Impact of cytokine genetic polymorphisms on the risk of renal parenchymal infection in children

Abstract

Acute pyelonephritis is associated with renal scarring in up to 30% of patients. Renal scarring may cause significant long-term morbidity. The pathogenesis of acute pyelonephritis remains unclear, although it involves interaction among uroepithelium, the immune system cells, and the locally produced cytokines. That some UTI-prone children develop acute pyelonephritis, and eventually renal parenchymal scarring, suggests a genetic role. Interleukin-6, interleukin-8, chemokine receptor-1 (CXCR1), and tumor necrosis factor-alpha (TNFα), the key regulators of the host immune responses, are proteins whose secretion is controlled by genes. We postulated that functional polymorphic variants of their genes might have a role in APN susceptibility. We sought to investigate a possible association of the common functional polymorphisms in genes encoding IL-6, IL-8, CXCR1, and TNFα with the risk of APN in children. Urine culture was used to diagnose 300 children with UTI, of mean age of 51.31±37.4 months (2-180 months). 99Tc-DMSA scans diagnosed 86 children with APN. Follow-up scans identified new renal scars in 18 children. Six functional single-nucleotide polymorphisms (SNPs) in genes encoding IL-6, IL-8, CXCR1, and TNFα were genotyped in all subjects (IL-6 rs1800795 (-174G/C), IL-6 rs1800796 (-572G/C), IL-8 rs2227306 (781C/T), IL8 rs4073 (-251A/T), CXCR1 rs2234671 (2607G/C), and TNFα rs1800629 (-308G/A)). TT genotype of IL-8 -251A/T polymorphism was significantly higher in APN patients (26.7%) than those with lower UTI (11.7%, p=0.01) and control individuals (12.2%, p=0.002). T allele was significantly more common in APN than in lower UTI (p=0.025) and was significantly more common in APN (46%) than in the controls (p=0.001). Similarly, TT genotype of IL-8 781C/T polymorphism was significantly more common in APN patients (31.4%) than those with lower UTI (17.3%, p=0.003) and the controls (14.3%, p=0.001). T allele was significantly more common in APN (55%) than lower UTI (40%, p=0.005) and controls (37%, p=0.001). However, IL-8 -251A/T and +781C/T SNPs did not qualify as an independent risk for parenchymal infection (OR 1.9, 95% CI 0.68-2.6, p=0.13 and OR 2.3, 95% CI 0.89-3.7, p=0.091, respectively). Lower UTI did not differ from the controls. The frequency of the genotypes and alleles of IL-6, CXCR1, and TNFα SNPs did not differ significantly among the different groups of the study. IL-8 -251A/T and +781C/T SNPs are associated with susceptibility to renal parenchymal infection in children and could be implicated in APN risk. However, none of these variants could clearly and independently predict this risk.