Adiponectin G276T gene polymorphism is associated with cardiovascular disease in Japanese patients with type 2 diabetes

ObjectiveAdiponectin has anti-atherogenic properties and reduced serum adiponectin levels are associated with cardiovascular disease (CVD). In this study, we examined the relationship between CVD and adiponectin (ADIPOQ) gene G276T polymorphism that is associated with serum adiponectin level in a large cohort of type 2 diabetic patients.Research design and methodsWe enrolled 2637 Japanese type 2 diabetic subjects (males, 61.1%; age, 54.9 ± 7.9 years old), determined their genotypes regarding ADIPOQ G276T polymorphisms, and evaluated the association between this polymorphism and the prevalence of CVD (myocardial infarction and/or cerebral infarction).ResultsThe prevalence of CVD tended to be higher as the number of G alleles increased [GG (9.5%), GT (6.8%), TT (5.6%), p value for trend = 0.0059] and was significantly higher in the subjects with GG genotype compared to those with GT or TT genotype (9.5% vs. 6.6%, p = 0.0060). Multiple logistic regression analyses revealed that the number of G alleles (Odds ratio (OR) = 1.49 with 95%CI 1.09–2.05, p = 0.0125) and GG genotype (OR = 1.66 with 95%CI 1.13–2.43, p = 0.0098) were significantly associated with CVD even after adjustment for conventional risk factors. Interestingly, the presence of obesity further and significantly increased the risk of CVD in the subjects with GG genotype (OR = 1.67 with 95%CI 1.14–2.44, p = 0.0090) but not in the subjects with TT or GT genotype (OR = 1.17 with 95%CI 0.73–1.89, NS).ConclusionsIt is likely that the G allele of the ADIPOQ G276T polymorphism is a susceptibility allele for CVD in Japanese type 2 diabetic patients, especially when they accompany obesity.     

MTHFR gene polymorphism is susceptible to diabetic retinopathy but not to diabetic nephropathy in Japanese type 2 diabetic patients

AIMS: Previously, we have proposed that methylenetetrahydrofolate reductase (MTHFR) gene polymorphism (C677T) could be a risk factor for diabetic retinopathy. To support our suggestion, we examined in detail the association of MTHFR polymorphism with diabetic retinopathy and nephropathy in Japanese type 2 diabetic patients. METHODS: Subjects (n=190) were free of cardiovascular diseases and were not on hemodialysis. Retinopathy was assessed according to fundamental differentiation; nephropathy was determined according to urinary albumin level; and MTHFR genotype was determined by polymerase chain reaction-restriction fragment length polymorphism. We also analyzed how hyperglycemia affected these three conditions in 131 patients with glycosylated hemoglobin > or =6.5% and fasting blood sugar > or =110 mg/dl. RESULTS: The frequency of 677T/677T homozygous subjects with retinopathy was higher than the frequencies of the other two genotypes, and a significant difference was observed in the distribution of the genotypes (677C/677C, 41.9%; 677C/677T, 31.1%; 677T/677T, 61.5%; P<.05). The susceptibility of 677T/677T homozygote to retinopathy approached significance [odds ratio (OR)=2.17; 95% confidence interval (95% CI)=0.87-5.42]. However, in the population with hyperglycemia, the 677T/677T homozygote modified the risk for retinopathy (OR=4.30; 95% CI=1.42-13.1), especially the risk for nonproliferative retinopathy. In contrast, the 677T/677T homozygote did not affect the risk for nephropathy (OR=1.17; 95% CI=0.45-3.05), even in subjects with hyperglycemia (OR=1.50; 95% CI=0.50-4.48). CONCLUSIONS: Our results are highly suggestive of an important role for MTHFR genotype in susceptibility to retinopathy under hyperglycemia, but not to nephropathy. Preventive therapies based on MTHFR polymorphism could delay the onset of retinopathy in type 2 diabetic patients.     

Aldose reductase C-106T gene polymorphism is associated with diabetic retinopathy in Japanese patients with type 2 diabetes

It is likely that the C allele of the polymorphism at position 29 of the translated sequence of transforming growth factor (TGF)-β1 gene, which codes a pleiotropic cytokine expressed in a variety of cells, is a susceptibility allele for cerebral infarction in Japanese type 2 diabetic patients.     

Aldose reductase C-106T gene polymorphism is associated with diabetic retinopathy in Japanese patients with type 2 diabetes

It is likely that the C allele of the polymorphism at position −106 in the promoter of aldose reductase gene, which codes a rate-limiting enzyme of the polyol pathway, is a susceptibility allele for diabetic retinopathy in Japanese type 2 diabetic patients.     

