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Genetic polymorphism in paraoxonase is a risk factor for childhood focal segmental glomerulosclerosis
Y Frishberg1, H Toledano, R Becker-Cohen
1Division of Pediatric Nephrology, Department of Surgery A and Cancer Cell Research Laboratory, Shaare Zedek Medical Center and Hadassah-Hebrew University School of Medicine, Jerusalem, Israel. yaacov@md2.huji.ac.il
Insights
Genetic variations in the PON1 gene, specifically homozygosity for the L allele, are linked to a higher risk and worse prognosis of focal segmental glomerulosclerosis (FSGS) in Arab children.
Area of Science:
- Nephrology
- Genetics
- Biochemistry
Background:
- Focal segmental glomerulosclerosis (FSGS) is a leading cause of pediatric end-stage renal failure.
- Arab children in Israel exhibit a poorer FSGS prognosis than Jewish patients.
- Lipid metabolism alterations and mechanisms similar to atherosclerosis are implicated in glomerulosclerosis progression.
Purpose of the Study:
- To investigate the frequency of two genetic polymorphisms in the Paraoxonase (PON1) gene in Arab and Jewish children with FSGS.
- To determine if these PON1 polymorphisms are associated with FSGS severity and outcome.
Main Methods:
- Studied 47 children with biopsy-proven FSGS (21 Arab, 26 Jewish) and 274 healthy controls.
- Analyzed PON1 gene polymorphisms: glutamine (A)-192-arginine (B) and methionine (M)-55-leucine (L).
- Compared allele and genotype frequencies between ethnic groups and patient/control cohorts.
Main Results:
- Allele frequencies for A and L were similar between FSGS patients and controls.
- The LL genotype prevalence was significantly higher in Arab FSGS patients compared to Jewish patients and Arab controls.
- A trend suggested an association between LL genotype (homozygosity for L allele) and renal disease progression in Arab children.
Conclusions:
- Homozygosity for the PON1 L allele is a risk factor for developing FSGS in Arab children.
- This genetic factor may also be associated with a worse prognosis for FSGS in this population.
- Highlights potential ethnic disparities in genetic predisposition to FSGS.
Abstract:
Focal segmental glomerulosclerosis (FSGS) is an important cause of end-stage renal failure (ESRF) in children. Our previous studies have shown that Arab children in Israel have a worse prognosis compared with Jewish patients despite similar clinical presentation and management. Progression of proteinuric glomerular diseases has been associated with alterations in lipid metabolism, and similarities have been drawn between the mechanisms underlying atherosclerosis and glomerulosclerosis. Paraoxonase (PON) is a high-density lipoprotein (HDL)-associated enzyme involved in preventing the oxidation of low-density lipoprotein (LDL), and an association has been shown between two genetic polymorphisms in PON1 and the risk of coronary artery disease. The aim of this study was to determine the frequency of these genetic polymorphisms in PON1 in Arab and Jewish children with FSGS and to determine any association with severity of outcome. Forty-seven children (21 Arab and 26 Jewish) with biopsy-proven FSGS and 274 healthy controls of matching ethnic origin were studied. The glutamine (A)-192-arginine (B) and the methionine (M)-55-leucine (L) polymorphisms were analyzed. The frequency of the A allele was similar in patients and controls (0.68 versus 0.71), as was that of the L allele (0.63 versus 0.6). When subgroups were analyzed, the prevalence of the LL genotype in Arab patients was significantly greater than in Jewish patients (57.1% versus 26.9%, P: < 0.05) and Arab controls (57.1% versus 28.9%, P: < 0.03). A trend in association was found between homozygosity for the L allele and progression of renal disease in Arab children. Homozygosity for the L allele is a risk factor for developing FSGS in Arab children and may be associated with a worse prognosis.