A functional polymorphism in the promoter region of TLR3 is associated with susceptibility to end-stage renal disease

Hsin Yi Yang, Shih Ming Huang, Kuo Cheng Lu, Chia Chao Wu, Chi Yu Kang, Yuh Feng Lin, Chin Lin, Fu Huang Lin, Sen Yeong Kao, Sui Lung Su

Research output: Contribution to journalArticle

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Abstract

Background/Aims: 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. Conclusion: 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.

Original languageEnglish
Pages (from-to)131-139
Number of pages9
JournalAmerican Journal of Nephrology
Volume40
Issue number2
DOIs
Publication statusPublished - May 22 2014

Fingerprint

Toll-Like Receptor 3
Genetic Promoter Regions
Chronic Kidney Failure
Alleles
Haplotypes
Dexamethasone
Genotype
Kidney
Double-Stranded RNA
Viral RNA
Luciferases
Restriction Fragment Length Polymorphisms
Disease Progression
Case-Control Studies
Real-Time Polymerase Chain Reaction

Keywords

  • End-stage renal disease
  • Single-nucleotide polymorphism
  • Toll-like receptor 3

ASJC Scopus subject areas

  • Nephrology
  • Medicine(all)

Cite this

A functional polymorphism in the promoter region of TLR3 is associated with susceptibility to end-stage renal disease. / Yang, Hsin Yi; Huang, Shih Ming; Lu, Kuo Cheng; Wu, Chia Chao; Kang, Chi Yu; Lin, Yuh Feng; Lin, Chin; Lin, Fu Huang; Kao, Sen Yeong; Su, Sui Lung.

In: American Journal of Nephrology, Vol. 40, No. 2, 22.05.2014, p. 131-139.

Research output: Contribution to journalArticle

Yang, Hsin Yi ; Huang, Shih Ming ; Lu, Kuo Cheng ; Wu, Chia Chao ; Kang, Chi Yu ; Lin, Yuh Feng ; Lin, Chin ; Lin, Fu Huang ; Kao, Sen Yeong ; Su, Sui Lung. / A functional polymorphism in the promoter region of TLR3 is associated with susceptibility to end-stage renal disease. In: American Journal of Nephrology. 2014 ; Vol. 40, No. 2. pp. 131-139.
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T1 - A functional polymorphism in the promoter region of TLR3 is associated with susceptibility to end-stage renal disease

AU - Yang, Hsin Yi

AU - Huang, Shih Ming

AU - Lu, Kuo Cheng

AU - Wu, Chia Chao

AU - Kang, Chi Yu

AU - Lin, Yuh Feng

AU - Lin, Chin

AU - Lin, Fu Huang

AU - Kao, Sen Yeong

AU - Su, Sui Lung

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AB - Background/Aims: 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. Conclusion: 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.

KW - End-stage renal disease

KW - Single-nucleotide polymorphism

KW - Toll-like receptor 3

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