A functional single-nucleotide polymorphism in the TRPC6 gene promoter associated with idiopathic pulmonary arterial hypertension

Ying Yu, Steve H. Keller, Carmelle V. Remillard, Olga Safrina, Ann Nicholson, Shenyuan L. Zhang, Weihua Jiang, Nivruthi Vangala, Judd W. Landsberg, Jian Ying Wang, Patricia A. Thistlethwaite, Richard N. Channick, Ivan M. Robbins, James E. Loyd, Hossein A. Ghofrani, Friedrich Grimminger, Ralph T. Schermuly, Michael D. Cahalan, Lewis J. Rubin, Jason X.J. Yuan

Research output: Contribution to journalArticle

122 Scopus citations

Abstract

BACKGROUND-: Excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) plays an important role in the development of idiopathic pulmonary arterial hypertension (IPAH), whereas a rise in cytosolic Ca concentration triggers PASMC contraction and stimulates PASMC proliferation. Recently, we demonstrated that upregulation of the TRPC6 channel contributes to proliferation of PASMCs isolated from IPAH patients. This study sought to identify single-nucleotide polymorphisms (SNPs) in the TRPC6 gene promoter that are associated with IPAH and have functional significance in regulating TRPC6 activity in PASMCs. METHODS AND RESULTS-: Genomic DNA was isolated from blood samples of 237 normal subjects and 268 IPAH patients. Three biallelic SNPs, -361 (A/T), -254(C/G), and -218 (C/T), were identified in the 2000-bp sequence upstream of the transcriptional start site of TRPC6. Although the allele frequencies of the -361 and -218 SNPs were not different between the groups, the allele frequency of the -254(C→G) SNP in IPAH patients (12%) was significantly higher than in normal subjects (6%; P<0.01). Genotype data showed that the percentage of -254G/G homozygotes in IPAH patients was 2.85 times that of normal subjects. Moreover, the -254(C→G) SNP creates a binding sequence for nuclear factor-κB. Functional analyses revealed that the -254(C→G) SNP enhanced nuclear factor-κB-mediated promoter activity and stimulated TRPC6 expression in PASMCs. Inhibition of nuclear factor-κB activity attenuated TRPC6 expression and decreased agonist-activated Ca influx in PASMCs of IPAH patients harboring the -254G allele. CONCLUSIONS-: These results suggest that the -254(C→G) SNP may predispose individuals to an increased risk of IPAH by linking abnormal TRPC6 transcription to nuclear factor-κB, an inflammatory transcription factor.

Original languageEnglish (US)
Pages (from-to)2313-2322
Number of pages10
JournalCirculation
Volume119
Issue number17
DOIs
StatePublished - May 5 2009
Externally publishedYes

Keywords

  • Calcium
  • Hypertension, pulmonary
  • Ion channels
  • Muscle, smooth
  • NF-kappa B

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Yu, Y., Keller, S. H., Remillard, C. V., Safrina, O., Nicholson, A., Zhang, S. L., Jiang, W., Vangala, N., Landsberg, J. W., Wang, J. Y., Thistlethwaite, P. A., Channick, R. N., Robbins, I. M., Loyd, J. E., Ghofrani, H. A., Grimminger, F., Schermuly, R. T., Cahalan, M. D., Rubin, L. J., & Yuan, J. X. J. (2009). A functional single-nucleotide polymorphism in the TRPC6 gene promoter associated with idiopathic pulmonary arterial hypertension. Circulation, 119(17), 2313-2322. https://doi.org/10.1161/CIRCULATIONAHA.108.782458