Association between the RAGE gene -374T/A, -429T/C polymorphisms and diabetic nephropathy: a meta-analysis

Abstract

Aim: The investigations into the association between the receptor for advanced glycation end products (RAGE) gene -374T/A, -429T/C polymorphisms and diabetic nephropathy (DN) in several case–control studies have rendered conflicting results. To shed light on these inconclusive findings, a meta-analysis of all the eligible studies relating these two polymorphisms to the risk of DN was conducted. Methods: The databases were searched for relevant articles up to July 2014. A pooled estimate of the genetic association, the heterogeneity between studies, and the publication bias were investigated. Results: Eight studies with 1725 cases and 1857 controls were enrolled in -374T/A polymorphism analysis. The main analysis indicated no association for the allele contrast, the recessive model and the dominant model. Subgroup analyses in Caucasians and in type 2 diabetes also showed no association between -374T/A polymorphism and DN. Five studies with 1019 cases and 792 controls were enrolled in -429T/C polymorphism analysis. The main analysis revealed heterogeneity and no association for the allele contrast and the dominant model. However, the recessive model for -429C allele diminished the heterogeneity and showed a marginal association overall [fixed-effects OR?=?2.83 (1.33–6.00) and random effects OR?=?2.50 (1.00–6.24), respectively]. Conclusions: Our meta-analysis indicated that the RAGE gene -429CC genotype might be a risk factor for DN in patients with type 2 diabetes.     

Diabetic nephropathy in children and adolescents

Type 1 diabetes mellitus (T1DM) commonly occurs in childhood or adolescence, although the rising prevalence of type 2 diabetes mellitus (T2DM) in these age groups is now being seen worldwide. Diabetic nephropathy (DN) develops in 15–20% of subjects with T1DM and in similar or higher percentage of T2DM patients, causing increased morbidity and premature mortality. Although overt DN or kidney failure caused by either type of diabetes are very uncommon during childhood or adolescence, diabetic kidney disease in susceptible patients almost certainly begins soon after disease onset and may accelerate during adolescence, leading to microalbuminuria or incipient DN. Therefore, all diabetics warrant ongoing assessment of kidney function and screening for the earliest manifestations of renal injury. Pediatric health care professionals ought to understand about risk factors, strategy for prevention, method for screening, and treatment of early DN. This review considers each form of diabetes separately, including natural history, risk factors for development, screening for early manifestations, and strategy recommended for prevention and treatment of DN in children and adolescents.     

尿胞外体1型辅助性T细胞/2型辅助性T细胞失衡与2型糖尿病肾病的相关性

目的 探讨2型糖尿病（DM）患者尿胞外体1型辅助性T细胞/2型辅助性T细胞（Th1/Th2）的变化与2型糖尿病肾病（DN）发生发展的相关性。 方法 选取120例2型糖尿病患者及健康对照组30例为对象,根据尿白蛋白肌酐比（UACR）,2型糖尿病患者分为糖尿病非肾病组（DM,40例,UACR<30 mg/gCr）、微量白蛋白尿组（DN1,50例,UACR≥30~300 mg/gCr）和临床白蛋白尿组（DN2,30例,UACR＞300 mg/gCr）。用特异性单克隆抗体提纯尿胞外体。用酶联免疫吸附法（ELISA）检测尿胞外体干扰素γ（IFN-γ）和白细胞介素4（IL-4）水平。用多元逐步回归方法分析尿胞外体IFN-γ/IL-4比值与糖化血红蛋白（HbA1c）、胆固醇（CH）、UACR、血肌酐（Scr）、尿素氮（BUN）相关性。 结果 DM、DN1、DN2组胞外体Th1/Th2水平显著高于健康对照组（0.8089±0.2458、0.8993±0.3515、0.8571±0.2470比 0.6198±0.1769,均P < 0.01）。DN1组胞外体Th1/Th2显著高于DM组（P < 0.01）。尿胞外体IFN-γ/IL-4与UACR（r = 0.213,P = 0.015）、BUN（r=0.292,P = 0.001）呈正相关。逐步多元回归分析显示, BUN是尿胞外体IFN-γ/IL-4的独立影响因素（β = 0.246,P = 0.006）。 结论 尿胞外体Th1/Th2漂移与2型糖尿病肾病密切相关,可能在糖尿病早期肾病发病过程中起重要的作用。     

