Meta-analysis of the relationship between ACE I/D gene polymorphism and end-stage renal disease in patients with diabetic nephropathy

Aims: Diabetic nephropathy (DN) is the major cause for end‐stage renal disease (ESRD) and the pathogenesis for DN developing into ESRD is not clear at present. Results from published studies on the relationship between angiotensin‐converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism and ESRD risk in DN patients are still conflicting. This meta‐analysis was performed to evaluate the association between ACE I/D gene polymorphism and ESRD risk in DN patients. Methods: Association studies were identified from the databases of PubMed, Embase and Cochrane Library on 1 October 2011, and eligible investigations were identified and synthesized using the meta‐analysis method. Results were expressed using odds ratios (OR) for dichotomous data and 95% confidence intervals (CI) were also calculated. Results: Twelve studies reporting the relation between ACE I/D gene polymorphism and ESRD risk in DN patients were identified. In overall populations, there was a notable association between D allele or DD genotype and ESRD susceptibility (D: OR = 1.32, 95% CI: 1.11–1.56, P = 0.002; DD: OR = 1.67, 95% CI: 1.25–2.21, P = 0.0004). In the sub‐group analysis according to ethnicity, D allele or DD genotype was associated with ESRD risk in Asians. In Caucasians, the association of DD genotype with ESRD risk was observed, but the D allele was not. Furthermore, ACE I/D gene polymorphism was associated with ESRD risk in patients with DN due to diabetes mellitus type 2, but the association was not found for patients with DN due to diabetes mellitus type‐1. Conclusions: Our results indicate that D allele or DD homozygous is associated with the ESRD susceptibility in DN patients. However, more investigations are required to further this association.     

Klotho Lacks an FGF23‐Independent Role in Mineral Homeostasis

Fibroblast growth factor‐23 (FGF23) is a bone‐derived hormone regulating vitamin D hormone production and renal handling of minerals by signaling through an FGF receptor/αKlotho (Klotho) receptor complex. Whether Klotho has FGF23‐independent effects on mineral homeostasis is a controversial issue. Here, we aimed to shed more light on this controversy by comparing male and female triple knockout mice with simultaneous deficiency in Fgf23 and Klotho and a nonfunctioning vitamin D receptor (VDR) (Fgf23/Klotho/VDR) with double (Fgf23/VDR, Klotho/VDR, and Fgf23/Klotho) and single Fgf23, Klotho, and VDR mutants. As expected, 4‐week‐old Fgf23, Klotho, and Fgf23/Klotho knockout mice were hypercalcemic and hyperphosphatemic, whereas VDR, Fgf23/VDR, and Klotho/VDR mice on rescue diet were normocalcemic and normophosphatemic. Serum levels of calcium, phosphate, and sodium did not differ between 4‐week‐old triple Fgf23/Klotho/VDR and double Fgf23/VDR or Klotho/VDR knockout mice. Notably, 3‐month‐old Fgf23/Klotho/VDR triple knockout mice were indistinguishable from double Fgf23/VDR and Klotho/VDR compound mutants in terms of serum calcium, serum phosphate, serum sodium, and serum PTH, as well as urinary calcium and sodium excretion. Protein expression analysis revealed increased membrane abundance of sodium‐phosphate co‐transporter 2a (NaPi‐2a), and decreased expression of sodium‐chloride co‐transporter (NCC) and transient receptor potential cation channel subfamily V member 5 (TRPV5) in Fgf23/Klotho/VDR, Fgf23/VDR, and Klotho/VDR mice, relative to wild‐type and VDR mice, but no differences between triple and double knockouts. Further, ex vivo treatment of live kidney slices isolated from wild‐type and Klotho/VDR mice with soluble Klotho did not induce changes in intracellular phosphate, calcium or sodium accumulation assessed by two‐photon microscopy. In conclusion, our data suggest that the main physiological function of Klotho for mineral homeostasis in vivo is its role as co‐receptor mediating Fgf23 action. © 2017 American Society for Bone and Mineral Research.     

