1. A functional single-nucleotide polymorphism in the TRPC6 gene promoter associated with idiopathic pulmonary arterial hypertension
- Author
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Ivan M. Robbins, Richard N. Channick, Weihua Jiang, Ralph T. Schermuly, Shenyuan L. Zhang, James E. Loyd, Patricia A. Thistlethwaite, Hossein Ardeschir Ghofrani, Jian Ying Wang, Ying Yu, Judd W. Landsberg, Michael D. Cahalan, Olga Safrina, Nivruthi Vangala, Lewis J. Rubin, Carmelle V. Remillard, Ann Nicholson, Friedrich Grimminger, Steve H. Keller, and Jason X.-J. Yuan
- Subjects
medicine.medical_specialty ,Genotype ,Myocytes, Smooth Muscle ,Single-nucleotide polymorphism ,Pulmonary Artery ,Polymorphism, Single Nucleotide ,Muscle, Smooth, Vascular ,Downregulation and upregulation ,Gene Frequency ,Physiology (medical) ,Internal medicine ,Gene expression ,medicine ,TRPC6 Cation Channel ,Humans ,Genetic Predisposition to Disease ,Allele ,Promoter Regions, Genetic ,Allele frequency ,Cell Proliferation ,TRPC Cation Channels ,Binding Sites ,business.industry ,NF-kappa B ,Promoter ,medicine.disease ,Pulmonary hypertension ,Endocrinology ,Case-Control Studies ,Hypertension ,Cardiology and Cardiovascular Medicine ,business - 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 2+ 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 2+ 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.
- Published
- 2009