Apolipoprotein E in childhood idiopathic nephrotic syndrome

Idiopathic nephrotic syndrome [INS] is one of the common renal disorders in childhood. Dyslipidemia is not only an important manifestation of INS, but is also involved in cardiovascular diseases and in progressive glomerular damage leading to renal failure. Apolipoprotein E [apo E] has been identified as an important candidate gene for lipid metabolism abnormalities. In the kidney, apo E gene mutation may play a role in aggravating the glomerular basement membrane lesion and promoting proteinuria. Our objective is to investigate the association of apo E serum level and genetic polymorphism [E[2], E[3], and E[4]] with responsiveness to steroid treatment as well as renal pathology in children with INS. Design: Case-control study. One study center at Center of Pediatric Nephrology and Transplantation [CPNT], Cairo University Children's Hospital. Forty seven pediatric patients with INS and 11 age and sex-matched controls were enrolled in the study, Twenty two of the patients had steroid-sensitive nephrotic syndrome [SSNS] and 25 had steroid-resistant nephrotic syndrome [SRNS]. Genomic DNA was extracted from children with INS and controls, and ape E genotype was determined by Real time-PCR analysis. The serum ape E, total cholesterol [TC], albumin, creatinine, and urine protein to creatinine ratio [UP/UCr] were also measured in both groups. Serum ape E was significantly higher in SRNS than SSNS [p=0.01] and controls [p=0.03]. Serum total cholesterol [TC] was significantly higher in SRNS than controls [p=0.028]. Significant positive correlation was found between serum apo E and UP/UCr [r=0.327, p=0.03]. Apo E[4] allele was only found in NS [8.5%] and absent in the control group. Apo E genotype E4E4 was found in one patient only in SRNS group with pathology of Focal segmental glomeruloscierosis [FSGS] while it was absent in SSNS and control groups, but this was not statistically significant. Heterozygous E[3]E[4] was only present in MS groups and not in control group [12% In SRNS and 13.64% in SSNS]. E[2]E[2] genotype was also found only in SRNS [4%] with the pathology of FSGS, which was not significant but the allelic frequency of E[2] was significantly higher in SRNS than SSNS [P=0.036]. E[3]E[3] was the most common genotype in the 3 groups and the allelic E[3] presentation was statistically higher in SSNS than in SRNS [P=0.04] The high frequency of E[4] only in nephrotic children and not in controls suggests that E[4] may share, as a genetic marker, in predisposition to childhood INS. The higher frequency of the E[2] allele in SRNS patients suggests that the E[2] allele gives a possible genetic predilection to steroid resistance in our population while the significantly higher E[3] in SSNS group may convey a readiness to steroid responsiveness related to E3, but further studies are needed to clarify this subject

Dnase I activity and gene polymorphism: role in SLE susceptibility and auto-antibody production

Previous studies have suggested that interrupted clearance of nuclear DNA-protein complexes after cell death might initiate and propagate systemic lupus erythematosus [SLE]. Deoxyribonuclease I [DNase I] may be responsible for the removal of DNA from nuclear antigens at sites of high cell turnover, thus preventing the onset of SLE. To investigate the association of serum DNase I activityand single nucleotide polymorphism [SNP]+2373A>G [Gln244Arg] of DNase I gene with susceptibility.to systemic lupus erythematosus [SLE] and the production of auto-antibodies to double-stranded DNA. A total of 42 SLE patients, all fulyilled the revised criteria of the American College of rheumatology for the diagnosis of SLE, were enrolled in the study and 17 healthy individuals with matching age and sex as a control group, 27 out of the 42 SLE patients had lupus nephritis proved by renal biopsy. DNase I gene+2373A>G SNP was studied by polymerase chain reaction followed by restriction fragment length polymorphism analysis. Serum DNase I activity [measured as percent of activity reduction;%AR] and anti-double-stranded DNA [anti ds-DNA] level were determined by solid phase enzyme immunoassay ELISA]. There was a significant decrease in DNase I enzyme activity [increase%AR] in the sera of SLE patients compared to the healthy individuals [p=O.000]. Anti ds-DNA antibody level was significantly higher in SLE patients compared to control group [p=0, 000]. There was a significant positive correlation between DNase I enzyme [%AR] and the level of anti ds-DNA antibody [r=0.596, p=0, 000]. Comparing the results of lupus patients with and without nephritis revealed an increase in both DNase enzyme%AR and the level of Anti ds-DNA antibody in the nephritis group but the difference is not statistically significant. There was no association of the+2373A>G SNP genotypes or alleles with SLE susceptibility. However SLE patients with GG genotype showed significant increase in both DNase I%AR [p=0.007] and anti ds-DNA body level [p=0.022] than those with AG and AA genotypes. The observed association of+2373A>G SNP of DNase I gene with DNase I activity and production of anti ds-DNA anti antibodies but not with SLE susceptibility calls into question how this SNP could contribute to SLE pathogenesis. A wider scale study with special emphasis on other auto-antibodies and genetic polymorphisms is recommended

Paraoxonase gene polymorphism and serum paraoxonase activity: relationship with type I diabetes and nephropathy

Human serum paraoxonase-I [PON1] is physically associated with high density lippprotein [HDL] and has been implicated in the prevention of LDL lipid peroxidation. PON1 gene displays several polymorphisms that influence both its level of expression and its catalytic activity. The goal of this study was to examine the association between paraoxonase-1 [PON1] activity and gene polymorphism and the micro-vascular complications in children and adolescence suffering from type 1 DM [TIDM]. Case-control study. One study centre at a University hospital. Thirty eight patients, with type 1 diabetes [n=38], 13 patients presenting with diabetic nephropathy [mean age 18.76 +/- 5.59 years. 8 males and 5 females] and 25 without diabetic nephropathy [mean age 14.48 +/- 3.69 years. 14 males and 11 females] and 16 healthy controls [mean age 12.38 +/- 8.25 years, 10 males and 6 females]. The allele variants of PON1 gene polymorphisms in the PON1 coding region Q192R and L55M have been identified by polymerase chain reaction followed by restriction fragment length polymorphism analysis. Serum PON1 enzyme activity was measured spectrophotometrically. Serum PON1 activity was significantly decreased in complicated diabetics when compared to both non-complicated patients and the control persons [103.33 +/- 35.46 nmol/ml/min, 462.57 +/- 200.69 nmol/ml/min and 1132 +/- 317.61 nmol/ml/min respectively]. As regards PON1 Q192R polymorphism, the R allele was more frequent in complicated diabetics versus both non-complicated diabetics and controls [p=0.0113 and p=0.001 respectively]. PON1 192QR genotype is a risk factor for developing type 1 diabetes OR=7.8; 95% CI [1.12-65.7] with p=0.043. PON1 192QR genotype and 192R allele are risk factors for developing micro-vascular complications with OR =6.40 and 4.00; 95% CI [1.44.28.29] and [1.15-13.87] with p=0.01 and 0.023 respectively. In PON1 L55M polymorphism, non significant differences in the genotype or allele frequency were found between T TIDM, both complicated and non-complicated diabetics and control persons. The association of PON1 Q192R polymorphisms, lower PON1 activity and poorer diabetic control found in patients with diabetic nephropathy further support an idea of genetic factors contributing to development of vascular complications in diabetes