Aldose reductase gene polymorphism is associated with progression of diabetic nephropathy in Japanese patients with type 1 diabetes mellitus

Aim: The objective of this study was to investigate cross-sectionally and longitudinally whether polymorphism of the (A-C)n dinucleotide repeat sequence of the aldose reductase ( AR ) gene may modulate risk for diabetic nephropathy or retinopathy in Japanese patients with type 1 diabetes.
Methods: We obtained DNA samples from 101 patients followed up after the onset of type 1 diabetes and analysed a (A-C)n dinucleotide repeat polymorphic marker in the AR gene by polymerase chain reaction (PCR) method.
Results: Ten alleles ranging from Z−10 (128 bp) to Z+8 (146 bp) in repeat number were identified. In cross-sectional studies, the prevalence of the Z+2 allele was higher than that of any other allele in patients with diabetic nephropathy (37.5% of patients in a microalbuminuria group, and 41.7% of those in a macroalbuminuria group including patients with chronic renal failure and maintenance haemodialysis treatment). Prevalence of the Z+2 allele was not increased in patients with diabetic retinopathy. In longitudinal Kaplan–Meier plots, the cumulative incidence of nephropathy was significantly associated with homozygosity for the Z+2 allele (log rank test, p = 0.031); respective prevalence of nephropathy after diabetes durations of 10 and 15 years was 42.9% and 100% in Z+2 homozygotes ( n  = 8), 17.6% and 27.4% in Z+2 heterozygotes ( n  = 44), and 6.1% and 17.4% in patients without the Z+2 allele ( n  = 49). However, occurrence of retinopathy was not influenced by the Z+2 allele (log rank test, p = 0.926).
Conclusions: Homozygosity for the Z+2 allele was associated with accelerated early progression of diabetic nephropathy in Japanese type 1 diabetic patients.     

RAGE基因启动区-429T/C多态与2型糖尿病肾病相关

采用PCR RFLP法对 3 98例 2型糖尿病 (DM )患者和 2 12名正常对照者 (NC) ,进行晚期糖化终末产物受体 (RAGE)基因启动区 -4 2 9T/C多态基因型检测。比较 2型DM合并或未合并肾病组以及NC组间 -4 2 9T/C多态的基因型频率和等位基因频率。结果提示 ,-4 2 9T/C多态与 2型DM肾病的进展有关 ,C等位基因可能是中国人 2型DM临床肾病的保护因素。     

Adiponectin gene polymorphism 45T>G is associated with carotid artery plaques in patients with type 2 diabetes mellitus

Adiponectin has been reported to have a wide range of antiatherogenic actions. Two common single nucleotide polymorphisms (SNPs) at the adiponectin locus (45T>G and 276G>T) have been reported to be associated with diabetes and cardiovascular diseases. The aim of this study was to examine the association between common polymorphisms of the adiponectin gene (ACDC) and carotid atherosclerosis in patients with type 2 diabetes mellitus. A total of 708 unrelated patients with type 2 diabetes mellitus were recruited. SNP45 and SNP276 ACDC were genotyped, and B-mode ultrasonography of the carotid arteries was performed to measure carotid intima-media thickness and assess the presence of carotid artery plaques (CAP). Although there was no significant difference in carotid intima-media thickness according to ACDC genotype, subjects carrying the SNP45 GG genotype had a significantly higher risk of having CAP (odds ratio, 2.468; P = .045) compared with carriers of the T allele after adjustment for possible confounding factors. This study suggests that the GG genotype at ACDC SNP45 is associated with the presence of CAP and may contribute to atherosclerosis in type 2 diabetes mellitus.     

Chemotactic cytokine receptor 5 (CCR5) gene promoter polymorphism (59029A/G) is associated with diabetic nephropathy in Japanese patients with type 2 diabetes: a 10-year longitudinal study

We previously showed that polymorphisms of the promoter area of chemokine receptor 5 (CCR5) gene (59029G/A) and its agonist, regulated upon activation, normal T-cell expressed and secreted (RANTES) gene (-28C/G) were new candidates for susceptibility to diabetic nephropathy. The aim of this study was to confirm the effect of these polymorphisms on the development and progression of diabetic nephropathy. We performed a 10-year retrospective study of 191 Japanese type 2 diabetic patients with normoalbuminuria at baseline. The subjects were classified into two groups: (1) those with persistent normoalbuminuria (group N) and (2) those with progression from normoalbuminuria to microalbuminuria or overt proteinuria (group P). Then, their association with CCR5 59029G/A and RANTES -28C/G polymorphisms was assessed. The frequency of the RANTES -28G(+) genotype did nor differ between the two groups, but the CCR5 59029A(+) genotype had a significantly higher frequency in group P than in group N (83% versus 71%, p=0.04). By discriminant analysis, only the CCR5 59029A(+) genotype showed an independent positive correlation with the onset or progression of nephropathy (p=0.03, odds ratio=2.41, 95% CI=1.09-5.33). Therefore, the CCR5 59029A(+) genotype seems to be related the etiology of diabetic nephropathy in Japanese type 2 diabetics.     

