodialysis patients). We selected patients with a diabetic duration of more than 15 years in the mild stage (groups I and II), but placed no limits on those in the advanced and end-stages (groups III, IV and V). The frequency of the DD genotype was slightly higher in the advanced and end stages. The frequency of the DD genotype in the mild stage differed from that in the end stage (II/ID/DD 47.8%/41.0%/11.2% vs. 37.0 %/43.3%/19.7% p = 0.07, II + ID/DD 88.8%/11.2% vs. 80.3%/19.7%, p < 0.05). D allele frequency in the mild stage also differed from that in the end stage (I/D 68.3%/31.7% vs. 58.7%/41.3%, p < 0.02). The presence of the DD genotype increased the risk of end-stage renal disease (ESRD) more than that of the other genotypes (odds ratio ID/II = 1.37, 95% CI 0.82-2.27; DD/II = 2.27, 95% CI 1.12-4.61). It appears that the DD genotype is associated with progression of Japanese type 2 diabetic nephropathy.     

Interleukin-1 receptor antagonist genotype is associated with coronary atherosclerosis in patients with type 2 diabetes

Recently, inflammation has received considerable attention in the pathogenesis of both type 2 diabetes and atherosclerosis. The interleukin-1 receptor antagonist (IL-1ra) is a major modulator of the interleukin-1 pro-inflammatory pathway. We studied the relationship between a variable number tandem repeat (VNTR) polymorphism in intron 2 of the IL-1ra gene (IL1RN) and coronary artery disease (CAD) in patients with and without type 2 diabetes, following 787 consecutive patients admitted for suspected CAD. According to the current criteria of the American Diabetes Association, 250 patients had type 2 diabetes. In this group of patients, allele 2 carriers (n = 108) had an increased prevalence of CAD compared with noncarriers (85.2 vs. 73.2%), a difference that remained significant in a multivariate logistic regression model (odds ratio 2.2, 95% CI 1.1-4.3, P = 0.02). No association of CAD with allele 2 carrier status was present among nondiabetic patients (n = 537). Enzyme-linked immunosorbent assays showed decreased baseline plasma levels of IL-1ra in patients with type 2 diabetes, which may in part explain the role of the IL1RN VNTR in these patients.     

The angiotensin-converting enzyme DD genotype is associated with glomerulopathy lesions in type 2 diabetes.

Genetic factors are important in conferring diabetic nephropathy (DN) risk. The insertion/deletion (I/D) polymorphism of the ACE gene has been described to be associated with DN risk and progression. The renal lesions underlying DN in type 2 diabetes are heterogeneous; only a subset of patients, characterized by a faster decline of renal function, have diabetic glomerulopathy. This study explored the relations between diabetic glomerulopathy and the ACE genotype distribution in 77 type 2 diabetic patients with an albumin excretion rate > or = 20 microg/min. Using morphometric analysis of kidney biopsies, mesangial and mesangial matrix fractional volumes [Vv(mes/glom) and Vv(MM/glom)] and glomerular basement membrane (GBM) width were estimated. We found that 13 patients were II, 30 were ID, and 34 were DD. Clinical features and renal function were similar in the three groups; in contrast, the DD patients had the highest Vv(MM/glom) and GBM width. Subdividing patients in tertiles of GBM width and Vv(MM/glom), from the lowest (I) to the highest (III) values, the DD carriers had an odds ratio of 6.11 (95% CI 1.84-20.3) and 10.67 (2.51-45.36), respectively, for the likelihood of being in tertile III than I for GBM width and Vv(MM/glom). Multiple regression analysis revealed the I/D polymorphism as an independent determinant of GBM thickening in addition to diabetes duration and HbA(1c). In conclusion, the ACE DD genotype is associated with diabetic glomerulopathy lesions, making the study of this polymorphism helpful in identifying those type 2 diabetic patients at higher risk of fast DN progression.     

Effect of MTHFR C677T genotype on survival in type 2 diabetes patients with end-stage diabetic nephropathy.

