Manganese superoxide dismutase gene polymorphism (V16A) is associated with stages of albuminuria in Korean type 2 diabetic patients

Several single-nucleotide polymorphisms of genes related to oxidative stress have been evaluated because intracellular reactive oxygen species are associated with development of diabetes and its microvascular complications. We performed a case-control study to investigate whether V16A polymorphism of manganese superoxide dismutase (Mn-SOD) gene is related to pathogenesis of diabetes and whether the polymorphism is associated with stages of albuminuria in Korean type 2 diabetic patients. Genotype distributions were studied in 178 nondiabetic subjects and 371 type 2 diabetic patients of 3 groups with a normoalbuminuria group (Normo group, n = 244), a microalbuminuria group (Micro group, n = 86), and an overt albuminuria group (Macro group, n = 41). The albumin/creatinine ratio (ACR) was defined as a urinary albumin/creatinine ratio. V16A genotypes were determined with polymerase chain reaction-restriction fragment length polymorphism method. Between nondiabetic subjects and type 2 diabetic patients, Mn-SOD genotype distribution (VV/VA + AA, 146/32 vs 314/57) and A allele frequency (0.121 vs 0.104) were not different. Patients with nephropathy, Micro and Macro groups, had significantly lower A allele frequency, longer diabetic duration, higher prevalence of hypertension, and greater ACR than those of patients without nephropathy (P < .05). A allele was significantly less frequent with progression of nephropathy (Normo group, 0.119; Micro group, 0.073; Macro group, 0.03; P < .05). In type 2 diabetic patients, A allele carriers had significantly lower prevalence of hypertension and lesser ACR than those of A allele noncarriers (P < .01). In multivariate analysis, hypertension, duration of diabetes, serum total cholesterol level, and A allele of Mn-SOD gene were independently associated with stages of albuminuria. These results suggest that V16A polymorphism of Mn-SOD gene is not related to pathogenesis of diabetes but is associated with stages of albuminuria in Korean type 2 diabetes.     

结合珠蛋白基因多态性与糖尿病视网膜病变（一）

目的探讨结合珠蛋白（Hp）基因多态性与2型糖尿病（T2DM）患者糖尿病视网膜病变（DR）发病的关系。方法将317例T2DM患者分为糖尿病无视网膜病变（NDR）组和DR组,并选取100名正常人作为对照（NC）组。采用PCR技术扩增Hp1和Hp2特异的目的片段,分析Hp基因型及糖尿病（DM）病程、尿白蛋白（UAlb）等生化指标与DR的关系。结果NDR组、DR组和NC组间Hp等位基因和基因型频率比较,均无统计学差异（P〉0．05）。经Logistic回归分析显示,DM病程和24hUAlb是DR的独立危险因素,Hp可能与DR无相关性。结论Hp基因多态性可能与DR无相关性,而DM病程和24hUAlb是DR的独立危险因素。     

天津地区内分泌科就诊的2型糖尿病患者视网膜病变及黄斑水肿的患病率调查

9 237例住院2型糖尿病患者的分析结果表明,糖尿病视网膜病变(DR)患病率为32.9%,其中轻度、中度、重度非增生性DR的患病率分别为10.1%、18.3%、3.2%,增生性DR患病率为1.3%;糖尿病黄斑水肿(DME)患病率为3.56%,占DR患者的10.8%;糖尿病病程和蛋白尿是DR和DME的共同危险因素.

Abstract：

According to the analysis of 9 237 hospitalized type 2 diabetic patients, the prevalence of diabetic retinopathy ( DR )was 32.9％ , with the prevalence of mild, moderate, and serious non-proliferative DR and proliferative DR being 10. 1％, 18. 3％, 3.2％, and 1.3％ respectively. The prevalence of diabetic macular edema ( DME ) was 3.56％ in type 2 diabetics and i 0. 8％ in patients with DR. Diabetes duration and proteinuria were the common risk factors of DR and DME.     

Scanning laser edema index: A reliable tool to correlate with diabetic retinopathy and systemic risk factors?

