Vitamin D receptor gene polymorphisms in chronic kidney disease Egyptian children: effect on biochemical markers of bone mineral disorders.

INTRODUCTION: The aim of this study was to assess the association between four vitamin D receptor (VDR) single nucleotide polymorphisms BsmI (rs1544410), ApaI (rs7975232), FokI (rs2228570) and TaqI (rs731236) and the susceptibility to chronic kidney disease (CKD) in Egyptian children and to evaluate their association with mineral status in these patients. MATERIAL AND METHODS: The current study included 305 patients with CKD and 100 apparently healthy children. We measured the serum vitamin D (VD), para-thyroid hormone (PTH) level and fibroblast growth factor 23 (FGF-23) levels by ELISA method. The genotyping of the four VDR gene variants was carried out by PCR-RFLP technique. RESULTS: The TaqI AG & the BsmI TT genotypes were associated with a significantly higher risk of CKD. The expression of 25-OH D serum level was decreased in patients with TaqI GG & AG genotypes groups and in patients with BsmI TT genotype group The expression of PTH serum level was increased in patients with BsmI CT genotype group. The expression of FGF-23 serum level was increased in patients with Taq1 AG genotype group. We found 3 specific haplotypes; AGCA, AGCC and GGCA for healthy controls. CONCLUSIONS: Our study showed an association between VDR TaqI, BsmI polymorphisms and the susceptibility to CKD. The existence of VDR vari-ants affected the protein expression of VD, FGF-23 and PTH. The AGCA, AGCC and GGCA haplotypes were considered as protec-tive factors against the development of renal nephropathy in our population.

Genetic polymorphisms in CLDN14 (rs219780) and ALP (rs1256328) genes are associated with risk of nephrolithiasis in Egyptian children.

OBJECTIVE: Nephrolithiasis results from metabolic and anatomic abnormalities together with genetic factors. Claudin 14 (CLDN14) is a protein that regulates the passage of small solutes through the kidneys. Alkaline phosphatase (ALPL) hydrolyzes the pyrophosphate to free phosphate, proposing its enabling role in nephrolithiasis development. Solute carrier family 13 member 2 (SLC13A2) encodes Na+-Pi cotransporter 2a, which is responsible for the renal absorption of phosphate. We aimed to detect the association between CLDN14, ALPL, and SLC13A2 genetic variants and susceptibility to nephrolithiasis in the Egyptian pediatric population. MATERIAL AND METHODS: We enrolled 204 consecutive pediatric patients with nephrolithiasis, and 126 normal individuals served as controls. Real-time polymerase chain reaction analysis of CLDN14 rs219780, ALPL rs1256328, and SLC34A1 rs11746443 single-nucleotide polymorphisms (SNPs) was performed. RESULTS: We found that individuals carrying the T allele of CLDN14 rs219780 and ALPL rs1256328 SNPs had a significantly higher risk of nephrolithiasis than the controls (p=0.001 and 0.001, respectively). Genetic association analyses identified that CLDN14 rs219780 and ALPL rs1256328SNPs were significantly associated with the nephrolithiasis status (odds ratio [OR] =4.51; 95% confidence interval [CI]=2.758-7.374; p=0.001 and OR=6.088; 95% CI=3.651-10.152; p=0.001, respectively). The sequence variant ALPL rs1256328 T allele had a significant correlation with the increased serum alkaline phosphatase levels in children with nephrolithiasis (p=0.02). No significant association was found between SLC34A1 rs11746443 SNP and the risk of nephrolithiasis (p=0.5). CONCLUSION: CLDN14 rs219780 and ALPL rs1256328 SNPs might raise the risk of nephrolithiasis in Egyptian children, and might be used as genetic markers in these patients.

Klotho G-395A gene polymorphism: impact on progression of end-stage renal disease and development of cardiovascular complications in children on dialysis.

BACKGROUND: Klotho G-395-A gene polymorphism may impact children with end-stage renal disease (ESRD). We investigated the relevance of Klotho G-395-A on ESRD development and progression, and its relationship with evolution of cardiovascular complications in pediatric dialysis patients. METHODS: Fifty-five children with chronic kidney disease (CKD) and seventy healthy children were genotyped for Klotho G-395A. RESULTS: Incidence of GA/AA genotypes and A allele were higher in ESRD patients compared with controls (54.5 vs. 7.1%, P < 0.001; 30.9 vs. 13.6%, P = 0.001, respectively). Also, children with GA/AA genotypes were 15.6 times more likely to develop ESRD than with GG genotype (95% CI 5.4-44.7, P < 0.001). A allele carriers have 2.8 times higher risk of developing ESRD than those with G allele (95% CI 1.5-5.35, P = 0.001). Also, the A allele could be considered a predictor of cardiovascular disease (CVD), as carriers have 161 times higher risk of cardiovascular complications than non-carriers (95% CI 21-1233, P < 0.001). All ESRD patients with CVD presented with left ventricular hypertrophy (LVH) and the frequency of A allele was significantly higher among ESRD children with LVH, whereas G allele frequency was significantly higher among ESRD children without LVH. CONCLUSIONS: The A allele of the G-395A Klotho gene polymorphism shows a significantly higher frequency among children with CKD and those with CVD and LVH. This mutant allele could be used as a risk marker for the development of ESRD as well as a predictor of CVD in these children.