BACKGROUND: The MTHFR C677T single nucleotide polymorphism TT genotype is associated with increased levels of plasma homocysteine and possibly an effect on cardiovascular mortality. We evaluated the effect of C677T genotype on mortality in a large end-stage renal disease (ESRD) cohort. METHODS: C677T genotype was determined in 439 Caucasians with end-stage diabetic nephropathy (DNP) (cases) recruited from 30 dialysis centres in Southern Germany. A total of 482 type 2 diabetes patients without DNP (no microalbuminuria) at inclusion served as a genotype control collective. Patients were prospectively followed for 4 years. Primary endpoint was all-cause mortality. RESULTS: In contrast to controls, the genotype distribution in cases was not in Hardy-Weinberg equilibrium (HWE, P = 0.003), due to a less than expected number of patients with the TT genotype. The requirements of HWE were met in cases with < 2 years dialysis therapy prior to study inclusion (n = 219). TT genotype was associated with a decreased body mass index (P = 0.002) and long diabetes duration in dialysis patients (P = 0.03). However, TT genotype was not associated with an increased risk of all-cause or cardiac mortality in the total dialysis collective or the subgroup. Also, we observed no association of MTHFR genotype with cardiovascular morbidity in cases or controls (P > 0.05), or with an increased rate of progression to novel microalbuminuria. CONCLUSION: MTHFR 677TT genotype was significantly underrepresented in patients with ESRD in our study, but was not associated with premature mortality in these patients. We found no evidence for survival bias due to C677T genotype in the ESRD cohort, or bias due to genetically determined accelerated progression to novel microalbuminuria in the controls. However, we cannot exclude that the TT genotype protects from progression from microalbuminuria to more advanced stages of DNP, or that TT genotype is associated with premature mortality before a patient progresses to ESRD.     

Oxidative stress markers in type 2 diabetes patients with diabetic nephropathy

Background

Epidemiological studies show that 5–40 % of type 2 diabetes (T2DM) patients have diabetic nephropathy, and oxidative stress is one of several underlying mechanisms. We investigated associations between oxidative stress markers and severity of diabetic nephropathy.

Methods

Fifty-nine T2DM patients from the endocrinology outpatient department were included, and their levels of oxidative stress markers were measured. Three groups were determined by their urine albumin-to-creatinine ratio (UACR): group A (UACR < 30 mg/g, n = 22); group B (30 ≤ UACR < 300 mg/g, n = 22); and group C (UACR ≥ 300 mg/g, n = 15).

Results

Vitamin C levels correlated negatively and moderately with serum creatinine (γ = ?0.459, p < 0.001), urine albumin (γ _s = ?0.458, p = 0.001) and UACR (γ _s = ?0.408, p = 0.001), but only weakly with hydroxy-2-deoxyguanosine (8-OHdG) and estimated glomerular filtration rate (eGFR). Vitamin C levels decreased as 8-OHdG, serum creatinine, albumin and UACR increased. T2DM patients with more severe diabetic nephropathy had lower vitamin C levels.

Conclusion

Our results identified several oxidative stress markers that may be clinically important in diabetic nephropathy. Studies with larger sample sizes should be undertaken to confirm these findings.

     

The human peroxisome proliferator-activated receptor gamma2 (PPARgamma2) Pro12Ala polymorphism is associated with decreased risk of diabetic nephropathy in patients with type 2 diabetes

