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Original Research: PULMONARY ARTERIAL HYPERTENSION |

Genetic Associations With Hypoxemia and Pulmonary Arterial Pressure in COPD

Peter J. Castaldi, MD; Craig P. Hersh, MD, MPH; John J. Reilly, MD, FCCP; Edwin K. Silverman, MD, PhD
Author and Funding Information

*From the Institute for Clinical Research and Health Policy Studies (Dr. Castaldi), Tufts Medical Center, Boston, MA; Channing Laboratory (Drs. Hersh and Silverman) and Pulmonary and Critical Care Division (Dr. Reilly), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Correspondence to: Craig P. Hersh, MD, MPH, Channing Laboratory, Brigham and Women's Hospital, 181 Longwood Ave, Boston, MA 02115; e-mail: craig.hersh@channing.harvard.edu


This work was supported by National Institutes of Health grants T32HS00060, K08HL080242, R01HL075478, R01HL71393, U01HL065899, and P01HL083069, and a grant from The Alpha One Foundation. The National Emphysema Treatment Trial was supported by contracts with the National Heart, Lung, and Blood Institute (contracts N01HR76101, N01HR76102, N01HR76103, N01HR76104, N01HR76105, N01HR76106, N01HR76107, N01HR76108, N01HR76109, N01HR76110, N01HR76111, N01HR76112, N01HR76113, N01HR76114, N01HR76115, N01HR76116, N01HR76118, and N01HR76119), the Centers for Medicare and Medicaid Services, and the Agency for Healthcare Research and Quality.

Drs. Castaldi, Hersh, and Reilly have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Dr. Silverman has received grant support, honoraria, and consulting fees from GlaxoSmithKline; honoraria and consulting fees from AstraZeneca; and honoraria from Wyeth and Bayer.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).


Chest. 2009;135(3):737-744. doi:10.1378/chest.08-1993
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Background:  Hypoxemia, hypercarbia, and pulmonary arterial hypertension are known complications of advanced COPD. We sought to identify genetic polymorphisms associated with these traits in a population of patients with severe COPD from the National Emphysema Treatment Trial (NETT).

Methods:  In 389 participants from the NETT Genetics Ancillary Study, single-nucleotide polymorphisms (SNPs) were genotyped in five candidate genes previously associated with COPD susceptibility (EPHX1, SERPINE2, SFTPB, TGFB1, and GSTP1). Linear regression models were used to test for associations among these SNPs and three quantitative COPD-related traits (Pao2, Paco2, and pulmonary artery systolic pressure). Genes associated with hypoxemia were tested for replication in probands from the Boston Early-Onset COPD Study.

Results:  In the NETT Genetics Ancillary Study population, SNPs in microsomal epoxide hydrolase (EPHX1) [p = 0.01 to 0.04] and serpin peptidase inhibitor, clade E, member 2 (SERPINE2) [p = 0.04 to 0.008] were associated with hypoxemia. One SNP within surfactant protein B (SFTPB) was associated with pulmonary artery systolic pressure (p = 0.01). In probands from the Boston Early-Onset COPD Study, SNPs in EPHX1 and in SERPINE2 were associated with the requirement for supplemental oxygen.

Conclusions:  In participants with severe COPD, SNPs in EPHX1 and SERPINE2 were associated with hypoxemia in two separate study populations, and SNPs from SFTPB were associated with pulmonary artery pressure in the NETT participants.

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