Impact of Apo E gene polymorphism on HCV therapy related outcome in a cohort of HCV Egyptian patients.

The functional apolipoprotein E (Apo E) gene polymorphism could be used as a determinant of outcome of HCV infection. This study aimed to demonstrate the impact of Apo E genotype on the response to HCV combined therapy. MATERIAL AND METHODS: The study has been implemented on 125 individuals with persistent HCV infection and 120 cases with sustained virologic response (SVR). All participants were genotyped for ApoE gene polymorphism by a real-time quantitative PCR (qPCR). RESULTS: Statistically significant differences were demonstrated regarding the Apo E genotypes between the two groups (P-value < .001) where the frequency of E3E3 was significantly higher among the chronic HCV-patients while E3E4 and E4E4 genotypes frequencies were higher among the SVR-subjects group and E3E3 genotype was associated with increased risk of chronicity (OR 4.7; 95% CI 1.9-12.1, P-value < .001). Moreover, There were statically significant differences regarding E3 and E4 alleles frequencies, where E3 allele display a higher frequency among the chronic HCV-patient group while the SVR-subjects group showed higher frequency of E4 allele and the carriers of E3 allele have 1.4 times more risk to develop chronicity than those with E4 allele (OR 1.4; 95% CI 1.0-2.0, P-value < .05). Meanwhile the protective E2 allele was absent in all infected participants. CONCLUSION: This study supports the hypothesis of the protective impact of Apo E4 allele that favors viral clearance of HCV infection and its recovery after combined therapy, while the Apo E3 allele is considered as a particular risk factor for the chronicity in HCV patients and resistance to therapy. Whereas the Apo E2 allele confers a resistance to HCV infection at a time of exposure.

Expression of JAZF1, ABCC8, KCNJ11and Notch2 genes and vitamin D receptor polymorphisms in type 2 diabetes, and their association with microvascular complications.

BACKGROUND: We studied JAZF1, ABCC8, KCNJ11and Notch2 gene expression and vitamin D receptor (VDR) polymorphisms (Fok1 and Bsm1) in patients with type 2 diabetes mellitus (T2DM) and tried to find out their association with microvascular complications in these patients. METHODS: The study was conducted on 180 patients (93 complicated and 87 noncomplicated) and 150 healthy subjects. Reverse-transcriptase polymerase chain reaction (RT-PCR) was used to assess gene expression and real-time PCR was used to detect VDR genotypes. Serum vitamin D was assessed using Elisa technique. RESULTS: After adjustment for age, sex, body mass index and glycated hemoglobin, altered Notch2 gene expression was found between patients and controls and between complicated and noncomplicated cases (p = 0.001 and 0.001, respectively) and ABCC8 gene expression showed significant difference between patients and controls only (p = 0.003), while JAZF1and KCNJ11 expression showed no significant difference between the studied groups (p = 0.3 and 0.4, respectively). Serum vitamin D level was decreased in patients compared with controls (p = 0.001), while no difference was detected between complicated and noncomplicated cases (p = 0.1). Our results revealed no significant difference in VDR Fok1 and Bsm1 genotype distributions (p = 0.7 and 0.1, respectively) and allele frequencies (p = 0.4 and 0.1, respectively) between patients and controls. Patients with complications showed increased frequencies of Fok1GG genotype and G allele, while patients without complications showed increased frequencies of AA, then AG Fok1 genotype and A allele (p = 0.001 and 0.001, respectively). In addition, the frequencies of CC Bsm1 genotype and C allele were significantly higher among patients with complications, while frequencies of TT Bsm1 genotype and T allele were significantly higher among patients without complications (p = 0.02 and 0.003, respectively). CONCLUSION: Altered expression of Notch2 and ABCC8 genes may play a role in the pathogenesis of T2DM. Altered expression of Notch2 and VDR polymorphisms may play a role in the development of microvascular complications in diabetic patients. These results may assist in early identification and management of diabetic complications.

Interactive Effects of Immunoglobulin Gamma and Human Leucocyte Antigen Genotypes on Response to Interferon Based Therapy of Hepatitis C Virus.

