Published Online
on May 22, 2006

A more recent version of this article appeared on May 30, 2006

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Submitted on November 17, 2005
Revised on February 6, 2006
Accepted on March 24, 2006

Relationship of BMPR2 Mutations to Vasoreactivity in Pulmonary Arterial Hypertension

C. Gregory Elliott MD^*, Eric W. Glissmeyer BS, Gregory T. Havlena BS, John Carlquist PhD, Jason T. McKinney MS, Stuart Rich MD, Michael D. McGoon MD, Mary Beth Scholand MD, Miryoung Kim BS, Robert L. Jensen PhD, Jon W. Schmidt , and Kenneth Ward MD

From the LDS Hospital and the University of Utah School of Medicine (C.G.E., E.W.G., G.T.H., J.C., M.B.S., M.K., R.L.J., J.W.S.), Salt Lake City, Utah; Johns Hopkins University School of Medicine (G.T.H.), Baltimore, Md; the University of Hawaii (K.W.), Honolulu; the Mayo Clinic College of Medicine (M.D.M.), Rochester, Minn; the University of Chicago (S.R.), Chicago, Ill; and Idaho Technology, Inc (J.T.M.), Salt Lake City, Utah.

^* To whom correspondence should be addressed. E-mail: ldgellio{at}ihc.com.

Background--Vasoreactivity tests are fundamental in evaluating pulmonary arterial hypertension (PAH). Mutations of the transforming growth factor- type II receptor gene, BMPR2, predispose to the development of pulmonary hypertension and may alter the response to vasodilators. Previous investigations have not examined the relationship of BMPR2 mutations to vasoreactivity.

Methods and Results--We identified 133 consecutive unrelated patients with either idiopathic or familial PAH. Sixty-six patients were excluded because we lacked either DNA samples (n=18) or complete data from a vasoreactivity test (n=48). The remaining 67 patients were screened for BMPR2 DNA sequence variations, and specific variations were confirmed by gene sequencing. The vasoreactivity of patients with nonsynonymous BMPR2 variations was compared with that of patients without nonsynonymous BMPR2 variations. We found nonsynonymous BMPR2 variations in 27 of 67 patients with idiopathic (n=16 of 52) or familial (n=11 of 15) PAH. Vasoreactivity was identified in 3.7% of 27 patients with nonsynonymous BMPR2 variations and in 35% of 40 patients without nonsynonymous BMPR2 variations (P=0.003). Five of the 27 nonsynonymous variations occur commonly in healthy individuals. None of the remaining 22 patients with BMPR2 variations demonstrated vasoreactivity, and the analysis remained unchanged when we assumed that nonsynonymous BMPR2 variations were present in all 15 patients with familial PAH.

Conclusions--Patients with familial or idiopathic PAH and nonsynonymous BMPR2 variations are unlikely to demonstrate vasoreactivity. Further trials are required to determine whether long-term therapy can be directed by tests for BMPR2 variations.

Key words: genetics • molecular biology • pulmonary arterial hypertension • vasoconstriction • vasodilation

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