title: A functional polymorphism in the promoter region of TLR3 is associated with susceptibility to end-stage renal disease.
abstract: OBJECTIVE
  End-stage renal disease (ESRD) is simultaneously associated with immune activation, systemic inflammation and immune deficiency. Toll-like receptor 3 (TLR3), a receptor for viral double-stranded RNA, is involved in immune cell activation in renal diseases and may contribute to chronic inflammatory disease progression. To date, effects of TLR3 polymorphisms on ESRD remain unknown. Therefore, we determined the predictive value of TLR3 polymorphisms and further functionally studied ESRD.
  
  
  METHODS
  We performed a case-control association study and genotyped 616 ESRD patients and 813 healthy controls. Patients were genotyped for -7C/A, 1377C/T and 1234C/T polymorphisms of TLR3 using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. The Haplotype association analysis was performed using the Haploview package. A luciferase reporter assay and real-time PCR were used to test the function of the -7C/A promoter polymorphism in TLR3 expression in human embryonic kidney 293 (HEK293) cells.
  
  
  RESULTS
  Genotype distributions of -7C/A and 1377C/T in TLR3 were significantly different in ESRD patients and healthy controls. The ATC haplotype of TLR3 was associated with a decreased risk of ESRD. We also found significant differences in TLR3 expression by dexamethasone treatment between various genotypes of -7C/A (p = 0.02). TLR3 transcriptional activity of the variant -7 C allele was higher than that of the -7 A allele after dexamethasone treatment.
  
  
  CONCLUSIONS
  RESULTS indicate that, in our population, the presence of the C allele of -7C/A in TLR3 increases the susceptibility to ESRD. In vitro studies demonstrated that -7C/A may be involved in ESRD development through transcriptional modulation of TLR3.
authors.affiliation: School of Public Health, National Defense Medical Center, New Taipei City, Taiwan.
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Yang
authors.forename: Shih-Ming
authors.initials: SM
authors.lastname: Huang
authors.forename: Kuo-Cheng
authors.initials: KC
authors.lastname: Lu
authors.forename: Chia-Chao
authors.initials: CC
authors.lastname: Wu
authors.forename: Chi-Yu
authors.initials: CY
authors.lastname: Kang
authors.forename: Yuh-Feng
authors.initials: YF
authors.lastname: Lin
authors.forename: Chin
authors.initials: C
authors.lastname: Lin
authors.forename: Fu-Huang
authors.initials: FH
authors.lastname: Lin
authors.forename: Sen-Yeong
authors.initials: SY
authors.lastname: Kao
authors.forename: Sui-Lung
authors.initials: SL
authors.lastname: Su
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People / Q000235:genetics*; D016022:Case-Control Studies; D003198:Computer Simulation; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D007676:Kidney Failure, Chronic / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D013624:Taiwan; D051196:Toll-Like Receptor 3 / Q000235:genetics* / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3