AIM: We examined the role that immunoglobulin GM 23 and KM allotypes-genetic markers of γ and κ chains, respectively-play in response to treatment of hepatitis C virus (HCV) infection in Egyptian patients. MATERIAL AND METHODS: A total of 120 persons who had responded to HCV treatment and 125 with persistent HCV infection were genotyped for the presence of GM23 and KM determinants. HLA -C genotyping was also done. RESULTS: Association of GM 23+ and KM3 was significantly associated with non response to treatment (P < 0.0001). Individuals who lacked this GM genotype (but were positive for KM1,2 and 3) were likely to respond to treatment (P=0.045). Association of heterozygous GM23 (+/-) with KM 1,2 and 3 or KM3 alone was significantly associated with SVR (P = 0.001) and (P = 0.0001) respectively. Particular combinations of HLA and GM genotypes were associated significantly with the response to HCV treatment. The combination of HLAC2C2 and GM23+ was associated with persistence of infection (P = 0.027) while the association of HLAC2C2 and heterozygous GM23+/- was associated with SVR (P = 0.001). The association of HLAC1C1 and heterozygous GM23+/- was significantly associated with SVR (P = 0.001) and also subjects with HLA C1/C2 and heterozygous GM23+/- were likely to respond to treatment (P = 0.003) while subjects with HLA C1/C2 and GM23+ show tendency to resist to treatment (P = 0.0001). CONCLUSION: Our results didn't support a role for KM allotypes, GM23 allotype plays a role in the persistence of HCV infection in the presence or absence of KM1,3. Interaction between certain GM and HLA-C genotypes may favor adequate response to interferon based therapies.

Fetuin-A and Ghrelin Levels in Children with End Stage Renal Disease and the Effect of a Single Hemodialysis Session on Them.

BACKGROUND: Fetuin-A and ghrelin have been implicated in cardiovascular diseases and mortality among end stage renal disease patients. The exact mechanisms have not been fully elucidated. There is robust data supporting an association between ghrelin and various cardiovascular conditions, and some common processes such as inflammation, oxidative stress, and endoplasmic reticulum stress have been implicated. AIM: This study was conducted to assay serum fetuin-A and ghrelin in chronic renal failure pediatric patients and to study changes in their level that may occur after a single hemodialysis. MATERIAL AND METHODS: Forty nine pediatric patients suffering from ESRD on maintenance hemodialysis (HD), 20 patients with chronic renal failure (CRF) not on dialysis and 35 healthy subjects as control group were included. The mean age of the study population was 10.58 ± 3.94, 10.62 ± 3.24 and 10.61 ± 3.97 years respectively. Serum fetuin-A and plasma acyl ghrelin levels were measured by using ELISA method. RESULTS: The present study revealed that predialysis serum fetuin-A level was significantly increased in pediatric HD patients compared with the normal population, while ghrelin levels were significantly reduced. Furthermore, serum levels of fetuin-A decreased significantly after a single HD session. CONCLUSION: Our study concluded that fetuin-A and acyl ghrelin may play a role in inflammatory process among HD pediatric patients which may account for cardiovascular insults and mortality but their use as biochemical markers among ESRD pediatric patients have limitations due to wide fluctuations.

Association of TNF-α -308G/A, SP-B 1580 C/T, IL-13 -1055 C/T gene polymorphisms and latent adenoviral infection with chronic obstructive pulmonary disease in an Egyptian population.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a leading cause of disability and death. The most common cause of COPD is smoking. There is evidence suggesting that genetic factors influence COPD susceptibility and variants in several candidate genes have been significantly associated with COPD. In this study, we aimed to investigate the possible association of the TNF-α -308, SPB+1580, IL-13 -1055 gene polymorphisms and latent adenovirus C infection with COPD in an Egyptian population. MATERIAL AND METHODS: Our study included 115 subjects (75 smokers with COPD, 25 resistant smokers and 15 non-smokers) who were subjected to spirometric measurements, identification of adenovirus C and genotyping of TNF-α -308G/A, SP-B+1580 C/T and IL-13 -1055 C/T polymorphisms by real-time PCR. RESULTS: The adenovirus C gene was identified in all subjects. The distribution of TNF-α genotypes showed no significant differences between different groups. However, homozygous A genotype was associated with a significant decrease in FEV(1), FEV(1)/FVC and FEF25/75% of predicted in COPD (p < 0.05). As regards SP-B genotypes, resistant smokers had a significantly higher homozygous T genotype frequency compared to COPD and non smokers (p = 0.005). Interleukin 13 genotypes showed no significant difference between different groups. There was a significant decrease in FEF25/75% of predicted in T allele carriers in COPD patients (p = 0.001). CONCLUSIONS: The COPD is a disease caused by the interaction of combined genes and environmental influences, in the presence of smoking and latent adenovirus C infection, TNF-α -308A, SPB +1580 T and IL-13 -1055 T polymorphisms predispose to the development of COPD.