To correlate Heidelberg Retina Tomograph (HRT) derived macular edema (DME) index with severity of diabetic retinopathy and systemic factors. A total of 300 diabetic patients were recruited for the study for each of them a value for the macular edema index was obtained using the HRT II. Patients' age, gender, duration and type of diabetes mellitus, latest HbA1c result and presence or absence of co-morbid factors (hypertension, ischemic heart disease, nephropathy) were recorded together with the stage of diabetic retinopathy. These were correlated with DME. Out of 300 patients, HRT defined macula edema was seen in 68 patients (22.6%). There is a wider and higher range (95% percentile) of macula edema index in the severe non proliferative diabetic retinopathy (NPDR) group. Independent samples t test showed significant difference between the severe NPDR group and no DR group (p<0.001), mild NPDR group (p<0.05) and moderate NPDR group (p<0.05). A higher macula edema index was also found to have a low degree of correlation with more advanced stages of retinopathy (r=0.310; p<0.001). Also nephropathy showed a strong and significant correlation with DME. Hypertension had moderately significant correlation with DME. This study found no correlation between ischemic heart disease and DME. HRT derived scanning laser edema index is a reliable objective tool to evaluate diabetic retinopathy and systemic risk factors.     

Association analysis of -429T/C and -374T/A polymorphisms of receptor of advanced glycation end products (RAGE) gene in Malaysian with type 2 diabetic retinopathy

Conflicting results have been reported in different populations on the association between two particular RAGE gene polymorphisms (-429T/C and -374T/A) and retinopathy in diabetic patients. Therefore this study was designed to assess the association between both gene polymorphisms with retinopathy in Malaysian diabetic patients. A total of 342 type 2 diabetic patients [171 without retinopathy (DNR) and 171 with retinopathy (DR)] and 235 healthy controls were included in this study. Genomic DNA was obtained from blood samples and the screening for the gene polymorphisms was done using polymerase chain reaction-restriction fragment length polymorphism approach. Overall, the genotype distribution for both polymorphisms was not statistically different (p>0.05) among the control, DNR and DR groups. The -429C minor allele frequency of DR group (12.0%) was not significantly different (p>0.05) when compared to DNR group (16.1%) and healthy controls (11.3%). The -374A allele frequency also did not differ significantly between the control and DNR (p>0.05), control and DR (p>0.05) as well as DNR and DR groups (p>0.05). This is the first study report on RAGE gene polymorphism in Malaysian DR patients. In conclusion, -429T/C and -374T/A polymorphisms in the promoter region of RAGE gene were not associated with Malaysian type 2 DR patients.     

Relation between polymorphisms G1704T and G82S of RAGE gene and diabetic retinopathy in Japanese type 2 diabetic patients

OBJECTIVE: To clarify whether polymorphisms G1704T and G82S of the rage gene were related to diabetic retinopathy, we performed a case-control study in Japanese type 2 diabetic patients. PATIENTS AND METHODS: Two hundred and sixty-eight patients with type 2 diabetes were examined for polymorphisms G1704T and G82S of the RAGE gene. The genotypes of G1704T and G82S of the RAGE gene were determined with a fluorescent allele-specific DNA primer assay system. Diabetic retinopathy (DR) was diagnosed in a masked manner by independent ophthalmologists using fundus photographs and was classified as non-diabetic retinopathy (NDR), non-proliferative retinopathy (NPDR), and proliferative retinopathy (PDR). RESULTS: The T allele frequency of G1704T and S allele frequency of G82S in patients with DR did not significantly differ from those without retinopathy. There were no differences among the genotypes of G1704T and G82S of the RAGE gene regarding age, duration of diabetes, BMI, HbA(1c), blood pressure, and lipids levels. CONCLUSION: These data suggest that polymorphisms G1704T and G82S of the RAGE gene are not related to DR in Japanese type 2 diabetic patients.     

Ten-year incidence of diabetic retinopathy and macular edema. Risk factors in a sample of people with type 1 diabetes

Aims

To determine the 10-year incidence of diabetic retinopathy (DR) and macular edema (DME), and its relationship with its risk factors in a sample of type 1 diabetes mellitus.

