title: Role of the functional Toll-Like receptor-9 promoter polymorphism (-1237T/C) in increased risk of end-stage renal disease: a case-control study.
abstract: Inflammation induced by infectious and noninfectious triggers in the kidney may lead to end stage renal disease (ESRD). Toll-like receptor 9 (TLR-9) a receptor for CpG DNA is involved in activation of immune cells in renal disease and may contribute to chronic inflammatory disease progression through an interleukin-6 (IL-6) dependent pathway. Previous studies indicate that -1237T/C confers regulatory effects on TLR-9 transcription. To date the effect of TLR-9 polymorphisms on ESRD remains unknown. We performed a case-control study and genotyped 630 ESRD patients and 415 controls for -1237T/C, -1486T/C and 1635G/A by real-time PCR assays and assessed plasma concentration of IL-6 by ELISA. 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 -1237T/C promoter polymorphism. A significant association between -1237T/C in TLR-9 and ESRD was identified. The TCA, TTA and CCA haplotype of TLR-9 were associated with ESRD. ESRD patients carrying -1237TC had a higher mean plasma IL-6 level when compared with -1237TT. The TLR-9 transcriptional activity of the variant -1237CC allele is higher than the -1237TT allele. The results indicate that in a Han Chinese population the presence of the C allele of -1237T/C in the TLR-9 gene increases susceptibility towards development of ESRD. In vitro studies demonstrate that -1237T/C may be involved in the development of ESRD through transcriptional modulation of TLR-9.
authors.affiliation: School of Public Health, National Defense Medical Center, Taipei, Taiwan, Republic of China.
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Yang
authors.forename: Kuo-Cheng
authors.initials: KC
authors.lastname: Lu
authors.forename: Herng-Sheng
authors.initials: HS
authors.lastname: Lee
authors.forename: Shih-Ming
authors.initials: SM
authors.lastname: Huang
authors.forename: Yuh-Feng
authors.initials: YF
authors.lastname: Lin
authors.forename: Chia-Chao
authors.initials: CC
authors.lastname: Wu
authors.forename: Donald M
authors.initials: DM
authors.lastname: Salter
authors.forename: Sui-Lung
authors.initials: SL
authors.lastname: Su
mesh_terms: D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006239:Haplotypes; D006801:Humans; D007249:Inflammation; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000235:genetics* / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D051217:Toll-Like Receptor 9 / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D015850:Interleukin-6; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9