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(Circulation. 2009;119:2313-2322.)
© 2009 American Heart Association, Inc.

Hypertension

A Functional Single-Nucleotide Polymorphism in the TRPC6 Gene Promoter Associated With Idiopathic Pulmonary Arterial Hypertension

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

From the Departments of Medicine (Y.Y., S.H.K., A.N., N.V., C.V.R., J.W.L., RNC., L.J.R., J.X.-J.Y.) and Surgery (P.A.T.), University of California, San Diego, La Jolla; Department of Physiology and Biophysics (Y.Y., O.S., S.L.Z., W.J., M.D.C.), University of California, Irvine; Department of Surgery (J.-Y.W.), University of Maryland, Baltimore; Department of Medicine (I.M.R., J.E.L.), Vanderbilt University School of Medicine, Nashville, Tenn; and the Department of Internal Medicine II/V (H.A.G., F.G., R.T.S.), Justus Liebig University Giessen, Giessen, Germany. Dr Yu is currently at Alcon Laboratories, Fort Worth, Tex.

Reprint requests to Jason X.-J. Yuan, MD, PhD, Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, San Diego, 9500 Gilman Dr, MC 0725, La Jolla, CA 92093-0725 (e-mail xiyuan{at}ucsd.edu); or Ying Yu, MD, PhD, Alcon Laboratories Inc, 6201 S Freeway, Ft Worth, TX 76134 (e-mail Ying.Yu@AlconLabs.com).

Received March 25, 2008; accepted February 2, 2009.

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 Ca²⁺ 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(CG) 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(CG) SNP creates a binding sequence for nuclear factor-B. Functional analyses revealed that the –254(CG) SNP enhanced nuclear factor-B-mediated promoter activity and stimulated TRPC6 expression in PASMCs. Inhibition of nuclear factor-B activity attenuated TRPC6 expression and decreased agonist-activated Ca²⁺ influx in PASMCs of IPAH patients harboring the –254G allele.

Conclusions— These results suggest that the –254(CG) SNP may predispose individuals to an increased risk of IPAH by linking abnormal TRPC6 transcription to nuclear factor-B, an inflammatory transcription factor.

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