Genetic variations of interleukin-8, CXCR1 and CXCR2 genes and risk of acute pyelonephritis in children

Acute pyelonephritis (APN) is the most severe form of urinary tract infection, the etiopathogenesis of which is still not well understood. Previous studies demonstrated that chemotaxis of neutrophils into the tissue and across the infected epithelial layer is a key step in rapid bacterial clearance. Variations within genes encoding the major chemokine interleukin-8 and its receptors CXCR1 and CXCR2 are therefore attractive candidates for participation in genetic predisposition to APN. The aim of our study was to evaluate the association of single nucleotide polymorphisms (SNPs) -251 T/A, +781 C/T, +1633 C/T and +2767 A/T in the IL-8 gene, +2608 G/C in the CXCR1 gene and +1208 C/T in the CXCR2 gene with susceptibility to APN in the Slovak population. PCR-SSP and PCR-RFLP were used to genotype SNPs in 147 children with APN (62 with recurrent and 85 with episodic form) and 215 healthy individuals. Statistical analysis revealed significantly increased frequency of CXCR1 +2608 C allele (P = 0.0238, OR = 2.452, 95% CI = 1.147-5.243) and GC genotype (P = 0.0201, OR = 2.627, 95% CI = 1.188-5.810) and lower frequency of CXCR2 +1208 T allele (P = 0.0408, OR = 0.645, 95% CI = 0.429-0.972) and TT+TC genotypes (P = 0.0497, OR = 0.5273, 95% CI = 0.288-0.964) in patients with recurrent APN compared with healthy controls. Furthermore, the A allele of IL-8 -251 T/A SNP was also significantly overrepresented in patients with recurrent APN when compared with those with only single episode of APN (P = 0.0439, OR = 1.627, 95% CI = 1.019-2.599). Our results indicate that the minor CXCR1 +2608 C allele is associated with significantly increased susceptibility to APN in childhood, while the CXCR2 +1208 T allele confers protection from recurrent APN. Moreover, allele A of the IL-8 -251 T/A may also increase the risk of developing recurrent attacks after the first-time APN.