Genetic Variation in Caveolin‐1 Correlates With Long‐Term Pancreas Transplant Function

Pancreas transplantation is a successful treatment for a selected group of people with type 1 diabetes. Continued insulin production can decrease over time and identifying predictors of long‐term graft function is key to improving survival. The aim of this study was to screen subjects for variation in the Caveolin‐1 gene (Cav1), previously shown to correlate with long‐term kidney transplant function. We genotyped 435 pancreas transplant donors and 431 recipients who had undergone pancreas transplantation at the Oxford Transplant Centre, UK, for all known common variation in Cav1. Death‐censored cumulative events were analyzed using Kaplan–Meier and Cox regression. Unlike kidney transplantation, the rs4730751 variant in our pancreas donors or transplant recipients did not correlate with long‐term graft function (p = 0.331–0.905). Presence of rs3801995 TT genotype (p = 0.009) and rs9920 CC/CT genotype (p = 0.010) in our donors did however correlate with reduced long‐term graft survival. Multivariate Cox regression (adjusted for donor and recipient transplant factors) confirmed the association of rs3801995 (p = 0.009, HR = 1.83;[95% CI = 1.16–2.89]) and rs9920 (p = 0.037, HR = 1.63; [95% CI = 1.03–2.73]) with long‐term graft function. This is the first study to provide evidence that donor Cav1 genotype correlates with long‐term pancreas graft function. Screening Cav1 in other datasets is required to confirm these pilot results.     

Association of single nucleotide polymorphisms in UBR2 gene with idiopathic aspermia or oligospermia in Sichuan,China

The associations between three single nucleotide polymorphisms (SNPs; rs3749897, rs16895863 and rs373341) of UBR2 gene and idiopathic aspermia or oligospermia were investigated in this study by a case–control experiment with 149 fertile and 316 infertile men, including 244 patients with idiopathic aspermia and 72 patients with severe oligospermia. The time‐of‐flight mass spectrometry (Sequenom MassARRAY^® system) was used in this study. A significant difference between the oligospermia men (oligospermia group) and the fertile men (control group) was observed in this research (odds ratio [OR]: 2.764; 95% CI: 95% confidence interval [CI]: 1.171–6.525; P = 0.017), which could indicate that the combined AT‐TC‐CC genotype in the UBR2 gene (rs16895863, rs373341, rs3749897 respectively) is a possible risk of idiopathic oligospermia for men in Sichuan, China.     

Impact of EGF,IL28B,and PNPLA3 polymorphisms on the outcome of allograft hepatitis C: a multicenter study

Hepatitis C virus (HCV) infection is accelerated following liver transplantation (LT). Single nucleotide polymorphisms (SNPs) near the epidermal growth factor (EGF) (rs4444903), IL28B (rs12979860), and PNPLA3 (rs738409) loci are associated with treatment response, fibrosis, and hepatocellular carcinoma in non‐transplant hepatitis C, but allograft population data are limited. We sought to determine the role of these SNPs in 264 patients with HCV who underwent LT between 1990 and 2008. Genotypes were determined from donor wedge/allograft biopsies and recipient explants. Cox proportional hazards model was used to assess time to cirrhosis, liver‐related death, and retransplantation, adjusting for donor age and sustained virological response (SVR). Over a median follow‐up of 6.3 yr, a trend toward increased progression to graft cirrhosis was observed among recipients of an EGF non‐AA vs. AA donor liver (adjusted HR 2.01; 95% CI 0.93–4.34; p = 0.08). No other genotypes predicted cirrhosis development or graft survival. The CC IL28B variant in both recipients and donors was associated with increased rate of SVR (R‐CC/D‐CC 8/12[67%], R‐non‐CC/D‐CC or R‐CC/D‐non‐CC 23/52[44%], R‐non‐CC/D‐non‐CC 12/45[27%], p linear trend = 0.009). Recipient EGF, IL28B, and PNPLA3, and donor IL28B and PNPLA3 genotypes do not predict adverse outcomes in HCV LT recipients. A potential association exists between donor EGF genotype and cirrhosis.     

Investigation of PNPLA3 and IL28B Genotypes on Diabetes and Obesity After Liver Transplantation: Insight Into Mechanisms of Disease

