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


METHODS
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.


RESULTS
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).


CONCLUSIONS
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.
Hawn
Thomas R
TR
Department of Medicine, University of Washington, Seattle, Washington, USA. thawn@u.washington.edu
Scholes
Delia
D
Wang
Hongwei
H
Li
Sue S
SS
Stapleton
Ann E
AE
Janer
Marta
M
Aderem
Alan
A
Stamm
Walter E
WE
Zhao
Lue Ping
LP
Hooton
Thomas M
TM
D000328:Adult; D001437:Bacteriuria / Q000235:genetics* / Q000276:immunology* / Q000382:microbiology / Q000652:urine; D018925:Chemokines / Q000652:urine; D003710:Demography; D005260:Female; D014644:Genetic Variation; D006090:Gram-Negative Bacteria / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D016209:Interleukin-8 / Q000652:urine; D009504:Neutrophils / Q000166:cytology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D023062:Receptors, Interleukin-8A / Q000235:genetics; D023063:Receptors, Interleukin-8B / Q000235:genetics; D051195:Toll-Like Receptor 2 / Q000235:genetics; D014551:Urinary Tract / Q000276:immunology* / Q000382:microbiology*; D014556:Urine / Q000166:cytology
C508606:CXCL8 protein, human; D018925:Chemokines; D016209:Interleukin-8; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2