The functional -374 T/A RAGE gene polymorphism is associated with proteinuria and cardiovascular disease in type 1 diabetic patients

The hyperglycemic milieu in diabetes results in the formation of advanced glycation end products (AGEs) that predominantly act through specific receptors, particularly the receptor for AGEs (RAGE). Two functional polymorphisms in the promoter of the RAGE gene (-429 T/C and -374 T/A) and one in the AGE binding domain in exon 3 (G82S) were studied in 996 Finnish type 1 diabetic patients. In patients with poor metabolic control (HbA(1c) >9.5%), the AA genotype of the -374 T/A polymorphism was more common in those with a normal albumin excretion rate than in those with proteinuria (30 vs. 10%, P = 0.01). We observed less coronary heart disease (6 vs. 14%, P < 0.05), acute myocardial infarction (2 vs. 14%, P = 0.01), and peripheral vascular disease (2 vs. 14%, P < 0.05) in patients with the AA genotype of the -374 T/A polymorphism than in those with the TT + TA genotype. Thus, the association between the RAGE -374 T/A homozygous AA genotype and cardiovascular disease as well as albumin excretion in type 1 diabetic patients with poor metabolic control suggests a gene-environment interaction in the development of diabetic nephropathy and cardiovascular complications.     

Polymorphisms in the Vitamin D Receptor Gene and Parathyroid Hormone Gene in the Development and Progression of Diabetes Mellitus and its Chronic Complications, Diabetic Nephropathy and Non-Diabetic Renal Disease

Background : We chose to study polymorphisms of vitamin D receptor gene (VDR) and parathyroid hormone genes (PTH), whose protein products significantly affect calcium-phosphate metabolism in kidneys and are implicated in the pathogenesis of diabetes, which may also involve kidney damage. Methods : Distribution of genotypes of four polymorphisms in VDR gene i.e TaqI (rs731236), BsmI (rs1544410) ApaI (rs7975232), FokI (rs2228570) and two polymorphisms of PTH gene, i.e. DraII (rs6256), BstBI (rs6264), were studied using PCR-RFLP. Examined groups consisted of 147 patients with diabetes (DM), 47 patients with nondiabetic renal disease (NDRD), 132 patients with diabetic nephropathy (DN) and 118 healthy subjects. Conclusion : Comparison of DN group and healthy subjects identified statistically significant difference for the FokI polymorphism in VDR gene (P<10-4) and also for the BstBI polymorphism in PTH gene (P=0,023). Differences in DraII polymorphism distribution in PTH gene were statistically significant in each group of patients compared to healthy subjects. In DN patients, the BBFFAATt combination of VDR gene was more frequent than in healthy subjects (P=0,046), and the BbFFAaTt variant was more frequent than in DM2 patients (P=0,018). The BBDD haplotype of PTH gene seems to be a predisposing factor for diabetes itself (P=0,019).     

Differential expression of renal AGE-receptor genes in NOD mice: possible role in nonobese diabetic renal disease

