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


CONCLUSIONS
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.
Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. craig.hersh@channing.harvard.edu
Craig P
CP
Hersh
Dawn L
DL
DeMeo
John J
JJ
Reilly
Edwin K
EK
Silverman
D000328:Adult; D000368:Aged; D004646:Emphysema / Q000453:epidemiology / Q000235:genetics* / Q000601:surgery*; D004851:Epoxide Hydrolases / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D051549:Glutathione S-Transferase pi / Q000235:genetics*; D006801:Humans; D008297:Male; D008404:Massachusetts / Q000453:epidemiology; D008875:Middle Aged; D011013:Pneumonectomy / Q000706:statistics & numerical data*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D018570:Risk Assessment / Q000379:methods*; D012307:Risk Factors; D012680:Sensitivity and Specificity; D016896:Treatment Outcome
C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D004851:Epoxide Hydrolases; C522330:EPHX1 protein, human