To identify genetic risks for obesity and diabetes postliver transplantation (LT), LT recipients underwent genotyping for IL28B rs12979860 (n = 295) and PNPLA3 rs738409 (n = 205) polymorphism in both donors and recipients. The development of obesity and diabetes/impaired fasting glucose (IFG) was determined 1–5 years post‐LT. Recipient PNPLA‐3 genotype was independently associated with obesity (BMI > 30) at 3 years posttransplant (genotype CC 33.7%, CG 48.3% and GG 82.4%, p = 0.002), with an odds ratio (OR 2.54, CI 1.38–4.66, p = 0.003), associated with the G allele. Diabetes/IFG diagnosed within 5 years posttransplant associated with PNPLA‐3 non‐CC genotype (HR 1.59, 1.12–2.26, p = 0.010), but not IL28B TT genotype (HR 1.46, 0.94–2.27, p = 0.092). No genotype variable was independently predictive of diabetes/IFG. The combination of PNPLA‐3 non‐CC and IL28B TT genotype was associated with increased risk of diabetes/IFG compared to PNPLA‐3 CC, IL28B non‐TT (HR 2.64, CI 1.30–5.39, p = 0.008). Donor genotypes were not associated with any of the outcomes analyzed. In conclusion, PNPLA‐3 non‐CC genotype is associated with posttransplant obesity but not independently with diabetes/IFG. The lack of donor related risk suggests a peripheral rather than central mechanism of insulin resistance in liver transplant recipients.     

The association of genes involved in the angiogenesis‐associated signaling pathway with risk of anterior cruciate ligament rupture

Angiogenesis‐associated signaling is a fundamental component in the remodeling of the extracellular matrix in response to loading. Genes encoding protein components within this signaling cascade are therefore suitable candidates for investigation into ACL injury susceptibility: namely, vascular endothelial growth factor A isoform (VEGFA), kinase insert‐domain receptor (KDR), nerve growth factor (NGF), and hypoxia inducible factor‐1α (HIF1A). A case‐control genetic association study was conducted on 227 asymptomatic control participants and 227 participants with surgically diagnosed ACL ruptures of which 126 participants reported a non‐contact mechanism of rupture. All participants were genotyped for seven polymorphisms within the four genes. The VEGFA rs699947 CC genotype (p = 0.010, OR: 1.92, 95% CI: 1.17–3.17) was significantly over‐represented within participants with non‐contact ACL ruptures. The VEGFA rs1570360 GA genotype was significantly over‐represented in the CON group (p = 0.007, OR: 1.70, 95% CI: 1.16–2.50). Furthermore, the KDR rs2071559 GA genotype was significantly over‐represented in the female controls (p = 0.023, OR: 2.16, 95% CI: 1.11–4.22). Inferred haplotype analyses also implicated genomic regions spanning the VEGFA and KDR genes. These novel findings suggest that regions within VEGFA and KDR may be implicated in the pathophysiology of ACL ruptures; highlighting the potential biological significance of angiogenesis‐associated signaling in the aetiology of ACL ruptures. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:1612–1618, 2014.     

Elevated FGF 23 and phosphorus are associated with coronary calcification in hemodialysis patients

Increased mortality of adult chronic hemodialysis (HD) patients is associated with coronary calcifications (CC), increased serum phosphorus (P), use of calcium (Ca)-containing P-binders, and vitamin D deficiency. Serum concentration of fibroblast growth factor 23 (FGF 23) is markedly elevated in adults receiving dialysis and is independently associated with increased mortality. Although coronary calcifications have been described in pediatric and adult HD patients, no significant association between serum FGF 23 and CC has been reported. In our study, 5/16 patients had CC. Patients with CC were older, had longer dialysis vintage and higher serum P. Serum Ca, total PTH, elemental Ca intake, and calcitriol doses were not different for CC patients. Serum FGF 23 levels were markedly elevated in all patients (mean 4,024, range 874–8,253), but significantly higher in patients with CC (4,247 ± 10,35 vs 2,427 ± 11,92, p = 0.01) and positively correlated with Agatston calcification score (r = 0.69, p = 0.003) and serum P (r = 0.49, p = 0.05). Using multivariate analysis, serum FGF 23 and serum P remained the most significant factors associated with Agatston score. This study confirms the occurrence of CC in pediatric HD patients and is the first to show a significant association between CC and elevated serum FGF 23 in children.     