BACKGROUND: Nonobese diabetic mice (NOD) are prone to glomerular pathology, which is accelerated with the onset of diabetes. Advanced glycation end product (AGE) interactions with AGE-receptors (AGE-Rs) in kidneys can contribute to glomerular injury and diabetic nephropathy (DN). The significant elevation in kidney AGE deposits noted in prediabetic NOD mice suggested that delayed AGE turnover in this model may contribute to its propensity toward DN. METHODS: To explore whether excess tissue AGE was linked to altered AGE-R status in the kidney, mRNA/protein expression, and of several AGE-Rs [AGE-R1, AGE-R2, AGE-R3, scavenger receptor II (ScR-II), and receptor for AGE (RAGE)], was determined in renal cortex and in mesangial cells (MCs) isolated from ND-, D-NOD, and ILE mice (N = 20 per group). Ligand binding, receptor site number, and affinity were determined in MCs from the same mouse groups. RESULTS: Prediabetic NOD kidney AGE-R1 mRNA and protein level were threefold lower than that of ILE mice (P < 0.01), while AGE-R3 mRNA was enhanced by twofold (P < 0.05) and AGE-R2, RAGE, and ScR-II mRNA remained close to normal (ILE). The onset of diabetes in NOD mice, while enhancing AGE-R1 mRNA expression by approximately twofold, failed to raise it above the normal (ILE) level, despite increases in tissue, and serum AGE. The latter was associated with higher elevation in AGE-R3 (sixfold, P < 0.05), RAGE (twofold, P = NS), and ScR-II mRNA (2. 8-fold, P = NS) above control. MCs from prediabetic NOD mice showed a threefold lower level of AGE-R1 mRNA (P < 0.02 vs. ILE) and AGE-R1-protein, and AGE-binding activity (<40% of control ILE). In contrast, AGE-R3 mRNA was enhanced (twofold), while AGE-R2 showed no change. Cultured ND-NOD MCs displayed only one fourth of the AGE-binding sites/cell present on ILE MCs (1.6 x 10(6) vs. 6.6 x 10(6), P < 0.05), which after the onset of diabetes rose to the normal range (7.0 x 10(6)/cell), but failed to exceed it. CONCLUSIONS: Reduced AGE-R1 gene expression in this strain may contribute to delayed AGE removal from and early AGE deposition in kidney tissues. This may act as a trigger for those AGE-R genes involved in growth-promoting changes, leading to DN in this strain.     

维生素D受体基因BsmI多态性与2型糖尿病肾病的关系

目的 研究维生素D受体(VDR)基因BsmI位点多态性与汉族人群2型糖尿病肾病(DN)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)技术检测304例2型糖尿病患者(DM组)及100例健康体检者(NC组)VDR Bsml位点基因型和等位基因频率.根据尿白蛋白情况将DM组分为非糖尿病肾病组(DN0组,122例)、微量白蛋白尿组(DN1组,87例)、大量白蛋白尿组(DN2组,95例).83例病程5年以上仍未出现肾病的DM患者纳入L-NDN组;64例起病1年内即出现肾病的DM患者纳入EDN组.结果 DM组BB+Bb基因型和B等位基因频率均高于NC组(x2=7.088,P=0.008;x2=5.865,P=0.015).DN2组BB+Bb基因型和B等位基因频率高于NC组(x2=14.287,P=0.000; x2=12.621,P=0.000)及DN0组(x2=8.063,P=0.005;x2=8.173,P=0.004).其余组间差异均无统计学意义.EDN组BB+Bb基因型和B等位基因频率均显著高于L-NDN组(x2=7.228,P=0.007;x2=5.853,P=0.016).B等位基因阳性DN患者的尿白蛋白排泄率显著高于B等位基因阴性DN患者,差异有统计学意义(P＜0.01).BsmI位点基因型与DN发生密切相关.B等位基因阳性是DN发生及早发的危险因素(OR=2.004;0R=2.394).结论 VDRBsmI基因多态性与DN易感性相关.B等位基因阳性患者更易出现大量白蛋白尿及早期发生肾病.     

Receptor for advanced glycation end products--soluble form and gene polymorphisms in chronic haemodialysis patients.

