The investigation of genetic susceptibility to recurrent urinary tract infections

Urinary tract infections (UTI) are among the most common infections in childhood. As urinary tract infections show familial predisposition, hereditary factors those may play a role have attracted attantion. This fact especially gained importance after the role of innate immunity on the pathogenesis was evident.Toll like receptors reside on the epithelial surfaces and help in recognition of the pathogens and the molecules those are formed as a result of cell damage. TLR4, which was shown to be present in the urinary system broadly, recognizes lipopolisaccaride which is the main structure of gram negative bacteria. After determination of the pathogen, the secretion of cytokines, especially IL-6, IL-8 triggered by the activation of the mediators in the cell. By the help of these cytokines neutrophile activation, migration to the area of infection and bacterial death occurs. It was shown that A896G polymorphism in TLR4 gene which plays an important role in innate immun response has been associated with gram negative infections and A2767G polymorphism in IL-8 gene has been associated with upper urinary tract infections.In this study DNA extractions were made from 33 patients with recurrent urinary tract infections in whom bladder dysfunction was determined as a risk factor, from 43 patients without any risk factors and from 110 healthy controls (control group) without a history of urinary tract infection or kidney disease. The A896G polymorphism in TLR4 gene and the A2767G polymorphism in the IL-8 gene were investigated by using realtime PCR and restriction fragment length polymorphism (RFLP). The history of infection with fever was accepted as pyelonephritis.All the 76 patients with recurrent urinary tract infections was females (%100) and the mean age was 9,2±3,5 (2-17) years. TLR4-896AG and GG genotypes (p=0,023 and p<0,001), TLR4 gene G allel (p<0,001) and IL-8-2767AG genotype (p=0,019) were more frequent in the patients with recurrent infections compared to the control group. It is considered that TLR4 gene G allele is associated with recurrent urinary tract infection and bladder dysfunction. In the patients without any risk factor, TLR4-896AG genotype was more frequent compared to the control group which was different than the patients with bladder dysfunction (p=0,013). IL-8-2767AG genotype in the patients with bladder dysfunction was more frequent compared to the control group (p<0,001 and p=0,015), which is thought to be associated with the disease. TLR4-896GG genotype and G allele (p=0,04 and p<0,001), IL-8-2767AG genotype (p=0,022) also occurred more frequently in patients with bladder dysfunction than in patients with any risk factors. In the patients with a history of recurrent fever TLR4-896AG and IL-8-2767AG genotypes were more frequent compared to the control group (p=0,004 and p=0,031) and this was thought to be related to the upper urinary tract infections.As a result, these data suggest that TLR4 A896G and IL-8 A2767G polymorphisms are involved in susceptibility to recurrent urinary tract infections, upper urinary tract infections and bladder dysfunction. Clinical studies are needed to demonstrate if those who carry these genetic variants should need a different approach of treatment.