Genetic association of FOXP3 gene polymorphisms with allograft rejection in renal transplant patients

Aim: FOXP3 gene is known to be important for regulatory T cell development and function, and is associated with the rejection of human kidney transplants. The present study was therefore conducted to determine the effect of FOXP3 polymorphisms on allograft rejection in renal transplant recipients. Methods: A total of 166 adult patients were categorized into either a Rejection group (65 patients) or a No rejection group (101 patients). Rs3761547, rs3761548 and rs2232365 variant alleles in the FOXP3 gene were genotyped using a TaqMan probe technique, and their relationships with rejection were investigated. Results: There was no significant difference in the genotype frequencies of rs3761547 and rs2232365 variants between patients with and without rejection history (P > 0.05). Binary logistic regression analysis showed that the rs3761548 AA genotype carriers were associated with about a fourfold greater risk for rejection compared with CC genotype (5 years post‐transplant: odds ratio 3.95, 95% confidence interval 1.27–12.29, P = 0.018). Kaplan–Meier analysis revealed a lower mean time to the first rejection in rs3761548 AA compared with CC genotype patients (Log rank = 4.303, P = 0.038). Multivariate Cox regression analysis indicated that rs3761548 AA genotype carriers have up to about a twofold (hazard ratio 2.37, 95% confidence interval 1.17–4.80, P = 0.017) higher risk for rejection than CC carriers. Conclusion: Our study suggests an association between FOXP3 rs3761548 polymorphisms and allograft rejection in renal transplantation. This association should be further proven in large prospective studies because of the small sample size and confounding factors in this retrospective study.     

Survival analysis of pediatric dialysis patients in Taiwan

Aim: The long‐term survival of Taiwanese children with end‐stage renal disease (ESRD) has not been reported before. This study aimed to determine the long‐term survival, mortality hazards and causes of death in paediatric patients receiving dialysis. Methods: Paediatric patients (aged 19 years and younger) with incident ESRD who were reported to the Taiwan Renal Registry from 1995 to 2004 were included. A total of 319 haemodialysis (HD) and 156 peritoneal dialysis (PD) patients formed the database. After stratification by dialysis modality, multivariate Cox proportional‐hazards model was constructed with age, sex and co‐morbidity as predictive variables. Results: The annual paediatric ESRD incidence rate was 8.12 per million of age‐related populations. The overall 1‐, 5‐, and 10‐year survival rates for PD patients were 98.1%, 88.0% and 68.4%, respectively, and were 96.9%, 87.3% and 78.5% for HD patients. The survival analysis showed no significant difference between HD and PD (P = 0.4878). Using ‘15–19 years’ as a reference group, the relative risk (RR) of the youngest group (0–4 years) was 6.60 (95% CI: 2.50–17.38) for HD, and 5.03 (95% CI: 1.23–20.67) for PD. The death rate was 24.66 per 1000 dialysis patient‐years. The three major causes of death were infection (23.4%), cardiovascular disease (13.0%) and cerebrovascular disease (10.4%). Hemorrhagic stroke (87.5%) was the main type of foetal cerebrovascular accident. Conclusion: We conclude that there was no significant difference of paediatric ESRD patient survival between HD and PD treatment in Taiwan. The older paediatric ESRD patients had better survival than younger patients.     

Activated injectable vitamin D and hemodialysis survival: a historical cohort study

Patients with ESRD commonly experience secondary hyperparathyroidism, a condition primarily managed with activated injectable vitamin D. The biologic effects of vitamin D, however, are widespread, and it is possible that activated injectable vitamin D alters survival in ESRD. This hypothesis was tested in a historical cohort study of incident hemodialysis patients who lived throughout the United States between January 1996 and December 1999. The primary outcome was 2-yr survival among those who survived for at least 90 d after initiation of chronic hemodialysis. During this period, 51,037 chronic hemodialysis patients survived for at least 90 d from the initiation of hemodialysis, and in the ensuing 2 yr, 37,173 received activated injectable vitamin D and 13,864 did not. At 2 yr, mortality rates were 13.8/100 person-years in the group that received injectable vitamin D compared with 28.6/100 person-years in the group that did not (P < 0.001). Cox proportional hazards analyses adjusting for several potential confounders and examining injectable vitamin D therapy as a time-dependent exposure suggested that compared with patients who did not receive injectable vitamin D, the 2-yr survival advantage associated with the group that did receive injectable vitamin D was 20% (hazard ratio, 0.80; 95% confidence interval, 0.76 to 0.83). The incidence of cardiovascular-related mortality was 7.6/100 person-years in the injectable vitamin D group, compared with 14.6/100 person-years in the non-vitamin D group (P < 0.001). The benefit of injectable vitamin D was evident in 48 of 49 strata examined, including those with low serum levels of intact parathyroid hormone and elevated levels of serum calcium and phosphorus, situations in which injectable vitamin D is often withheld. Repeating the entire analysis using marginal structural models to adjust for time-dependent confounding by indication yielded a survival advantage of 26% (hazard ratio, 0.74; 95% confidence interval, 0.71 to 0.79) associated with the injectable vitamin D group. In this historical cohort study, chronic hemodialysis patients in the group that received injectable vitamin D had a significant survival advantage over patients who did not. Randomized clinical trials would permit definitive conclusions.     

