Genetic variants of microsomal epoxide hydrolase and glutamate-cysteine ligase in COPD

¹ The University of Nottingham. Division of Clinical Chemistry, Molecular Medical Sciences, Institute of Genetics, University Hospital, Queens Medical Centre, Nottingham, NG7 2UH, UK
² University College Dublin. UCD School of Public Health & Population Science, UCD, Belfield, Dublin 4, IRELAND
³ Hospital Clinico y Provincial de Barcelona. Service de Pneumologia, Hospital Clinic, Villarroel, 170, 08036, Barcelona, SPAIN.
⁴ University of Bristol. Lung Research Group, Department of Clinical Science at North Bristol, Southmead Hospital, Westbury on Trym, Bristol BS10 5NB, UK
⁵ University College Dublin. UCD School of Medicine and Medical Science, The Conway Institute, UCD, Belfield, Dublin 4, IRELAND
⁶ Letterkenny General Hospital, Letterkenny, Co. Donegal, Ireland
⁷ ELEGI Colt Laboratories, MRC Centre for Inflammation Research, Level 2, Room C2.29, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ.
⁸ Leiden University Medical Center, Department of Pulmonology (C3-P), Albinusdreef 2, P.O. Box 9600, 2300 RC Leiden, THE NETHERLANDS
⁹ CNR Institute of Clinical Physiology, Via G. Moruzzi 1-56124, Pisa, ITALY
¹⁰ University College Dublin. UCD School of Medicine and Medical Science, The Conway Institute, UCD, Belfield, Dublin 4, IRELAND; and Joint senior authors.
¹¹ The University of Nottingham. Division of Clinical Chemistry, Molecular Medical Sciences, Institute of Genetics, University Hospital, Queens Medical Centre, Nottingham, NG7 2UH, UK; and Joint senior authors.

^* To whom correspondence should be addressed. E-mail: noor.kalsheker{at}nottingham.ac.uk.

	Abstract

The genetic factors that contribute to the development of Chronic Obstructive Pulmonary Disease (COPD) are poorly understood. Many candidate genes have been proposed, including enzymes which protect the lung against oxidative stress such as microsomal epoxide hydrolase (EPHX1) and glutamate-cysteine ligase (GCL). To date, most reported findings have been for EPHX1, particularly in relation to functional variants associated with fast and slow metabolism of epoxide intermediates. We aimed to identify any association of variation in these genes with COPD susceptibility or severity.

We genotyped 1, 017 Caucasian COPD patients and 912 non-diseased age and sex matched smoking controls for six single nucleotide polymorphisms (SNPs) in EPHX1 (including the fast and slow variants and associated haplotypes), and eight SNPs in the two genes encoding GCL. GCL is a rate-limiting enzyme in the synthesis of glutathione, a major contributor to anti-oxidant protection in the lung.

We found no association of variation in EPHX1 or GCL with susceptibility to COPD or disease severity.

This is the largest reported study to date and is well powered to detect associations that have been previously suggested. Our data indicate that these genetic variants are unlikely to be related to susceptibility or disease severity in COPD in Caucasians.

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