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Hum. Reprod. Advance Access published online on September 18, 2006

Human Reproduction, doi:10.1093/humrep/del377
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© The Author 2006. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received January 5, 2006
Revised July 19, 2006
Accepted August 21, 2006

Article

Toll-like receptor 4 polymorphisms and idiopathic chromosomally normal miscarriage

A.F. Hirschfeld 1, R. Jiang 2, W.P. Robinson 2, D.E. McFadden 3, and S.E. Turvey 1 *

1 Department of Paediatrics, BC Children’s Hospital and Child & Family Research Institute, Vancouver, BC, Canada
2 Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
3 Department of Pathology, University of British Columbia, Vancouver, BC, Canada

* To whom correspondence should be addressed.
S.E. Turvey, E-mail: sturvey{at}cw.bc.ca


   Abstract

BACKGROUND: Lipopolysaccharide (LPS or endotoxin) exposure resulting from microbial invasion of the endometrium disturbs the Th1/Th2 balance at the feto-maternal interface and has been linked to the risk of idiopathic miscarriage in a range of human and animal studies. Toll-like receptor 4 (TLR4) mediates LPS signalling, and the human TLR4 gene harbours two single-nucleotide polymorphisms (SNPs) known to reduce LPS responsiveness. We hypothesized that genetic variation altering TLR4 function may influence the risk of idiopathic pregnancy loss. METHODS AND RESULTS: We examined fetal TLR4 genotypes in a case-control cohort of chromosomally normal miscarriages (n = 96) and healthy term newborns (n = 113). The allele frequencies of the Asp299Gly and Thr399Ile TLR4 SNPs were determined by quantitative PCR using DNA extracted from extraembryonic tissues and umbilical cord blood, respectively. TLR4 genotype frequencies were not significantly different between cases and controls. CONCLUSIONS: There was no association between fetal TLR4 polymorphisms, Asp299Gly and Thr399Ile, known to blunt LPS responsiveness, and the risk of idiopathic, chromosomally normal miscarriage. Nevertheless, TLR4 or perhaps other LPS-binding chaperone molecules are biologically plausible candidate genes that may alter the risk of idiopathic miscarriage.

Keywords: miscarriage/TLR4/polymorphism/innate immunity/lipopolysaccharide.
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