The peroxisome proliferator-activated receptor gamma2 (PPARgamma2) Pro12Ala polymorphism has been associated with a decreased risk of type 2 diabetes and a lower albumin excretion rate (AER) in patients with established diabetes. We performed a case-control study aiming to evaluate the association between the Pro12Ala polymorphism and diabetic nephropathy. Genomic DNA was obtained from 104 type 2 diabetic patients (case subjects) with chronic renal insufficiency (78 on dialysis and 26 with proteinuria [AER >or=200 microg/min] and serum creatinine >or=2.0 mg/dl) and 212 normoalbuminuric patients (AER <20 microg/min) with known diabetes duration >or=10 years (control subjects). The genotypic distribution of the PPARgamma2 Pro12Ala polymorphism in these diabetic patients was in Hardy-Weinberg equilibrium, and the Ala allele frequency was 9%. The frequency of Ala carriers (Ala/Ala or Ala/Pro) was 20.3% in control subjects and 10.6% in case subjects (P = 0.031). The odds ratio of having diabetic nephropathy for Ala carriers was 0.465 (95% CI 0.229-0.945; P = 0.034). Carriers of the Ala allele were not different from noncarriers (Pro/Pro) regarding sex (38.9 vs. 44.1% males) or ethnicity (77.4 vs. 71.7% white) distribution, age (61 +/- 10 vs. 61 +/- 10 years), known diabetes duration (17 +/- 7 vs. 16 +/- 7 years), BMI (27 +/- 4 vs. 28 +/- 5 kg/m(2)), fasting plasma glucose (184 +/- 81 vs. 176 +/- 72 mg/dl), HbA(1c) (6.7 +/- 2.3 vs. 6.9 +/- 2.4%; high-performance liquid chromatography reference range: 2.7-4.3%), and systolic (145 +/- 27 vs. 0.144 +/- 24 mmHg) or diastolic (87 +/- 14 vs. 85 +/- 14 mmHg) blood pressure, respectively. In conclusion, the presence of the Ala allele may confer protection from diabetic nephropathy in patients with type 2 diabetes.     

Replication study for the association of 3 SNP loci identified in a genome-wide association study for diabetic nephropathy in European type 1 diabetes with diabetic nephropathy in Japanese patients with type 2 diabetes

Background

A recent genome-wide association study for diabetic nephropathy in European type 1 diabetes identified 3 candidate loci for diabetic nephropathy. In this study, we examined the association of the 3 single nucleotide polymorphism (SNP) loci with susceptibility to diabetic nephropathy in Japanese subjects with type 2 diabetes.

Methods

We genotyped 3 SNPs, rs7583877 in AFF3, rs12437854 in the RGMA-MCTP2 locus and rs7588550 in ERBB4, for 2,300 Japanese patients with type 2 diabetes [initial study, 1,055 nephropathy cases with overt proteinuria or with end-stage renal disease (ESRD) and 1,245 control patients with normoalbuminuria]. The association of these SNPs with diabetic nephropathy was examined by using a logistic regression analysis.

Results

We observed a significant association of rs7588550 in ERBB4 with diabetic nephropathy in the Japanese patients with type 2 diabetes, although the effect direction was not consistent with that in the European study [p = 0.0126, odds ratio (OR) = 0.79, 95 % confidence interval (CI): 0.65–0.95]. We further examined the association of rs7588550 with diabetic nephropathy in an independent Japanese cohort (596 nephropathy cases and 311 controls) and observed the same trend of the association with the initial study. We did not observe any association of the remaining 2 SNP loci with diabetic nephropathy in the present Japanese sample.

Conclusion

The association of SNP loci derived from GWAS in European type 1 diabetes with diabetic nephropathy was not replicated in the Japanese patients with type 2 diabetes, although the ERBB4 locus may have some effect also in Japanese type 2 diabetes.     

Risk of advanced diabetic nephropathy in type 1 diabetes is associated with endothelial nitric oxide synthase gene polymorphism

Risk of advanced diabetic nephropathy in type 1 diabetes is associated with endothelial nitric oxide synthase gene polymorphism. BACKGROUND: Polymorphisms in the endothelial nitric oxide synthase gene (eNOS) may be implicated in the development of nephropathy in patients with type 1 or insulin-dependent diabetes mellitus (IDDM). METHODS: Three groups of IDDM patients were selected to study this hypothesis: cases with advanced diabetic nephropathy (N = 78), cases with overt proteinuria but normal serum creatinine (N = 74), and controls with normoalbuminuria despite 15 years of diabetes (N = 195). Parents of 132 cases and 53 controls were also examined and were used for the transmission disequilibrium test, a family-based study design to test association. RESULTS: We examined four eNOS polymorphisms, and two were associated with diabetic nephropathy in the case-control comparisons: a T to C substitution in the promoter at position -786 and the a-deletion/b-insertion in intron 4. For the former, the risk of developing advanced nephropathy was higher for C allele homozygotes than for the other two genotypes (odds ratio 2.8, 95% CI, 1.4 to 5.6). For the latter polymorphism, it was the a-deletion carriers that had the higher risk (odds ratio 2.3, 95% CI, 1.3 to 4.0) in comparison with noncarriers. Both polymorphisms were analyzed together as haplotypes in a family-based study using the transmission disequilibrium test. The C/a-deletion haplotype was transmitted from heterozygous parents to cases with advanced diabetic nephropathy with a significantly higher frequency than expected (P = 0.004). CONCLUSION: The findings of the case-control and family-based studies demonstrate clearly that DNA sequence differences in eNOS influence the risk of advanced nephropathy in type 1 diabetes.     

