Functional polymorphisms in transforming growth factor-beta-1 (TGF -1) and vascular endothelial growth factor (VEGF) genes modify risk of renal parenchymal scarring following childhood urinary tract infection

Abstract

The risk of renal scar formation following urinary tract infection (UTI) varies markedly between individuals. We sought to investigate a possible role of the common polymorphisms in the gene encoding for VEGF and TGFbeta-1, key regulators of tissue repair, in renal scarring. Acute pyelonephritis was diagnosed in 104 children (63 males) aged 2 months to 12 years by urine culture and 99Tc-DMSA renal scan. A follow-up isotope scan was performed 4-6 months later to identify new renal scar formation. Vesicoureteral reflux (VUR) was examined by micturating cystourethrogram. Controls comprised 300 healthy children with no evidence of renal disease. Three single-nucleotide polymorphisms (SNPs) in the TGFbeta-1 (-800 A/G, -509 C/T and 869 C/T) and four SNPs in the VEGF gene (-2578 C/A, -1154 G/A, -460 T/C and +405 G/C) were genotyped in all subjects. Forty-six of the 104 patients developed renal parenchymal scarring (44.2%). VUR was found in 35.6%. The -509 T allele in the TGFbeta-1 promoter was significantly more common in cases with renal scarring (51%) than in non-scarring patients (22.4%) and controls (23.6%) (both P < 0.0001). At the haplotype level, the GTC combination at -800/-509/+869 was strongly associated with renal scarring (P = 0.0002). VEGF-460 CC was more common in UTI cases with renal scarring than in non-scarring patients and controls (P = 0.03 and 0.001, respectively). Multiple logistic regression testing identified the presence of VUR (odds ratio 12.4, CI 3.8-40; P < 0.001) and the TGFbeta-1 -509 T allele (OR 6.1, CI 2.4-15.5; P < 0.001) as independent risk factors for renal scarring after UTI. In contrast, age, gender and the type of underlying organism were not predictive of renal scarring. Activating variants in the TGFbeta-1 and VEGF gene promoters are associated with post-UTI renal scar formation in children. The TGFbeta-1 509T allele predicts renal scarring independent of VUR.