Methods

A total of 334 patients without diabetic retinopathy at baseline underwent a 10-year prospective study, the risk factors included: age, gender, diabetes duration, HbA1c, LDL-C, HDl-C, TC/HDL-C ratio, ApoA1, ApoB, ApoB/ApoA1 ratio, and triglycerides were recorded. Risk factors for diabetic macular edema (DME) were also recorded.

Results

The 10-year incidence of any DR was 35.90%, and 11.07% developed DME. The risk factors for DR and DME were: diabetes duration, high glycosylated level, and arterial hypertension, and overt nephropathy was well correlated with DME. The lipid study demonstrated that ApoB/ApoA1 ratio was significant for any DR [HRR: 0.594 (0.416-0.848), p = 0.01], and DME [HRR: 0.601 (0.433-0.894), p = 0.009]. The TC/HDL ratio was only significant for DME [HRR: 0.624 (0.440-0.886), p = 0.008]; other lipids values were not significant for any groups studied.

Conclusions

In the present study, the ApoB/ApoA1 ratio was significant to the 10-year incidence of diabetic retinopathy and to macular edema; and the TC/HDL ratio was significant to a 10-year incidence of macular edema.     

Association of Gly82Ser polymorphism in the RAGE gene with diabetic retinopathy in type II diabetic Asian Indian patients

Aim/hypothesis: The binding of advanced glycation end products (AGE) to the receptor induces cellular oxidative stress and vascular dysfunction and this is implicated in the pathogenesis of diabetic retinopathy (DR). This study aims to investigate the frequency of Gly82Ser polymorphism in exon 3 of the receptor for AGE (RAGE) gene and its association with DR in Asian Indian patients who have type II diabetes. Methods: 200 Asian Indian patients with at least 15-year duration of type II diabetes were identified. This group included (1) 100 patients with retinopathy (DR) and (2) 100 patients without retinopathy (DNR). Fifty unrelated healthy controls (CT) were also included in the study. Genotype frequencies of Gly82Ser polymorphism were studied by polymerase chain reaction (PCR) amplification and restriction fragment length polymorphism analysis using AluI enzyme. Later, the nucleotide change was confirmed by DNA sequencing. Results: The frequency of the Ser82 allele was significantly higher, 18% in the DNR group compared to 7% in the DR group (P=.03). The same genotype was 2% in the CT group. Conclusion/interpretation: Our result suggests that Ser82 allele in the receptor for AGE gene is a low-risk allele for developing DR in Asian Indian patients who have type II diabetes.     

结合珠蛋白基因多态性与糖尿病视网膜病变（二）

目的探讨结合珠蛋白（Hp）多态性与2型糖尿病（T2DM）患者糖尿病视网膜病变（DR）发病的关系。方法418例T2DM患者分为3组：糖尿病无视网膜病变（NDR）组、非增生型糖尿病视网膜病变（NPDR）组、增生型糖尿病视网膜病变（PDR）组,另选取100名性别构成、年龄与之相匹配的健康者作为对照（NC）组。采用PCR技术扩增Hp1和Hp2特异目的片段,利用聚丙烯酰胺凝胶电泳技术对Hp分型,分析Hp多态性及各项临床指标与DR的关系。结果NDR组、NPDR组与PDR组两两组间,T2DM组与NC组间,Hp基因型及等位基因频率均无统计学差异（P〉0．05）。经Logistic回归分析显示：DM病程、SBP、TC、24h尿白蛋白（24h UAlb）是DR的独立危险因素（P〈0．05）,Hp与DR发病无关。结论Hp多态性与天津地区DR发病可能无相关性。     

MMP-9基因二核苷酸重复序列多态标志与2型糖尿病视网膜并发症相关

采用基因扫描方法 ,检测 2型糖尿病视网膜并发症患者 (DR )及无该并发症 (DR -)患者基质金属蛋白酶 9(MMP 9)基因二核苷酸串联重复序列多态标记 (AC)n的基因型。与DR -组相比 ,DR 组AC2 1基因型及等位基因频率显著减少 ,提示MMP 9基因的AC2 1等位基因可能与中国人 2型糖尿病视网膜并发症相关     