Risk of diabetic nephropathy in type 1 diabetes is associated with functional polymorphisms in RANTES receptor gene (CCR5): a sex-specific effect

Chemokines and their receptors have been implicated in the development of diabetic nephropathy. To determine whether the risk of diabetic nephropathy is influenced by two functional polymorphisms in the regulated upon activation normal T-cell expressed and secreted (RANTES) receptor gene (CCR5), we recruited patients with type 1 diabetes, including 496 case subjects with overt proteinuria or end-stage renal disease and 298 control subjects with normoalbuminuria. Male carriers of the 59029G allele, which is associated with diminished expression of CCR5 on the surface of immunocompetent cells, had significantly higher risk of developing diabetic nephropathy than noncarriers (OR [95% CI] 1.9 [1.2-3.0]). Similarly, male carriers of the 32-bp deletion, which causes truncation of the protein, had significantly higher risk of diabetic nephropathy than noncarriers (2.3 [1.3-4.2]). Combining both polymorphisms, three haplotypes were distinguished: one nonrisk haplotype carrying the 59029A allele and the 32-bp insertion and two risk haplotypes carrying the 59029A allele with the 32-bp deletion and carrying the 59029G allele with the 32-bp insertion. The distribution of these haplotypes differed significantly (P < 0.00001) in men with and without diabetic nephropathy but was not associated with diabetic nephropathy in women. In conclusion, two functional polymorphisms in CCR5 that decrease expression of the RANTES receptor on immunocompetent cells are associated with increased risk of diabetic nephropathy in type 1 diabetes, but only in men.     

Rodent models of nephropathy associated with type II diabetes.

End-stage renal disease from diabetic nephropathy, mainly due to type II diabetes, is an increasing problem in Western countries. The pathogenesis of diabetic nephropathy is still incompletely understood and much of the experimental insight has been obtained from insulinopenic animal models, resembling type I diabetes. This review therefore aims to describe available rodent models of nephropathy associated with type II diabetes. The review focusses on the metabolic as well as renal functional and structural changes. The usefulness of these rodent models to study renal involvement in type II diabetes is discussed with particular emphasis on confounding factors such as hyperlipidemia, hypertension, immunologic abnormalities, urogenital structural abnormalities and other associated pathological conditions. In addition recent observations on two rat strains, the obese Zucker (fatty) and Goto Kakizaki (GK) rat, are discussed in detail.     

Polymorphism of the aldosterone synthase gene is not associated with progression of diabetic nephropathy, but associated with hypertension in type 2 diabetic patients

Aim: Inhibition of aldosterone system is beneficial in diabetic nephropathy, and aldosterone synthesis is regulated at the gene-encoding aldosterone synthase (CYP11B2). Considering the role of aldosterone in diabetic nephropathy, genetic polymorphism of this gene may contribute to the development and progression of diabetic nephropathy. In this study, we investigated whether it is associated with diabetic nephropathy in type 2 diabetic patients. Methods: 197 type 2 diabetic patients and 71 healthy controls were enrolled. The study subjects were divided into four groups: healthy controls with normoalbuminuria (n = 71), normoalbuminuric diabetic group (n = 71), microalbuminuric diabetic group (n = 51) and overt proteinuria group (n = 51). Polymorphism of aldosterone synthase gene was determined using standard PCR technique. Results: Higher frequency of TT genotype and T allele in steroidogenic factor-1 (SF-1) binding site and wild type (WT) in intronic conversion (IC) in CYP11B2 was observed in diabetic patients than controls. However, there was no significant difference in SF-1 and IC genotype among diabetic patients according to the state of diabetic nephropathy. Subgroup analysis based on SF-1 polymorphism demonstrated that TT genotype is associated with higher systolic and diastolic blood pressure and higher plasma aldosterone level. In addition, WT in IC genotype showed a significantly higher urinary albumin excretion rate. Plasma aldosterone level was significantly related with systolic blood pressure. Conclusion: Our study suggests that aldosterone synthase gene polymorphism is not associated with progression of diabetic nephropathy, but it may contribute to the development of hypertension associated with increased aldosterone secretion in type 2 diabetic patients.     

