TY - JOUR
T1 - Single nucleotide polymorphisms in the promoter of the gene encoding the lipopolysaccharide receptor CD14 are associated with bacterial diarrhea in US and Canadian travelers to Mexico
AU - Mohamed, Jamal A.
AU - Dupont, Herbert L.
AU - Flores, Jose
AU - Palur, Himaja
AU - Nair, Parvathy
AU - Jiang, Zhi Dong
AU - Guo, Dongchuan
AU - Belkind-Gerson, Jaime
AU - Okhuysen, Pablo C.
N1 - Funding Information:
Financial support. This work was supported by the National Institutes of Health (R01 AI54948-01 to P. C. O.), the University of Texas Center for Clinical and Translational Sciences (UL1RR024148) of the University of Texas Medical School at Houston, and DK56338, which funds the Texas Gulf Coast Digestive Diseases Center.
PY - 2011/6/1
Y1 - 2011/6/1
N2 - Background. Under normal conditions, the expression of CD14, which is the principal receptor for bacterial lipopolysaccharide, is down-regulated in the intestinal mucosa but increases in response to inflammatory stimuli. The aim of the present study was to investigate whether fecal CD14 levels increased in response to infection with diarrheagenic Escherichia coli and whether single nucleotide polymorphisms (SNPs) in the CD14 gene were associated with an increased susceptibility to traveler's diarrhea (TD) in US visitors to Mexico. Methods .Six SNPs located at the promoter, exon, and untranslated regions of CD14 were typed in a prospective cohort study of 1360 visitors to Mexico at risk for TD. Stools from visitors with TD were studied for enteric pathogens by culture, colony hybridization, and polymerase chain reaction. Fecal soluble CD14 (sCD14) was measured in a subgroup of 203 adults with diarrhea and 66 healthy controls by enzyme-linked immunosorbent assay. Results .The minor allele frequencies for CD14 SNPs were significantly different among the various racial and ethnic groups studied. Two SNPs in the promoter region of CD14 (-159 C > T; rs2569190 and -4191 C > T; rs5744441) were found to be associated with TD in White visitors. The -159 TT genotype was associated with a higher risk for TD (Relative risk [RR], 1.21; 95% confidence interval [CI], 1.05-1.38; P =. 008), whereas individuals with the -4191 TT genotype were protected from infection (RR, 0.82; 95% CI, 0.71-0.92; P =. 006). Subjects with TD excreted higher levels of fecal CD14 than did healthy controls (33,480 pg/mL vs 6178 pg/mL; P <. 02). Fecal sCD14 levels were higher in stool samples from visitors with TD and the -159 TT genotype than they were in visitors with the CC/CT genotypes (P =. 02), and stool samples from subjects with the -4191 CC genotype had higher fecal sCD14 levels than did stool samples from visitors with the CT/TT (P =. 005) genotype. In a multivariate analysis with haplotypes constructed with the 6 SNPs studied, subjects with the haplotype containing the -159 C and the -4191 T allele were less likely to acquire TD (P =. 015). Conclusion s.Our study suggests that CD14 levels increase in response to bacterial diarrhea and that polymorphisms in the CD14 gene influence susceptibility to TD. Intestinal CD14 plays an important role in the innate immune response to enteric pathogens.
AB - Background. Under normal conditions, the expression of CD14, which is the principal receptor for bacterial lipopolysaccharide, is down-regulated in the intestinal mucosa but increases in response to inflammatory stimuli. The aim of the present study was to investigate whether fecal CD14 levels increased in response to infection with diarrheagenic Escherichia coli and whether single nucleotide polymorphisms (SNPs) in the CD14 gene were associated with an increased susceptibility to traveler's diarrhea (TD) in US visitors to Mexico. Methods .Six SNPs located at the promoter, exon, and untranslated regions of CD14 were typed in a prospective cohort study of 1360 visitors to Mexico at risk for TD. Stools from visitors with TD were studied for enteric pathogens by culture, colony hybridization, and polymerase chain reaction. Fecal soluble CD14 (sCD14) was measured in a subgroup of 203 adults with diarrhea and 66 healthy controls by enzyme-linked immunosorbent assay. Results .The minor allele frequencies for CD14 SNPs were significantly different among the various racial and ethnic groups studied. Two SNPs in the promoter region of CD14 (-159 C > T; rs2569190 and -4191 C > T; rs5744441) were found to be associated with TD in White visitors. The -159 TT genotype was associated with a higher risk for TD (Relative risk [RR], 1.21; 95% confidence interval [CI], 1.05-1.38; P =. 008), whereas individuals with the -4191 TT genotype were protected from infection (RR, 0.82; 95% CI, 0.71-0.92; P =. 006). Subjects with TD excreted higher levels of fecal CD14 than did healthy controls (33,480 pg/mL vs 6178 pg/mL; P <. 02). Fecal sCD14 levels were higher in stool samples from visitors with TD and the -159 TT genotype than they were in visitors with the CC/CT genotypes (P =. 02), and stool samples from subjects with the -4191 CC genotype had higher fecal sCD14 levels than did stool samples from visitors with the CT/TT (P =. 005) genotype. In a multivariate analysis with haplotypes constructed with the 6 SNPs studied, subjects with the haplotype containing the -159 C and the -4191 T allele were less likely to acquire TD (P =. 015). Conclusion s.Our study suggests that CD14 levels increase in response to bacterial diarrhea and that polymorphisms in the CD14 gene influence susceptibility to TD. Intestinal CD14 plays an important role in the innate immune response to enteric pathogens.
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U2 - 10.1093/cid/cir228
DO - 10.1093/cid/cir228
M3 - Article
C2 - 21596674
AN - SCOPUS:79957498961
SN - 1058-4838
VL - 52
SP - 1332
EP - 1341
JO - Clinical Infectious Diseases
JF - Clinical Infectious Diseases
IS - 11
ER -