Genetic variation of the human urinary tract innate immune response and asymptomatic bacteriuria in women

• Published in: PloS one Vol. 4; no. 12; p. e8300
• Main Authors: Hawn, Thomas R, Scholes, Delia, Wang, Hongwei, Li, Sue S, Stapleton, Ann E, Janer, Marta, Aderem, Alan, Stamm, Walter E, Zhao, Lue Ping, Hooton, Thomas M
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 15.12.2009; Public Library of Science (PLoS)
• Subjects: Adult; Age; Bacteria; Bacteriuria; Bacteriuria - genetics; Bacteriuria - immunology; Bacteriuria - microbiology; Bacteriuria - urine; Bladder; Borrelia burgdorferi; Cancer; Chemokines; Chemokines - urine; CXCR2 protein; Demography; Deoxyribonucleic acid; DNA; Female; Gene polymorphism; Genes; Genetic aspects; Genetic diversity; Genetic factors; Genetic polymorphisms; Genetic Variation; Gram-Negative Bacteria - physiology; Health risk assessment; Human behavior; Humans; Immune response; Immune system; Immunity, Innate - genetics; Immunology/Genetics of the Immune System; Immunology/Innate Immunity; Infectious Diseases/Urological Infections; Inflammation; Innate immunity; Intercellular adhesion molecule 1; Interleukin-8 - urine; Kidney diseases; Leprosy; Leukocytes (neutrophilic); Lyme disease; Medical research; Medicine; Neutrophils; Neutrophils - cytology; Pathogenesis; Polymorphism; Polymorphism, Single Nucleotide - genetics; Population studies; Pyelonephritis; Receptors, Interleukin-8A - genetics; Receptors, Interleukin-8B - genetics; Risk factors; Sepsis; Signal transduction; Signaling; Studies; TLR1 protein; TLR2 protein; TLR4 protein; TLR5 protein; Toll-Like Receptor 2 - genetics; Toll-like receptors; Tuberculosis; Urinary bladder; Urinary tract; Urinary Tract - immunology; Urinary Tract - microbiology; Urinary tract diseases; Urinary tract infections; Urine; Urine - cytology; Urogenital system; Women; Womens health; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0008300

Although several studies suggest that genetic factors are associated with human UTI susceptibility, the role of DNA variation in regulating early in vivo urine inflammatory responses has not been fully examined. We examined whether candidate gene polymorphisms were associated with altered urine inflammatory profiles in asymptomatic women with or without bacteriuria. We conducted a cross-sectional analysis of asymptomatic bacteriuria (ASB) in 1,261 asymptomatic women ages 18-49 years originally enrolled as participants in a population-based case-control study of recurrent UTI and pyelonephritis. We genotyped polymorphisms in CXCR1, CXCR2, TLR1, TLR2, TLR4, TLR5, and TIRAP in women with and without ASB. We collected urine samples and measured levels of uropathogenic bacteria, neutrophils, and chemokines. Polymorphism TLR2_G2258A, a variant associated with decreased lipopeptide-induced signaling, was associated with increased ASB risk (odds ratio 3.44, 95%CI; 1.65-7.17). Three CXCR1 polymorphisms were associated with ASB caused by gram-positive organisms. ASB was associated with urinary CXCL-8 levels, but not CXCL-5, CXCL-6, or sICAM-1 (P< or =0.0001). Urinary levels of CXCL-8 and CXCL-6, but not ICAM-1, were associated with higher neutrophil levels (P< or =0.0001). In addition, polymorphism CXCR1_G827C was associated with increased CXCL-8 levels in women with ASB (P = 0.004). TLR2 and CXCR1 polymorphisms were associated with ASB and a CXCR1 variant was associated with urine CXCL-8 levels. These results suggest that genetic factors are associated with early in vivo human bladder immune responses prior to the development of symptomatic UTIs.