Polymorphism in methylenetetrahydrofolate reductase gene: its impact on plasma homocysteine levels and carotid atherosclerosis in ESRD patients receiving hemodialysis

The methylenetetrahydrofolate reductase (MTHFR) gene polymorphism has been shown to be associated with cardiovascular disease in healthy subjects as well as in patients with end-stage renal disease (ESRD). In this study, we examined the allelic frequency and genotype distribution of the MTHFR gene in 151 Chinese ESRD patients receiving hemodialysis and 135 healthy controls. In addition, we investigated the relationship between the MTHFR gene polymorphism and the plasma homocysteine (Hcy) level as well as the intima-media thickness of common carotid artery (CC-IMT) in these patients. The allelic frequency of the MTHFR gene with the C677T mutation in ESRD patients was 24.5% and that in healthy controls was 23%. Mean plasma Hcy level of the ESRD patients (23.1 +/- 7.4 micromol/l) was significantly higher than that of the controls (10.1 +/- 5.0 micromol/l), but did not correlate with vitamin B(6) and vitamin B(12) status. Moreover, the extent of hyperhomocysteinemia was genetically affected by the C677T mutation of the MTHFR gene. The plasma Hcy levels for the patients with the CC, CT and TT genotypes of the MTHFR gene were 22.3 +/- 6.8, 22.8 +/- 7.3, and 28.3 +/- 2.8 micromol/l, respectively. In addition, we found that the patients bearing the TT genotype had the highest CC-IMT (0.93 +/- 0.07 mm), whereas the lowest values (0.79 +/- 0.13 mm) were observed in those who had the CC genotype. One-way ANOVA showed that the CC-IMT in the patients with the TT genotype was significantly greater than that of the patients with the CC genotype (p < 0.05). Moreover, the mean CC-IMT of the patients carrying either TT or CT genotype of the MTHFR gene was significantly higher than that of the patients bearing the CC genotype (0.86 +/- 0.14 vs. 0.79 +/- 0.13 mm, p = 0.002). Multiple regression analysis, in which the change in CC-IMT was used as the dependent variables, identified age, smoking, the MTHFR genotype (CC = 0, CT = 1, TT = 2) and diabetes mellitus as the independent variables significantly associated with the increase of CC-IMT (p < 0.001). These risk factors jointly explained 43.9% of the CC-IMT variation and age explained most of the variation (R(2) = 0.34). We conclude that both the TT genotype and the T allele of the MTHFR gene are associated with the increase of CC-IMT in hemodialysis patients. The C677T mutation of the MTHFR gene may be an independent risk factor that predicts the development of carotid atherosclerosis in ESRD patients.     

Post–hip fracture use of prescribed calcium plus vitamin D or vitamin D supplements and antiosteoporotic drugs is associated with lower mortality: A nationwide study in Finland

We previously found a positive association between calcium plus vitamin D and antiosteoporotic drugs and survival among hip fracture patients. Our aim was to verify this observation using a nationwide database. A retrospective cohort of home‐discharged hip fracture patients aged 50 years or older (n = 23,615) was enrolled from the national database. Primary exposure was medical treatment for osteoporosis, and the outcome was all‐cause mortality. Cumulative mortalities were calculated using the Kaplan‐Meier estimator. The relationship between mortality and medication purchases was modeled using Cox's proportional hazards regression with time‐dependent covariates for medication use. One in 4 women and 1 in 10 men with a hip fracture were treated for osteoporosis in Finland. Unadjusted 1‐year mortality was lower among patients who purchased calcium plus vitamin D or vitamin D supplements and antiosteoporotic drugs than among those who did not purchase these medications [hazard ratio (HR) = 0.74, 95% confidence interval (CI) 0.67–0.81]. The difference in unadjusted cumulative mortality remained in favor of the drug users for at least 5 years. Among men, the use of calcium plus vitamin D or vitamin D supplements was associated with lower 1‐year mortality even after adjustments for observed confounders (HR = 0.74, 95% CI 0.56–0.97). Among women, the use of antiosteoporotic drugs was associated with lower mortality (HR = 0.79, 95% CI 0.67–0.93). There was a tendency to even better survival in both genders if calcium plus vitamin D or vitamin D supplements and antiosteoporotic drugs were used simultaneously, the HR being 0.72 (95% CI 0.50–1.03) in men and 0.62 (95% CI 0.50–0.76) in women. © 2011 American Society for Bone and Mineral Research     