Higher urinary IgM excretion in type 2 diabetic nephropathy compared to type 1 diabetic nephropathy.

BACKGROUND: Proteinuria, due to impairment of the charge- and/or size selectivity of the glomerular capillary wall (GCW) is the earliest clinical evidence of diabetic nephropathy (DN). To study the pathophysiological differences between patients with DN in type 1 diabetes mellitus (type 1 DN) and type 2 diabetes mellitus (type 2 DN), we compared the patterns of urinary proteins of different size and charge in the two entities of diabetic kidney disease. METHODS: Urine concentrations of albumin, IgG2, IgG4 and IgM were assessed in 22 (15 males and 7 females) patients with type 1 DN, and in 20 (18 males and 2 females) patients with type 2 DN. Comparisons with one control group of 13 (12 males and one female) patients with nephrosclerosis due to systemic hypertension and a second control group of 16 (14 males and 2 females) healthy controls were made. RESULTS: The urine excretion of IgG2 and IgM and the ratio of IgG2 to IgG4 (IgG2/IgG4), were significantly higher in type 2 DN compared to type 1 DN (P < 0.01). Patients with type 2 DN and patients with nephrosclerosis had significantly higher urine excretion of IgG and IgM compared to the age-matched healthy subjects (P < 0.001). The IgG2/IgG4 ratio was higher in type 2 DN compared to nephrosclerosis and healthy controls (P < 0.01). CONCLUSION: The increased urine excretion of IgG and IgM that accompanies albuminuria in type 2 DN suggests that the dominant pathophysiological mechanism of proteinuria in type 2 DN might be an alteration of the size selective properties of the glomerular capillary wall, including the occurrence of non-discriminatory "shunt pathways." The charge selective properties of the glomerular capillary wall seem to be intact in type 2 DN, as indicated by the high IgG2/IgG4 ratio. The mechanisms of proteinuria in type 1 DN seem to be merely a consequence of an impaired charge selectivity of the glomerular capillary wall.     

Association between single nucleotide polymorphisms within genes encoding sirtuin families and diabetic nephropathy in Japanese subjects with type 2 diabetes

Background

Sirtuin is a member of the nicotinamide adenine dinucleotide (NAD)-dependent deacetylases, and has been reported to play a pivotal role in energy expenditure, mitochondrial function and pathogenesis of metabolic diseases, including aging kidneys. In this study, we focused on the genes encoding sirtuin families, and examined the association between single nucleotide polymorphisms (SNPs) within genes encoding sirtuin families and diabetic nephropathy.

Methods

We examined 52 SNPs within the SIRT genes (11 in SIRT1, 7 in SIRT2, 14 in SIRT3, 7 in SIRT4, 9 in SIRT5, and 4 in SIRT6) in 3 independent Japanese populations with type 2 diabetes (study 1: 747 cases (overt proteinuria), 557 controls; study 2: 455 cases (overt proteinuria) and 965 controls; study 3: 300 cases (end-stage renal disease) and 218 controls). The associations between these SNPs were analyzed by the Cochran?CArmitage trend test, and results of the 3 studies were combined with a meta-analysis. We further examined an independent cohort (195 proteinuria cases and 264 controls) for validation of the original association.

Results

We identified 4 SNPs in SIRT1 that were nominally associated with diabetic nephropathy (P?SIRT1 locus had a stronger association (P?=?0.0028).

Conclusion

These results indicate that SIRT1 may play a role in susceptibility to diabetic nephropathy in Japanese subjects with type 2 diabetes.     