BACKGROUND: The receptor for advanced glycation end products (RAGE) is involved in the pathogenesis of vascular and inflammatory diseases. The pathological effects mediated via RAGE are physiologically inhibited by soluble RAGE (sRAGE). Our aim was to study sRAGE and RAGE gene polymorphisms in haemodialysis (HD) patients. METHODS: A total of 261 stable HD patients were enrolled in the study and prospectively followed up for 30 months. At the begining of the study, sRAGE inflammatory and nutritional parameters were determined. RAGE polymorphisms were determined in a subgroup of 214 HD patients. A group of 100 healthy controls was used for comparison. RESULTS: In HD patients, sRAGE is elevated in comparison with healthy controls (3427+/-1508 vs 1758+/-637 pg/ml, P<0.001). It correlates negatively with residual diuresis (r=-0.193, P<0.05), with the acute phase reactants fibrinogen (r=-0.174, P<0.05) and orosomucoid (r=-0.135, P<0.05) and with the leucocyte count (r=-0.158, P<0.05). On the other hand, it is not related to the presence of diabetes mellitus, cardiovascular disease, nutritional status and mortality. The highest sRAGE levels are found in -429 CC and 2184 GG polymorphisms of the RAGE gene. The same results as for sRAGE were obtained for endogenous secretory RAGE (esRAGE), which correlated significantly with sRAGE (r=0.88, P<0.001). CONCLUSION: We conclude that in HD patients, sRAGE is increased due to decreased renal function, which is a very strong determinant of sRAGE levels, and is inversely related to inflammation. The highest sRAGE levels are influenced genetically. In our study, sRAGE levels were not related to mortality of HD patients.     

Type 2 diabetes is not independently associated with spinal trabecular volumetric bone mineral density measured by QCT in the Diabetes Heart Study

The purpose of this study was to investigate the association between type 2 diabetes mellitus (DM2) and trabecular volumetric bone mineral density (vBMD) of the thoracic and lumbar spine measured by quantitative computed tomography (QCT) in 483 female (410 with DM2) and 398 male (365 with DM2) adults (age 36-86 years, BMI 16-58, 88% with DM2) in the Diabetes Heart Study. After accounting for familial correlation using generalized estimating equations (GEE), lumbar spine vBMD was positively associated with BMI (r = 0.24, P < 0.0001) and inversely associated with age (r = -0.51, P < 0.0001). In women, age-adjusted thoracic spinal vBMD (mg/ml, mean +/- SE) was higher in diabetics (147.6 +/- 2.3) compared to unaffected individuals (138.6 +/- 3.4) (P = 0.02), with age-adjusted lumbar spinal vBMD showing a similar but non-significant trend (132.9 +/- 2.1 in diabetics vs. 127.2 +/- 3.6 in unaffected individuals, P = 0.15). In contrast, in men, age-adjusted lumbar and thoracic vBMD were not different between diabetics and unaffected controls (lumbar vBMD = 125.0 +/- 1.8 in diabetics and 125.8 +/- 5.6 in unaffected individuals, P = 0.89; thoracic vBMD = 137.4 +/- 2.1 in diabetics vs. 134.2 +/- 5.5 in controls, P = 0.56). After multivariate analysis adjusting for age, sex, race, BMI, physical activity, dietary intake, smoking, and alcohol use, interaction between diabetes status and trabecular vBMD of the spine was no longer observed. In women only, age-adjusted areal BMD (determined by dual X-ray absorptiometry (DXA)) of the spine and hip were significantly higher in diabetics than non-diabetic (all P < 0.05), although the differences disappeared after additional adjustment for BMI. These data suggest that areal BMD measured by DXA and trabecular volumetric BMD measured by QCT are not associated with type 2 diabetes independently from BMI.     