Association Between Attributed Cause of End-Stage Renal Disease and Risk of Death in Brazilian Patients Receiving Renal Replacement Therapy

Background. Studies conducted in several countries have indicated that the survival of patients undergoing renal replacement therapy (RRT) depends on the attributed cause of end-stage renal disease (ESRD). Objectives. This study was conducted to evaluate the association between attributed cause of ESRD and mortality risk in RRT patients in Brazil. Methods. We analyzed 88,881 patients from the Brazilian Ministry of Health Registry who were undergoing RRT between April 1997 and July 2000. Cox proportional hazards models were used to estimate the relative risk (RR) of death in patients with ESRD secondary to diabetes mellitus (DM), polycystic kidney disease (PKD), and primary glomerulopathies (GN) compared with a reference group comprised of patients with ESRD caused by hypertensive nephropathy. Patient's age, gender, and length of time (years) in RRT before inclusion in the registry (vintage) were included in the adjusted Cox model. Results. Compared with the reference group, the mortality risk was 27% lower in patients with PKD (RR = 0.73, 95% CI: 0.65–0.83, p< 0.0001); 29% lower in patients with GN (RR = 0.71, 95% CI: 0.68–0.74, p< 0.0001); and 100% greater in DM patients (RR = 2.00, 95% CI: 1.92–2.10, p< 0.0001). These relative risks remained statistically significant after adjustment for age, gender, and length of time in RRT before inclusion in the registry. Conclusions. Our data indicate that compared with the patients with hypertensive nephrosclerosis as attributed cause of ESRD, patients undergoing RRT in Brazil with idiopathic glomerulopathy and polycystic kidney disease have a lower risk of mortality, and patients with diabetes mellitus have a greater risk of mortality.     

Vitamin D receptor genetic variants among patients with end-stage renal disease

Back ground and objectives: Vitamin D receptor (VDR) gene polymorphism is reported to be associated with end-stage renal disease (ESRD). We have investigated the potential role of VDR gene polymorphisms among ESRD. Design and methods: The influence of VDR gene polymorphism in 258 ESRD patients comprising of 226 (87.5%) male and 32 (12.5%) females was investigated in this study. We compared ESRD patients with 569 healthy controls. The distribution of male and female among controls was 485 (85.3%) males and 84 (14.7%) females. This polymorphism was studied by using polymerase chain reaction (PCR). The product was digested by using restriction enzymes Apa1, Taq1, Fok1, and Bsm1. Results: We observed a significant difference in the genotype frequencies of the Apa1-aa (p = 0.0001, OR = 2.1, 95% CI = 1.45–3.08), Fok1-ff (p = 0.001, OR = 3.44, 95% CI = 1.76–6.76), and Bsm1-BB (p = 0.0004, OR = 6.8, 95% CI = 2.2–21.58). At allelic level B allele of Bsm1 was significantly different among ESRD patients as compared to controls (p = 0.0001). The combined analysis revealed that ESRD patients with Fok1 and Bsm1 polymorphism were at increased risk of 4.33-fold. The haplotype analysis revealed individuals with a/t/F/b haplotype were at greater risk of 11.0-fold (95% CI = 1.38–87.69). The serum calcium levels were significantly higher (p = 0.001) in Bsm1 “BB” genotype. Interpretations and conclusions: Bsm1 and Fok1 gene polymorphism of VDR gene were associated with ESRD among north Indians.     