Nephrinuria in diabetic nephropathy of type 1 diabetes

Diabetic nephropathy is the leading cause of end-stage renal disease. Because early diagnosis and treatment may prevent the complication, new tools for an early detection are needed. One of the key components of the glomerular filtration slit spanning between neighboring podocytes is nephrin. Its expression is altered in experimental models of diabetes and also in various human proteinuric diseases, including diabetes. We studied whether type 1 diabetic patients with or without nephropathy exhibit immunoreactive nephrin in the urine, reflecting early damage of the filtration barrier. Diabetic patients with normoalbuminuria (n = 40), with microalbuminuria (n = 41), and with macroalbuminuria (n = 39) and patients previously normoalbuminuric but now testing positive for microalbuminuria (newMicro, n = 39) were screened for nephrinuria with Western blotting using two affinity-purified anti-nephrin antibodies. Nondiabetic healthy subjects (n = 29) were also studied. Nephrinuria was present in 30% of normoalbuminuric, 17% of microalbuminuric, 28% of macroalbuminuric, and 28% of newMicro patients. Of female patients, 35% were nephrinuric compared with only 19% of male patients (P = 0.02). None of the control subjects was nephrinuric. In conclusion, glomerular filtration barrier may be affected in one-third of diabetic patients manifesting as early nephrinuria. Nephrinuria may have prognostic value and become a marker of susceptibility for kidney complications in diabetes.     

Urinary albumin as an indicator of diabetic nephropathy lesions in Japanese type 2 diabetic patients

Caucasian type 2 diabetic patients with microalbuminuria (MA) or overt nephropathy (ON) show greater heterogeneity of renal lesions than type 1 diabetic patients. We examined whether a similar situation exists in 30 Japanese type 2 diabetic patients [21 male, age 48 +/- (SD) 8 years, known duration 11 +/- (SD) 8 years] without definable renal disease other than diabetic nephropathy. Six patients were normoalbuminuric (NA), 11 MA, and 13 had ON. Normal controls were 9 age-matched Japanese living-related renal transplant donors. Electron microscopic morphometry was performed on renal biopsy specimens and related to renal function. Glomerular basement membrane width and mesangial fractional volume [Vv(Mes/glom)] were increased in all type 2 diabetic patients groups (NA, MA, ON) as compared with normal controls. The Vv(Mes/glom) correlated directly with urinary albumin/creatinine. However, Vv(Mes/glom) as well as glomerular basement membrane width overlapped among the three functional categories (NA, MA, ON) and normal controls. In conclusion: (1) similar to Caucasian type 2 diabetic patients, Japanese type 2 diabetic patients have greater heterogeneity of renal structure than Caucasian type 1 diabetic patients, and (2) urinary albumin is not a reliable indicator of underlying renal structure in Japanese type 2 diabetic patients.     

No association of glutathione S-transferase M1 gene polymorphism with diabetic nephropathy in Japanese type 2 diabetic patients

Oxidative stress possibly contributes to the development of diabetic nephropathy. Therefore, the levels of endogenous antioxidants may be one of determinants of the susceptibility to diabetic nephropathy. Glutathione S-transferases (GSTs) can work as one of endogenous antioxidants to protect cells from oxidative stress. The M1 member of GST mu class (GSTM1) is polymorphic and only expressed in 55-60% of Caucasians because of the homozygous deletion of the gene (null genotype). Recent studies have provided evidence that the GSTM1 null genotype, i.e. lack of the GSTM1 activity, is associated with an increased susceptibility to lung cancer and colorectal cancer. The present study was conducted to determine whether the genetic polymorphism influences the development of diabetic nephropathy. We examined 105 patients with diabetic nephropathy and 69 patients without diabetic nephropathy in Japanese type 2 diabetic patients with proliferative diabetic retinopathy. GSTM1 genotyping was performed by polymerase chain reaction. The two patient groups were well matched with regard to age, body mass index and HbAlc. GSTM1 null genotype was observed in 48.6% of patients with nephropathy versus 55.1% of patients without nephropathy. The frequency of GSTM1 null genotype was not significantly higher in the patient group with nephropathy than in the patient group without nephropathy. This study is the first to investigate the association of GSTM1 gene polymorphism with the development of diabetic nephropathy. The present results suggest that GSTM1 null genotype does not contribute to the development of diabetic nephropathy in Japanese type 2 diabetic patients.