Association between diabetic retinopathy and genetic variations in alpha2beta1 integrin, a platelet receptor for collagen

Platelets might be involved in the pathogenesis of diabetic microangiopathy. Wide interindividual variations in the density of a platelet collagen receptor (alpha2beta1 integrin or glycoprotein Ia/IIa) are reportedly associated with polymorphism(s) in the gene encoding the alpha subunit of the receptor, including a Bgl II polymorphism in intron 7. The aim of the present study was to determine the relationship between the Bgl II polymorphism and the susceptibility to diabetic microangiopathy. A case-control study comparing 227 patients with type II diabetes mellitus (119 with versus 108 without diabetic retinopathy) as well as 169 nondiabetic subjects demonstrated that genotypes with Bgl II (+) allele had a significant increase in the risk for retinopathy. The odds ratio for Bgl II (+/+) to Bgl II (-/-) was 3.41 (95% CI, 1.49-7.78, P =.0036) when analysis was confined to those with a disease duration of diabetes of 10 years or more. The present study suggests that the presence of a Bg II (+) allele is a genetic risk factor for diabetic retinopathy. (Blood. 2000;95:1560-1564)     

Down-regulation of angiogenic inhibitors: a potential pathogenic mechanism for diabetic complications

Diabetic retinopathy (DR) and diabetic nephropathy (DN) are the most common microvascular complications of diabetes. DR is a leading cause of blindness, and DN is a major cause of end-stage renal diseases. Diabetic macular edema (DME) resulting from increased vascular permeability in the retina and retinal neovascularization (NV) represent two major pathological changes in DR and are the primary causes of vision loss in diabetic patients. Previous studies have shown that angiogenic factors such as vascular endothelial growth factor (VEGF) play a key role in the development of DME and retinal NV. Studies in recent years have demonstrated that a number of endogenous angiogenic inhibitors are present in the normal retina and counter act the effect of VEGF in the regulation of angiogenesis and vascular permeability. Decreased levels of angiogenic inhibitors in the vitreous and retina have been found in diabetic patients and diabetic animal models. The decreased levels of angiogenic inhibitors shift the balance between angiogenic factors and angiogenic inhibitors and consequently, lead to the development of DME and retinal NV. Recently, we have found that these angiogenic inhibitors are expressed at high levels in the normal kidney and are down-regulated in diabetes. Moreover, these inhibitors inhibit the activity of VEGF and TGF-beta, two major pathogenic factors of DN. Therefore, decreased levels of these angiogenic inhibitors in diabetes may be associated with pathologies of DN. This review will summarize recent progress in these fields and therapeutic approaches to use angiogenic inhibitors for the treatment of diabetic complications.     

Correlation between diabetic retinopathy severity and elevated skin autofluorescence as a marker of advanced glycation end-product accumulation in type 2 diabetic patients

AimsWe evaluated skin autofluorescence (AF) as a marker of tissue advanced glycation end-product (AGE) accumulation and examined whether it was related to the prevalence and severity of diabetic retinopathy (DR) and of diabetic macular edema (DME) in patients with type 2 diabetes mellitus (DM).MethodsThis study included 138 type 2 DM patients consisting of 31 patients with proliferative DR, 71 patients with non-proliferative DR, and 36 patients without retinopathy, in addition to 111 non-DM control subjects. At the time of skin AF and HbA1c measurement, self-assessed duration of DM was also determined. DR and DME stages were classified according to international guidelines.ResultsSkin AF was significantly increased in patients with DM as compared with non-DM controls. Furthermore, skin AF was correlated with the severity of DR, whereas single measurement of HbA1c and self-assessed DM duration were not. None of these 3 factors showed a correlation with DME prevalence or severity.ConclusionsSkin AF levels, which can be measured non-invasively on a screening basis without skin biopsy or blood sampling, have a greater predictive ability for the presence and severity of DR than single measurement of HbA1c or self-assessed DM duration in patients with type 2 DM.     