晚期糖基化终产物及其受体对大鼠阴茎海绵体组织中内皮素-1活性的影响

目的:通过观察大鼠阴茎海绵体组织中晚期糖基化终产物(AGEs)及其受体(RAGE)的变化对内皮素1(ET-1)活性的影响,探讨AGEs在糖尿病性勃起功能障碍(DMED)发生发展中的作用。方法:成年雄性SD大鼠60只,随机取40只用于制作糖尿病模型,造模后共27只大鼠成模,将其分为两组:糖尿病(DM)组15只和糖尿病+氨基胍给药(DM+AG)组12只;另20只大鼠平分为两组:正常对照(NC)组和正常对照+氨基胍给药(NC+AG)组;两组氨基胍(AG)给药组大鼠造模后即在其饮水中按1g/L剂量加入AG。饲养8周后取各组大鼠阴茎海绵体组织,一部分用于免疫组化法观察分析AGEs及其受体的分布和表达,剩余部分匀浆后检测AGE-肽(AGE-P)含量和ET-1活性。结果:DM组阴茎海绵体组织中AGEs和RAGE的表达、AGE-P含量及ET-1活性明显高于正常对照组(P<0.05);正常对照组与NC+AG组间比较在各项指标上则无明显差异(P>0.05)。结论:糖尿病状态下AGEs与RAGE的结合效应可以引起大鼠阴茎海绵体组织中ET-1活性的增强,从而促进DMED的发生发展。     

Microvascular complications in South African patients with long-duration diabetes mellitus.

OBJECTIVE: To determine the prevalence of microvascular complications in South African black and Indian patients with long-duration diabetes mellitus (DM). DESIGN: A retrospective analysis was undertaken of clinical records of 219 DM patients (132 black, 87 Indian) with long-duration DM (over 10 years) attending a diabetes clinic in Durban. Data recorded on each subject included demographic details (age, gender, ethnic group, type of diabetes, age of onset and duration of diabetes), presence of retinopathy, markers of nephropathy and biochemical variables. The prevalence of complications and the clinical and biochemical parameters were evaluated for type 1 and type 2 diabetes and for each ethnic group. RESULTS: Of the 219 patients, 47 had type 1 DM (36 blacks, 11 Indians) and 172 were classified as type 2 DM (96 blacks, 76 Indians). The mean age of onset of DM was later in blacks than Indians, both for type 1 (P < 0.05) and type 2 DM (P < 0.01). In patients with type 1 DM, the prevalence of retinopathy was 53.2% (blacks 55.6%, Indians 45.5%), persistent proteinuria was found in 23.4% (blacks 25%, Indians 18.2%) and hypertension in 34%. No ethnic difference was found except for the prevalence of hypertension which was higher in blacks than Indians (41.7% v. 9.1%, P < 0.5). Onset of retinopathy from time of diabetes diagnosis occurred earlier in blacks than Indians (13.0 +/- 4.6 yrs v. 18.0 +/- 4.6 yrs, P < 0.05). For the type 2 DM group, retinopathy was found in 64.5% (black v. Indian 68.8 v. 59.2%) and persistent proteinuria in 25% (black v. Indian 30.2 v. 18.4%). Hypertension was observed in 68% and was more prevalent in blacks (84.4 v. 47.4%, P < 0.01) There was an earlier onset of retinopathy (P < 0.05) and hypertension (P < 0.01) from time of diabetes diagnosis in blacks than Indians. In the type 1 DM group retinopathy was associated with a significantly longer duration of diabetes (P < 0.05) and higher glycated haemoglobin (HbA1) (P < 0.05). For type 2 DM subjects there was a significant association between retinopathy and longer duration of diabetes (P < 0.05) and higher systolic blood pressure (P < 0.05). CONCLUSION: This study has shown that there is a high prevalence of microvascular complications in South African patients with long-duration diabetes mellitus.     