No association between MTHFR gene polymorphism and diabetic nephropathy in Japanese type II diabetic patients with proliferative diabetic retinopathy

The development of diabetic nephropathy shows marked variation among individuals. Not only hyperglycemia, but also genetic factors may contribute to the development of diabetic nephropathy. Methylenetetrahydrofolate reductase (MTHFR) is involved in remethylation of homocysteine to methionine. Decreased activity of MTHFR which can result in hyperhomocysteinemia may lead to cerebrovascular disease and coronary artery disease. Recently, a common C to T mutation at nucleotide position 677 of the MTHFR gene (MTHFR677C>T) has been reported to be correlated with hyperhomocysteinemia and the severity of coronary artery disease as macroangiopathy. In the present study, we recruited 173 of Japanese type II diabetic patients with proliferative diabetic retinopathy who would be exposed to long-term hyperglycemia, and examined the contribution of the MTHFR gene polymorphism to the development of diabetic nephropathy as microangiopathy. The frequency of the mutated allele was 43.3% in patients with nephropathy (n = 105) versus 41.9% in those without nephropathy (n = 68). The genotype frequencies were +/+, 16.2%; +/−, 54.3%; −/−, 29.5% in patients with nephropathy versus +/+, 13.2%; +/−, 57.4%; −/−, 29.4% in those without nephropathy (+ indicates the presence of the mutation). The MTHFR genotype and allele frequencies were not significantly different between patients with and without nephropathy. Therefore, we conclude that the MTHFR gene polymorphism is not associated with the development of diabetic nephropathy in Japanese type II diabetic patients.     

Maternal history of type 2 diabetes is associated with diabetic nephropathy in type 1 diabetic patients

AIMS: Insulin resistance is a key feature of type 2 diabetes. It is also involved in the development and progression of microvascular complications. We analysed the relationship between parental history of diabetes, insulin resistance and diabetic nephropathy (DN) and assessed the specific maternal and paternal influences of history of type 2 diabetes on DN in type 1 diabetic offspring. METHODS: We recorded information regarding family history of type 2 diabetes and of cardiovascular disease in 160 consecutive, unrelated type 1 diabetic patients. Insulin resistance was assessed using a validated estimation of the glucose disposal rate (eGDR). RESULTS: Type 1 diabetic patients with a maternal history of type 2 diabetes were more likely to be insulin-resistant (P=0.043) and to have renal complications (P=0.0041) than those from the reference group (without parental history of diabetes), while patients with a paternal history were not different from those from the reference group, regarding eGDR and DN. Time to development of abnormal albuminuria was significantly affected by maternal history of type 2 diabetes (log-rank=12.66; P=0.0004) and by familial history of premature cardiovascular disease (log-rank=5.48; P=0.0234). In multivariate analysis, a maternal history of type 2 diabetes was independently associated with nephropathy after adjustment for sex, diabetes duration and familial history of premature cardiovascular disease. CONCLUSION: Maternal history of type 2 diabetes is independently associated with DN in type 1 diabetic patients. This might suggest the transmission of a maternal trait related to microvascular complications, raising the hypothesis of imprinted genes predisposing to diabetic renal disease.     

血管内皮生长因子基因3'-非翻译区C936T多态性与2型糖尿病肾病相关

采用PCR-RFLP方法分析了194例2型糖尿病患者血管内皮生长因子(VECF)基因3'-非翻译区C936T变异与糖尿病肾病的关系.发现糖尿病肾病组C等位基因及CC基因型频率显著高于非肾病组和正常对照组,提示C等位基因及CC基因型患者可能是糖尿病易于发生肾病危险性的遗传标志.     

Association study of fatty acid binding protein 2 gene polymorphism for diabetic nephropathy in Japanese patients with type 2 diabetes

To test the hypothesis whether the Ala54Thr polymorphism of the fatty acid binding protein 2 (FABP2) gene was associated with diabetic nephropathy, we studied a total of 397 Japanese type 2 diabetic patients. The diagnosis of diabetic nephropathy was based on measurements of urinary albumin:creatinine ratio (ACR). We subdivided subjects as those with normoalbuminuria (ACR < 30 mg/g Cr), those with micro- albuminuria (ACR:30–300 mg/g Cr), and those with macroalbuminuria (ACR ³300 mg/g Cr). FABP2 genotypes were determined with a fluorescent allele-specific DNA primer assay system. The results showed that the genotypes of Ala54Thr polymorphism of the FABP2 gene were not significantly different among normo-, micro- and macro-albuminuria groups, suggesting that polymorphism of this gene was not associated with diabetic nephropathy in Japanese type 2 diabetic subjects.     

