Toll-Like Receptor Polymorphisms and Susceptibility to Urinary Tract Infections in Adult Women

et al. (2009) Toll-Like Receptor Polymorphisms and Susceptibility to Urinary Tract Infections in Adult Women. PLoS ONE 4(6): e5990. doi:10.1371/journal.pone.0005990 Toll-Like Receptor Polymorphisms and Susceptibility to Urinary Tract Infections in Adult Women Thomas R. Hawn 0 Delia Scholes 0 Shuying S. Li 0 Hongwei Wang 0 Yin Yang 0 Pacita L. Roberts 0 Ann E. Stapleton 0 Marta Janer 0 Alan Aderem 0 Walter E. Stamm 0 Lue Ping Zhao 0 Thomas M. Hooton 0 Ludovic Tailleux, Institut Pasteur, France 0 1 Department of Medicine, University of Washington, Seattle, Washington, United States of America, 2 Department of Epidemiology, University of Washington, and Center for Health Studies, Group Health Cooperative, Seattle, Washington, United States of America, 3 Fred Hutchinson Cancer Research Center , Seattle , Washington, United States of America, 4 Institute for Systems Biology, Seattle, Washington, United States of America, 5 Department of Medicine, University of Miami , Miami, Florida , United States of America Background: Although behavioral risk factors are strongly associated with urinary tract infection (UTI) risk, the role of genetics in acquiring this disease is poorly understood. Methodology/Principal Findings: To test the hypothesis that polymorphisms in Toll-like receptor (TLR) pathway genes are associated with susceptibility to UTIs, we conducted a population-based case-control study of women ages 18-49 years. We examined DNA variants in 9 TLR pathway genes in 431 recurrent cystitis (rUTI) cases, 400 pyelonephritis cases, and 430 controls with no history of UTIs. In the Caucasian subgroup of 987 women, polymorphism TLR4_A896G was associated with protection from rUTI, but not pyelonephritis, with an odds ratio (OR) of 0.54 and a 95% confidence interval (CI) of 0.31 to 0.96. Polymorphism TLR5_C1174T, which encodes a variant that abrogates flagellin-induced signaling, was associated with an increased risk of rUTI (OR(95%CI): 1.81 (1.00-3.08)), but not pyelonephritis. Polymorphism TLR1_G1805T was associated with protection from pyelonephritis (OR(95%CI): 0.53 (0.29-0.96)). Conclusions: These results provide the first evidence of associations of TLR5 and TLR1 variants with altered risks of acquiring rUTI and pyelonephritis, respectively. Although these data suggest that TLR polymorphisms are associated with adult susceptibility to UTIs, the statistical significance was modest and will require further study including validation with independent cohorts. - Funding: This work was supported by grant NIH/NIDDK #1 PO1 DK53369-06. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Acute uncomplicated urinary tract infections (UTIs) in young women are exceedingly common and result in substantial morbidity, time lost from work, and medical costs. Treatment requires the frequent use of antibiotics which contributes to drug resistance. Recurrent UTI (rUTI) is a common syndrome in otherwise young healthy women. Previous studies suggest that 27% to 44% of women who experience an initial UTI develop rUTI [1,2]. The vast majority of these women do not have underlying functional or anatomic abnormalities of the urinary tract. Although pyelonephritis is less common than cystitis, it is a serious illness that can result in expensive hospitalization. Behavioral factors, such as sexual intercourse and spermicide use, are strongly associated with an increased risk of rUTI and pyelonephritis [3,4,5]. However, many women with uncomplicated UTI do not have obvious behavioral, functional or anatomic risk factors, suggesting that genetic risk factors may be present. A series of studies over several decades indicates that host genetic factors influence susceptibility to human infections [6,7,8]. More recent studies suggest an influence of genetics on susceptibility to UTIs. In one family study, 15% of relatives of pyelonephritis-prone children had a UTI history compared to 3% of relatives of controls [9]. In adults, 65.5% of mothers, 60.7% of daughters, and 48.6% of sisters of women with rUTI had a similar history [10]. We previously found that adult women with rUTI or pyelonephritis were more likely to have a mother with a UTI history in comparison to controls [4,5]. Aside from associations of non-secretor blood group antigens and P1 phenotype with RUTI and/or pyelonephritis, we are not aware of any associations of polymorphisms with UTIs in adults [11,12,13,14,15,16]. Genetic studies in children have reported associations of polymorphisms in CXCR1, TLR2, and TLR4 with UTI susceptibility [17,18,19,20]. In addition, reduced expression levels of CXCR1, CXCR2 and TLR4 on neutrophils was associated with pyelonephritis, recurrent cystitis and asymptomatic bacteriuria, respectively [18,21,22,23]. Mouse studies have also suggested a role for CXCR1 in UTI susceptibility [21]. Although these studies suggest a possible role for genetics in human UTI susceptibility, the genes involved remain largely unknown. Toll-like receptors (TLRs) are a family of germline-encoded receptors that orchestrate the innate immune response and recognize Pathogen-Associated Molecular Patterns (PAMPs) such as bacterial flagellin (TLR5), lipopolysaccharide (LPS) (TLR4), and bacterial lipopeptides (TLR1/2/6) [24,25,26]. During a UTI, bacteria colonize the urethra and ascend to the bladder, where they can persist at high levels and cause cystitis [27]. In addition, pathogens may ascend to the kidney and cause serious complications, including pyelonephritis and bacteremia [28]. The initial recognition of bacteria occurs at the epithelial cell surface of the urogenital tract, a site of TLR expression in humans [29]. E. coli, which causes 7090% of all uncomplicated UTIs, is recognized by several TLRs, including TLR1,2,4,5,6 and 11 [24,25,26]. Although previous studies in mice indicate that TLR4, TLR5, and TLR11 regulate susceptibility to cystitis and pyelonephritis, the role of TLRs in human UTI pathogenesis is poorly understood [30,31,32,33]. We and others have characterized human TLR pathway polymorphisms that are associated with altered gene function and susceptibility to different infections [34,35,36,37,38,39,40,41,42,43]. Although two previous studies suggest that polymorphisms TLR2_G2258A and TLR4_A896G are associated with susceptibility to UTIs in children, the role of the other functionally significant TLR polymorphisms in UTI pathogenesis is not currently known [19,20]. In addition, it is also not known whether any TLR variants are associated with cystitis or pyelonephritis in adults. In this manuscript, we summarize the results of a population-based case-control study examining whether polymorphisms in TLR genes are associated with susceptibility to cystitis and pyelonephritis in adult women ages 1849 years. Materials and Methods Study Setting and Par (...truncated)