Xenobiotic metabolizing enzyme gene polymorphisms predict response to lung volume reduction surgery

Abstract

Background: In the National Emphysema Treatment Trial (NETT), marked variability in response to lung volume reduction surgery (LVRS) was observed. We sought to identify genetic differences which may explain some of this variability.

Methods: In 203 subjects from the NETT Genetics Ancillary Study, four outcome measures were used to define response to LVRS at six months: modified BODE index, post-bronchodilator FEV1, maximum work achieved on a cardiopulmonary exercise test, and University of California, San Diego shortness of breath questionnaire. Sixty-four single nucleotide polymorphisms (SNPs) were genotyped in five genes previously shown to be associated with chronic obstructive pulmonary disease susceptibility, exercise capacity, or emphysema distribution.

Results: A SNP upstream from glutathione S-transferase pi (GSTP1; p = 0.003) and a coding SNP in microsomal epoxide hydrolase (EPHX1; p = 0.02) were each associated with change in BODE score. These effects appeared to be strongest in patients in the non-upper lobe predominant, low exercise subgroup. A promoter SNP in EPHX1 was associated with change in BODE score (p = 0.008), with the strongest effects in patients with upper lobe predominant emphysema and low exercise capacity. One additional SNP in GSTP1 and three additional SNPs in EPHX1 were associated (p < 0.05) with additional LVRS outcomes. None of these SNP effects were seen in 166 patients randomized to medical therapy.

Conclusion: Genetic variants in GSTP1 and EPHX1, two genes encoding xenobiotic metabolizing enzymes, were predictive of response to LVRS. These polymorphisms may identify patients most likely to benefit from LVRS.

Figure 1

Frequency distributions of changes in outcomes at six months in 203 lung volume reduction surgery patients in the NETT Genetics Ancillary Study. BODE = Body mass index, airflow Obstruction Dyspnea Exercise tolerance; FEV₁= forced expiratory volume in 1 second; CPET = cardiopulmonary exercise test; UCSD SOBQ = University of California, San Diego shortness of breath questionnaire

Figure 2

Effect of GSTP1 rs612020 polymorphism in patient subgroups defined by emphysema distribution and baseline exercise capacity. Six month change in BODE score is shown. The grey box represents the interquartile range, and the black line marks the median. One individual with T/T genotype has been removed for clarity of presentation.

Figure 3

Effect of EPHX1 rs3753658 promoter polymorphism in patient subgroups defined by emphysema distribution and baseline exercise capacity. Six month change in BODE score is shown. The grey box represents the interquartile range, and the black line marks the median. Three individuals with T/T genotype have been removed for clarity of presentation.