Screening for diabetic retinopathy by non-mydriatic fundus camera in a Turkish population

To investigate the prevalence and risk factors of diabetic retinopathy (DR) in a diabetic population in Turkey using a non-mydriatic fundus camera. Patients presenting to our diabetes screening center were evaluated by fundus photography using a non-mydriatic fundus camera. Patients’ age at presentation, diabetes duration, hemoglobin A1c (HbA1c) levels, and treatments used for diabetes were recorded. The data of 1797 female (55%) and 1470 male (45%) diabetes patients (total 3267) were analyzed. The prevalence of DR was 28.6%. DR stage was mild non-proliferative DR (NPDR) in 345 patients (12.9%), moderate NPDR in 300 (11.2%), severe NPDR in 108 (4%), and proliferative DR (PDR) in 12 patients (0.4%). Diabetic macular edema (DME) was detected 98 patients (3.7%). Fundus pictures were inadequate for assessment in 18% of cases (588 patient). Advanced age, longer diabetes duration, higher HbA1c level, and being treated for diabetes were found as risk factors for DR. In this study, we used a non-mydriatic fundus camera to determine the prevalence and risk factors of diabetic retinopathy in a Turkish population. In developing countries, the non-mydriatic fundus camera may be an appropriate way to detect DR in the early stages before it progresses to the proliferative stage.     

Angiotensin-converting enzyme gene polymorphism is correlated to diabetic retinopathy: a meta-analysis

The angiotensin-converting enzyme (ACE) displays potent vasoconstrictive effects, attenuation of fibrinolysis, and platelet activation and aggregation. The ACE gene has been the main probable candidate gene predisposing the development of diabetic retinopathy (DR). However, the correlation between ACE gene polymorphism and progression of DR still requires further approval. Here, the author performs a summative analysis on recent previous reports on ACE gene polymorphism and its correlation to DR. The meta-analysis was performed in order to assess the correlation between the pattern of ACE gene polymorphism and DR. From four studies available, the author evaluated type II diabetic patients with (Group 1; n=432) and without DR (Group 2; n=329). The frequency of the DD genotype in Group 1 is not significantly different from that in Group 2 (P>.05). In addition, the author first reports a nonsignificant correlation between ethnicity and ACE gene polymorphism.     

Advances in the treatment of diabetic retinopathy

As the diabetes epidemic in the United States continues to worsen, so too does the prevalence of diabetic retinopathy (DR). DR is divided broadly into nonproliferative and proliferative stages, with or without vision-threatening macular edema. Progression to proliferative DR is associated with vision loss that is often irreparable, and a rapid decline in health-related quality of life. Vascular endothelial growth factor (VEGF)-A is upregulated in the diabetic eye, and has been identified as a key driver of DR pathogenesis. With this perspective, we review the published phase III clinical trial data of anti-VEGF therapies approved for the treatment of DR in the United States. Using the Early Treatment Diabetic Retinopathy Study Diabetic Retinopathy Severity Scale, in which an improvement of ≥2 steps is considered clinically significant, approximately one-third of patients with DR and macular edema experience this level of improvement after 1 year of treatment with either ranibizumab or aflibercept. The rates of clinically significant DR improvement with ranibizumab could be twice that in the subgroup of patients with moderately severe or severe nonproliferative DR and macular edema. These clinical trial data indicate that intraocular inhibition of VEGF is a rational approach for the management of DR.     