止血相关参数对2型糖尿病和糖尿病肾病预测的临床意义

目的本研究旨在评估止血相关参数对2型糖尿病(type 2 diabetes mellitus,T2DM)和糖尿病肾病(diabetic nephropathy,DN)的预测价值。方法研究纳入96例T2DM患者分为两组,无并发症T2DM组(52例)和DN组(44例),同时纳入同期进行体检的50例性别、年龄匹配的健康人群作为对照组,测量各组基线实验室指标和止血相关参数,分析T2DM和DN的危险因素及其预测指标。结果无并发症的T2DM患者与对照组相比,活化部分促凝血酶原激酶时间(activated partial thromboplastin time,APTT)、血小板(platelets,PLT)和D-二聚体(D-Dimer,D-D)水平显著不同(P<0.01)。与没有并发症的T2DM患者相比,DN患者的纤维蛋白原(fibrinogen,FIB)、PLT和D-D增加(P<0.05)。APTT和PLT均为T2DM的独立危险因素(OR值分别为1.743、1.238,P<0.01),FIB和PLT是DN的独立危险因素(OR值分别为1.642、1.317,P<0.01)。APTT和PLT预测T2DM的ROC曲线下面积(area under curve,AUC)分别为0.601和0.642,且灵敏度较低。FIB取临界值3.15 g/L时预测DN的AUC为0.876,灵敏度(84%)和特异度(77%)较高,PLT取临界值245×109/L预测的DN的AUC为0.571,灵敏度为61%,特异度为89%。当联合FIB和PLT时,其预测DN能力增加(AUC:0.887,95%CI:0.841~0.937,灵敏度:91%,特异度:74%)。结论止血相关参数对T2DM的预测价值较低,而FIB是DN的独立危险因素,对DN有较高的预测价值。     

A hepatocyte nuclear factor-4 alpha gene (HNF4A) P2 promoter haplotype linked with late-onset diabetes: studies of HNF4A variants in the Norwegian MODY registry

Variants in hepatocyte nuclear factor (HNF)-4alpha cause maturity-onset diabetes of the young, type 1 (MODY1) and may also be risk factors for type 2 diabetes. We sequenced the HNF4A gene of 95 MODY3-negative probands from the Norwegian MODY Registry. We found three novel coding variants in exon 8 of HNF4A: G326R, T339I, and W340X. In intron 7, we noted a single nucleotide polymorphism in the binding site of a previously published primer pair, which in some cases caused allelic drop out when amplifying exon 8. We also detected two novel sequence variants of the P2 promoter region, of which P2 -192C>G showed linkage with diabetes in two families (maximal logarithm of odds score of 3.1 and 0.8, respectively). This variant and a surrounding haplotype restricted by 3.7 Mb was also found in two Danish MODY pedigrees. The age of onset was higher in the P2 -192C>G carriers (median 45 years) compared with that reported for other MODY1 individuals. We could not support a biological role of the P2 promoter variant by in vitro transfection assays. In conclusion, we have identified three novel HNF4A mutations and a 3.7-Mb haplotype, including the HNF4A P2 promoter, which was linked with diabetes.     

APOE polymorphisms and the development of diabetic nephropathy in type 1 diabetes: results of case-control and family-based studies

The goal of this study was to examine the association between known polymorphisms in the apolipoprotein E gene (APOE) and diabetic nephropathy (DN) in type 1 diabetes. We used both a case-control comparison and a family-based study design known as the transmission/disequilibrium test (TDT). For the case-control comparison, we collected DNA from 223 subjects with clinically diagnosed DN and 196 control subjects with normoalbuminuria and long-duration type 1 diabetes (> or = 15 years). For the family-based study, we obtained DNA from both parents of 154 DN subjects and 81 control subjects. The frequency of the epsilon2 allele of exon 4 of APOE was significantly higher in DN subjects than in control subjects. The risk of DN was 3.1 times higher (95% CI 1.6-5.9) in carriers of this allele than in noncarriers. In the family study, heterozygous parents for the E2 allele preferentially transmitted epsilon2 to DN offspring (64 vs. 36%, P < 0.03). Four additional polymorphisms (i.e., -491 A/T, -219 G/T, IE1 G/C, and APOCI insertion/deletion [I/D]) that flank the APOE locus were not associated with DN in either the case-control comparison or in the family-based study. In conclusion, the results of the case-control as well as the family-based study provide evidence that the epsilon2 allele of APOE increases the risk of DN in type 1 diabetes. The molecular mechanisms underlying this risk are unclear at present.     

