Chest
Volume 135, Issue 3, March 2009, Pages 737-744
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Original Research
Pulmonary Arterial Hypertension
Genetic Associations With Hypoxemia and Pulmonary Arterial Pressure in COPD

https://doi.org/10.1378/chest.08-1993Get rights and content

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.

Section snippets

Study Participants

The current analysis was performed in severe COPD subjects in two populations, the NETT Genetics Ancillary Study and the Boston Early-Onset COPD Study. Subject enrollment and data collection in the NETT and the Boston Early-Onset COPD Study have been described elsewhere.23, 24, 25 The study populations consisted of 389 participants from the NETT Genetics Ancillary Study and 139 probands from the Boston Early-Onset COPD Study. After providing written informed consent, participants from both

Study Participants

Baseline characteristics of the NETT and Boston Early-Onset COPD Study participants are described in Table 1, Table 2, respectively. Both populations are characterized by severe COPD and a history of heavy smoking. Compared to the NETT population, the Boston Early-Onset COPD Study probands are younger and composed of a larger percentage of women.

For the case-control analysis of hypoxemia in the Boston Early-Onset COPD Study probands, comparison of baseline variables between groups is included

Discussion

In this study, we tested five candidate genes for association with three COPD-related phenotypes. We found associations in EPHX1 and SERPINE2 for Pao2, and in SFTPB for PASP. To confirm the associations with Pao2, we tested the same SNPs from EPHX1 and SERPINE2 in a different population and demonstrated gene-level, but not SNP-level, association with a closely related phenotype.

This is the first study of the relationship between genetic polymorphisms and hypoxemia in subjects with COPD. While

Acknowledgment

Coinvestigators in the NETT Genetics Ancillary Study include Joshua Benditt, Gerard Criner, Malcolm DeCamp, Philip Diaz, Mark Ginsburg, Larry Kaiser, Marcia Katz, Mark Krasna, Neil MacIntyre, Barry Make, Rob McKenna, Fernando Martinez, Zab Mosenifar, Andrew Ries, Paul Scanlon, Frank Sciurba, and James Utz.

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  • Cited by (0)

    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.

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

    1

    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.

    2

    Dr. Silverman has received grant support, honoraria, and consulting fees from GlaxoSmithKline; honoraria and consulting fees from AstraZeneca; and honoraria from Wyeth and Bayer.

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