Relationship between polymorphisms 804C/A and 252A/G of lymphotoxin-alpha gene and -308G/A of tumor necrosis factor alpha gene and diabetic retinopathy in Japanese patients with type 2 diabetes mellitus

To clarify whether polymorphisms of the lymphotoxin-alpha (LTA) gene and tumor necrosis factor alpha (TNF-alpha) gene were related to diabetic retinopathy (DR), we performed a case-control study in 251 Japanese patients with type 2 diabetes mellitus participating in a multicenter research protocol. Genetic analyses were performed by using a fluorescent allele-specific DNA primer assay system. Diabetic retinopathy was diagnosed in a masked manner by an independent ophthalmologist using fundus photographs and was classified as nondiabetic retinopathy (NDR), nonproliferative retinopathy (NPDR), and proliferative retinopathy (PDR). The results showed that the genotype frequencies of 804C/A in exon 3 and 252A/G in intron 1 of the LTA gene were not significantly different among patients with NDR, NPDR, and PDR. A allelic frequency of the TNF-alpha gene (-302A/G in promoter) was also identical among NDR, NPDR, and PDR groups. Multivariate logistic regression analyses showed that significant associations with DR were glycosylated hemoglobin level and diabetes duration, but not polymorphisms of the LTA gene or TNF-alpha gene. In conclusion, the present study showed no association between polymorphisms 804C/A and 252A/G of the LTA gene and -302A/G of the TNF-alpha gene and DR in Japanese type 2 diabetic patients.     

亚甲基四氢叶酸还原酶基因多态性与2型糖尿病微血管病变易感性的研究

目的 探讨亚甲基四氢叶酸还原酶（methylenetetrahydrofolate reductase,MTHFR)基因多态性与中国北方汉族2型糖尿病患者微血管并发症（DMAP）易感性的关系。方法 应用聚合酶链反应－限制性片段长度多态性（PCR－RFLP）的方法检测291名中国北方汉族[2型糖尿病患者229例,其中无微血管并发症（NCD）组102例,糖尿病视网膜病变（DR）组60例,糖尿病肾病（DN）组和67例;健康人对照（CON）组62例]MTHFR基因的多态性,比较各组间MTHFR等位基因和基因型的频率。结果 基因型BB在DN及DR组（34．3％和31．7％）高于NCD组和CON组（13．7％和12．9％）;DN及DR组的等位基因B频率（54．4％和59．9％）,也高于NCD组和CON组（41．2％和35．5％）,差异均有显著性意义。基因型BB和等位基因B在NCD和CON组之间的分布无统计学差异。结论 MTHFR基因C677T变异与中国北方汉族2型DM患者DMAP的发生有关。等位基因B可能是DMAP的易感基因。     

PAI-1基因启动子区4G/5G基因多态和Enos第4内含子a/b基因多态与糖尿病肾病的相关性研究

为探讨 PAI- 1基因启动子区 4 G/ 5 G基因多态性、一氧化氮合酶 (e NOS)第 4内含子 2 7bp插入 /缺失 (a/b)多态性与糖尿病肾病 (DN)的相关性 ,采用发色底物法测定 PAI- 1活性 ;等位基因特异性引物 PCR扩增技术测定 PAI- 1基因 4 G/ 5 G多态性 ;聚合酶链反应测定 e NOS基因第 4内含子 2 7bp的 a/ b多态性。结果显示 ,Hb A1c、SBP、TC、e NOS基因第 4内含子 a/ b多态均属 DN的独立危险因素。早期糖尿病肾病组 (DN+组 ) a等位基因及 ab基因型频率显著高于糖尿病非肾病组 (DN-组 ) (P<0 .0 5 )。DN+组血浆 PAI- 1活性明显高于 DN-组 (P<0 .0 5 ) ;4 G纯合子组 PAI- 1活性明显高于 4 G/ 5 G杂合子及 5 G纯合子组 (P<0 .0 0 5 )。2型糖尿病患者中 ,4 G纯合子和a/ b杂合子携带者 DN的相对风险明显增加 (P<0 .0 5 ) ,4 G杂合子携带者 DN的相对风险增加不明显 (P>0 .0 5 )。当 a/ b杂合子和 4 G纯合子基因多态并存时 DN的发病风险明显增加。认为 PAI- 1基因启动子区 4 G/ 5 G基因多态、e NOS基因第 4内含子 a/ b多态与 DN的发生、发展有关。两种基因多态同时存在时 ,DN的发病风险明显增加