Higher frequency of apolipoprotein E2 allele in type 2 diabetic patients with nephropathy in Taiwan

BACKGROUND: Diabetes is one of the major causes of end stage renal failure in Taiwan. Previous studies have indicated that lipid abnormalities might contribute to the development and progression of diabetic nephropathy (DN). Apolipoprotein E (apo E) regulates the metabolism of lipoproteins. Three different apo E alleles (epsilon2, epsilon3 and epsilon4) produce apo E isoproteins, apo E2, apo E3 and apo E4. Thus, the apo E gene polymorphism may be associated with DN. METHODS: To investigate the distribution of apo E genotype in type 2 diabetic Taiwanese, we examined 314 patients with type 2 diabetes (100 without nephropathy and 214 with nephropathy) and 150 age-matched normal controls. The diagnosis of nephropathy was made when daily protein loss exceeded 500 mg. The apo E gene polymorphism was analyzed by polymerase chain reaction. RESULTS: Our study found that the frequency of apo E2 allele was significantly higher in the diabetics with nephropathy- non-dialysis group (7.7%) and diabetics with nephropathy- dialysis group (7.7%) than in normal controls (1.7%) (p < 0.001) and diabetics without nephropathy (2.0%) (p < 0.01). The E3 and E4 allele frequencies were not significantly different among groups. CONCLUSION: These findings imply that apo E polymorphism is apparently related to the development of DN in type 2 diabetes in Taiwan.     

Haplotype combinations of calpain 10 gene polymorphisms associate with increased risk of impaired glucose tolerance and type 2 diabetes in South Indians

Haplotype combination 112/121 and its intrinsic variants (UCSNP43, -19, and -63) identified within the calpain 10 gene are associated with increased risk of type 2 diabetes in Mexican-Americans. We evaluated whether this haplotype combination and its constituent haplotypes and variants contribute to increased susceptibility to impaired fasting glucose (IFG)/impaired glucose tolerance (IGT) and type 2 diabetes in a South Indian population. Two study groups were used: 95 families ascertained through a proband with type 2 diabetes and 468 subjects recruited as part of an urban survey (69.1% with normal glucose tolerance, 12.8% with IFG/IGT, and 18.2% with type 2 diabetes). The four-locus haplotype combination 1112/1121 (UCSNP44, -43, -19, and -63) in South Indians conferred both a 10.7-fold increased risk for IFG/IGT (P = 0.001) and a 5.78- to 6.52-fold increased risk for type 2 diabetes in the two study groups (families P = 0.025, urban survey P = 0.015). A combination of the 1112 haplotype with the 1221 haplotype also appeared to increase risk for both IFG/IGT and type 2 diabetes. Contrary to what might be expected, quantitative trait analysis in the families found that transmission of the disease-related 1121 and 1112 haplotypes was associated with a reduced hip size and lower waist-to-hip ratio, respectively. This study supports the paradigm that specific haplotype combinations of calpain 10 variants increase risk of both IFG/IGT and type 2 diabetes. However, the relative infrequency of the "at-risk" combinations in the South Indian population suggests that calpain 10 is not a common determinant of susceptibility to type 2 diabetes.     

No evidence of association of ENPP1 variants with type 2 diabetes or obesity in a study of 8,089 U.K. Caucasians