Glycated albumin levels predict long-term survival in diabetic patients undergoing haemodialysis

Aim: Glycated albumin (GA) is recognized as a reliable marker for monitoring glycemic control particularly in patients with end‐stage renal disease (ESRD). Here, we investigated the impact of GA levels on long‐term survival in diabetic patients with ESRD. Methods: We enrolled ESRD patients with diabetic nephropathy into our single‐centre prospective follow‐up study (n = 98, 66 men and 32 women; age 68.2 12.3 years) with a mean follow‐up period of 47.7 months. All patients had started haemodialysis between December 1992 and November 2003. They were categorized into two groups according to their GA levels at the initiation of haemodialysis; GA < 29% (low‐GA group; n = 54) and GA 29% (high‐GA group; n = 44). Results: Between low‐GA and high‐GA groups, there were no significant differences in various clinical parameters except GA and HbA1c levels. The cumulative survival rate of low‐GA group was significantly higher than that of high‐GA group (P = 0.034, log–rank test). After adjustment for age, sex, total cholesterol, C‐reactive protein and albumin, high‐GA was a significant predictor of survival (hazard ratio 1.042 per 1.0% increment of GA, 95% CI 1.014–1.070, P < 0.05), but not in the case with HbA1c. Cox proportional hazard model demonstrated that high‐GA group was a significant predictor for cardiovascular death (hazard ratio 2.971 (1.064–8.298), P = 0.038). Conclusion: We conclude that poor glycemic control (GA 29%) before starting haemodialysis is associated with increased cardiovascular morbidity and shortened survival in diabetic patients with ESRD.     

Rapidity of fibrosis progression in liver transplant recipients with recurrent hepatitis C is influenced by toll‐like receptor 3 polymorphism

Liver transplantation activates the innate immune system through toll‐like receptors (TLRs), potentially leading to allograft rejection and graft failure. We evaluated the association of single‐nucleotide polymorphisms in TLR genes with the severity of hepatitis C virus recurrence after liver transplantation (LT). This is a two‐center study of 176 adult patients who received a first LT from deceased donors for hepatitis C virus (HCV) cirrhosis. Eleven polymorphisms were evaluated by real‐time polymerase chain reaction and melting curves analyses: TLR1 (Asp248Ser and Ser602Ile), TLR2 (Arg753Gln), TLR3 (Leu412Phe), TLR4 (Asp299Gly), TLR5 (Arg392Stop), TLR6 (Ser249Pro), TLR7 (Gln11Leu), TLR8 (Met1Val), and TLR9 (−1237T/C and −1486C/T). The CC genotype of TLR3 Leu412Phe in liver recipients was associated with severe recurrence (odds ratio (OR) = 2.01, 95% confidence interval (95% CI) = 1.02‐3.93, p = 0.04). We also analyzed this polymorphism in 72 of their donors but no association was found with severity of HCV recurrence (p = 0.89). Multivariate analysis showed donor age older than 40 yr (OR=2.93; 95% CI = 1.49–5.8, p = 0.002) and the TLR3 Leu412Phe CC genotype (OR=2.02, 95%CI=1.01–4.05, p = 0.046) were independently associated with severe HCV recurrence. Our results show that the TLR3 Leu412Phe CC genotype is independently associated with severity of hepatitis C recurrence after LT.     

Association between MTHFR C677T polymorphism and diabetic nephropathy in the Chinese population: An updated meta‐analysis and review

To clarify the effects of MTHFR C677T polymorphism on the risk of diabetic nephropathy (DN) in the Chinese population, an updated meta‐analysis was performed. Related studies were identified from PubMed, Springer Link, Ovid and Chinese Databases up to 24 February 2015. A total of 15 studies including 1227 DN cases, 586 healthy controls and 1277 diabetes mellitus (DM) controls were involved in this meta‐analysis. Overall, a significantly elevated risk of DN was associated with all variants of MTHFR C677T when compared with the healthy group (T vs C, odds ratio (OR) = 2.22, 95% confidence interval (CI) = 1.88–2.61; TT vs CC, OR = 4.22, 95% CI = 3.02–5.90; TT + CT vs CC, OR = 2.62, 95% CI = 2.07–3.31; TT vs CC + CT, OR = 2.81, 95% CI = 2.08–3.81) or DM (T vs C, OR = 1.78, 95% CI = 1.59–2.00; TT vs CC, OR = 2.95, 95% CI = 2.33–3.73; TT + CT vs CC, OR = 1.93, 95% CI = 1.63–2.29; TT vs CC + CT, OR = 2.31, 95% CI = 1.87–2.84). In subgroup analyses stratified by ethnicity and geographic areas, it revealed the significant results in Chinese Han, in North and South China. The risk conferred by MTHFR C677T polymorphism is higher in North China than in South China. This meta‐analysis showed that the MTHFR C677T variants may influence DN risk in Chinese, and further studies with gene–gene and gene–environment interactions are required for definite conclusions.