载脂蛋白E基因多态性与糖尿病肾病的相关性研究

目的 探讨载脂蛋白E(ApoE)基因多态性与糖尿病肾病(DN)的关系.方法 应用聚合酶链反应-限制性片断长度多态性技术检测218例2型糖尿病患者[正常白蛋白尿(DN0)组41例,微量白蛋白尿(DN1)组129例,临床白蛋白尿(DN2)组 48例]和102名健康对照者(NC)的ApoE基因多态性.结果 (1)DN1组、DN2组及DN组(DN1+DN2组)ApoE 2/3基因型和ε2等位基因频率均高于DN0组(P均＜0.05).(2)ApoE 2/3基因型为DN发生的危险因素(P＜0.05).(3)ε4等位基因频率与TC负相关(P＜0.05).结论 2型糖尿病患者中,ApoE 2/3基因型可能是DN发生的危险因素,ε4等位基因可能是高TC血症的保护因素.     

Leukocyte-endothelial cell adhesion molecule 1 (LECAM-1) polymorphism is associated with diabetic nephropathy in type 2 diabetes mellitus

BACKGROUND/AIMS: Glomerular infiltration with monocytes/macrophages has been implicated in the pathogenesis of diabetic nephropathy. In this study, we evaluated the relationship between the genetic polymorphism in leukocyte-endothelial adhesion molecule-1 (LECAM-1) and diabetic nephropathy in patients with type 2 diabetes mellitus. METHODS: We determined the frequency of the LECAM-1 P213S genotype in 102 diabetic patients with diabetic nephropathy, 90 diabetic patients with no evidence of diabetic nephropathy, and 200 healthy control individuals. RESULTS: The frequency of the LECAM-1 213PP genotype and P allele in patients with diabetic nephropathy was significantly higher than that in patients without nephropathy (genotype 68% vs. 53%, chi(2)=6.78, P=.034; allele 83% vs. 72%, chi(2)=6.26, P=.012). The LECAM-1 P213 genotype was associated with a 1.86-fold increased risk for nephropathy independently of other risk factors. CONCLUSION: The data suggest that the LECAM-1 213PP genotype is a genetic risk factor for the development of nephropathy in type 2 diabetes mellitus.     

Adiponectin is inversely associated with renal function in type 1 diabetic patients

OBJECTIVE: Adipose tissue is a source of several adipocytokines that may contribute to vascular complications. We examined the relation of adiponectin with several cardiovascular risk factors and with micro- and macrovascular outcomes in type 1 diabetic patients. DESIGN: Cross-sectional data on 543 type 1 diabetic patients from the EURODIAB Prospective Complications Study were analyzed. We determined adiponectin, TNF-alpha, IL-6, C-reactive protein, soluble vascular cell adhesion molecule (sVCAM-1), and sE-selectin by ELISA. RESULTS: We found that adiponectin was negatively correlated with body mass index, waist to hip ratio, insulin, and fasting triglyceride, and positively with high-density lipoprotein, low-density lipoprotein, and total cholesterol, TNF-alpha, and sVCAM-1, but was not related to C-reactive protein, IL-6, and sE-selectin. Surprisingly, significantly raised concentrations of adiponectin were found with albuminuria, retinopathy, and cardiovascular diseases (for all, P < 0.0001). Adiponectin levels were inversely associated with glomerular filtration rate (GFR) (P < 0.0001). Multivariate regression models showed that the associations of adiponectin with albuminuria and GFR were independent of established risk factors. The association between adiponectin and albuminuria was attenuated by GFR, whereas the association of adiponectin with retinopathy and cardiovascular disease disappeared after adjustments for established risk factors. The association of adiponectin with sVCAM-1 was independent of established risk factors. CONCLUSION: We conclude that in type 1 diabetic patients, adiponectin is associated with impaired renal function. Adiponectin may be enhanced in type 1 diabetic patients as a physiological counterregulatory response to mitigate endothelial damage and vascular damage.     

小泛素样修饰蛋白4基因163A／G多态性与2型糖尿病肾病的相关性研究

目的探讨小泛素样修饰蛋白4（SUMO4）基因163A／G多态性与2型糖尿病肾病（DN）的相关性。方法运用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）方法对232例T2DM患者,其中正常白蛋白尿103例（N-UAIb组）、微量白蛋白尿65例（M-UAlb组）、大量白蛋白尿64例（L-UAlb组）,以及102名健康对照（NC组）的SUM04基因163A／G多态性进行检测,并比较各组间基因型频率、等位基因频率及相关临床资料。结果NC组和T2DM组基因型和等位基因频率无统计学差异;M-UAlb和L-UAlb组的GA基因型频率高于N—UAlb组（P〈0．05）。结论在昆明地区汉族人群中,SUM04基因GA基因型可能是DN发生的危险因素。