Ectoenzyme nucleotide pyrophosphate phosphodiesterase 1 (ENPP1) is an inhibitor of insulin-induced activation of the insulin receptor. There is strong evidence from several previous studies that a common coding variant of ENPP1 (K121Q) and a three-marker haplotype (Q121, IVS20delT-11, and G+1044TGA) are associated with type 2 diabetes and obesity. We examined the impact of ENPP1 variation on type 2 diabetes and obesity in a large U.K. genetic association study. We genotyped the three previously associated polymorphisms in 2,363 type 2 diabetic case and 4,045 control subjects, as well as 1,681 subjects from 529 type 2 diabetic families. We used the same subjects for morbid and moderate obesity association studies. For type 2 diabetes, moderate and morbid obesity, and for both the Q121 and three-marker haplotype, our results exclude with >95% confidence the effect sizes from previous studies (Q121 allele: odds ratio 1.02 [95% CI 0.93-1.12], P = 0.61; 1.00 [0.85-1.18], P = 0.99; and 0.92 [0.70-1.20], P = 0.41; three-marker haplotype: 1.10 [0.96-1.26], P = 0.17; 0.97 [0.77-1.23], P = 0.81; and 0.86 [0.57-1.30], P = 0.46 for type 2 diabetes, moderate, and morbid obesity, respectively). A K121Q type 2 diabetes meta-analysis of all previously published studies remained significant after the inclusion of this study (1.25 [1.10-1.43], P = 0.0007), although there was some evidence of publication bias. In conclusion, we find no evidence that previously associated variants of ENPP1 are associated with type 2 diabetes or obesity in the U.K. population.     

Peroxisome proliferator-activated receptor alpha gene variation influences age of onset and progression of type 2 diabetes

Dysregulation of fatty acid metabolism is important in the pathogenesis of type 2 diabetes. Peroxisome proliferator-activated receptor (PPAR)alpha is a master regulator of fatty acid catabolism, and PPARalpha activators delay the onset of type 2 diabetes. We examined association between three PPARalpha gene polymorphisms (an A-->C variant in intron 1, the L162V variant, and the intron 7 G-->C variant) and age at diagnosis of type 2 diabetes in 912 Caucasian type 2 diabetic subjects. Individually, PPARalpha gene variants did not influence age at diagnosis, but in combination, the rare alleles of both the intron 1 A-->C (P < 0.001) and intron 7 G-->C (P = 0.025) variants synergistically lowered age at diagnosis (interaction P < 0.001). Overall, the PPARalpha haplotype signficantly influenced age at diagnosis (P = 0.027), with the C-L-C and C-V-C haplotypes (intron 1-L162V-intron 7) accelerating onset of diabetes by 5.9 (P = 0.02) and 10 (P = 0.03) years, respectively, as compared with the common A-L-G haplotype, and was associated with an odds ratio for early-onset diabetes (age at diagnosis 相似文献   

Analysis of clinical manifestations and outcomes of idiopathic membranous nephropathy compared with diabetic nephropathy in patients with type 2 diabetes

Objective To evaluate the predictive factors and renal outcomes of idiopathic membranous nephropathy (IMN) in patients with type 2 diabetes (T2DM). Methods In this retrospective study, clinical data of 101 IMN patients with T2DM and 96 patients with diabetic nephropathy (DN) were consecutively collected. Logistic regression was used to assess potential clinical factors indicating IMN and COX regression was employed to analyze risks of IMN in developing to end-stage renal disease (ESRD), as compared with that of DN, in patients with T2DM. Results In a multivariate model, age≥55 years old, presence of nephrotic syndrome, estimated glomerular filtration rate (eGFR)＞60 ml?min-1?(1.73 m2)-1, duration of diabetes≤5 years and absence of diabetic retinopathy, were associated with IMN, as compared with DN, in patients with T2DM. In T2DM patients presented with nephrotic syndrome, age≥55 years old, eGFR＞60 ml?min-1?(1.73 m2)-1, duration of diabetes≤5 years and absence of diabetic retinopathy, were also associated with IMN, as compared with DN. Receiver operating characteristic curve (ROC) showed eGFR 65.5 ml?min-1?(1.73 m2)-1 was an optimal cutoff in differentiating DN and IMN. DN was associated with 16.8 times as high risk of incident ESRD as compared with IMN in T2DM patients. Conclusions In patients with T2DM, age≥55 years, presence of nephrotic syndrome, early stage of CKD, duration of diabetes≤5 years and absence of retinopathy, may indicate IMN rather than DN. T2DM patients with IMN have much better renal prognosis as compared with DN.