Elsevier

The Lancet

Volume 350, Issue 9078, 30 August 1997, Pages 630-633
The Lancet

Early Report
Association between polymorphism in gene for microsomal epoxide hydrolase and susceptibility to emphysema

https://doi.org/10.1016/S0140-6736(96)08061-0Get rights and content

Summary

Background

The first-pass metabolism of foreign compounds in the lung is an important protective mechanism against oxidative stress. We investigated whether polymorphisms in the gene for microsomal epoxide hydrolase (mEPHX), an enzyme involved in this protective process, had any bearing on individual susceptibility to the development of chronic obstructive pulmonary disease (COPD) and emphysema.

Methods

We designed PCR-based genotyping assays to detect variant forms of mEPHX that confer slow and fast activity. We used these assays to screen 203 blood-donor controls and groups of patients with asthma (n=57), lung cancer (n=50), COPD (n=68), and emphysema (n=94), who were attending specialised clinics in Edinburgh, UK.

Findings

The proportion of individuals with innate slow mEPHX activity (homozygotes) was significantly higher in both the COPD group and the emphysema group than in the control group (COPD 13 [19%] vs control 13 [6%]; emphysema 21 [22%] vs 13 [6%]). The odds ratios for homozygous slow activity versus all other phenotypes were 4·1 (95% CI 1·8–9·7) for COPD and 5·0 (2·3–10·9) for emphysema.

Interpretation

Genetic polymorphisms in xenobiotic enzymes may have a role in individual susceptibility to oxidant-related lung disease. Epoxide derivatives of cigarette-smoke components may be the cause of some of the lung damage characteristic of these diseases.

Introduction

The lungs are subject to oxidative stress from cigarette smoke, occupational exposure to solvents, and other chemicals and environmental pollutants. All these potential hazards contain factors (xenobiotics and oxidants) that can induce severe macromolecular, cellular, and tissue damage through direct cytotoxic effects, promotion of primary genotoxic events, or generation of reactive oxygen intermediates.

Chronic obstructive pulmonary disease (COPD) is characterised by fixed and irreversible air-flow limitation in the lungs, and emphysema is distinguished by abnormal, permanent distal air-space enlargement accompanied by destruction of lung parenchyma. Two lines of research are relevant to the study of emphysema in particular. First, some findings suggest that lung damage can be attributed to an imbalance in the endogenous protease/antiprotease equilibrium, promoting tissue hydrolysis;1–3 examples of such imbalance include the genetically determined α1-antitrypsin deficiency,3, 4 and the overexpression of elastases and collagenases that mimics the development of pulmonary emphysema.7, 8 Second, the oxidant/antioxidant theory postulates that an excess of oxidants and free radicals in the lung promotes cellular and tissue damage and is the major initiator of the disease process.9, 10 Cigarette smoke, oxidants, xenobiotics, and reactive oxygen intermediates directly inhibit antiproteases and promote cell and tissue proteolysis.1, 11, 12

Tobacco smoke is the commonest identifiable risk factor for both emphysema and COPD. Combustion products released into the respiratory tract include various highly reactive oxygen and carbon-centred species, free radicals in the vapour phase, and stable radicals in particulate matter.

Microsomal epoxide hydrolase (mEPHX) is an enzyme involved in the first-pass metabolism of highly reactive epoxide intermediates. We investigated whether genetic polymorphisms in the gene for this enzyme have any bearing on the development of oxidant-related lung disease. Epidemological studies show that mEPHX activity in the liver, lung, and peripheral blood leucocytes varies as much as 50-fold in white populations.13 Two common aberrant alleles can be detected, which confer slow and fast enzyme activity.14 We have designed PCR assays to detect these mutations and have used them to study the role of the gene in protection against oxidative damage to the lung.

Section snippets

Patients and methods

203 control blood samples were obtained from the Scottish National Blood Transfusion Service. These anonymous donors were all white individuals aged between 18 and 65 years; roughly equal numbers were male and female. Because emphysema is a morphological diagnosis, we cannot be certain that some controls did not have early emphysema; however, all were clinically healthy on routine questioning and therefore met the usual criteria for blood donation.

All patients were fully investigated clinically

Results

The PCR produced amplimers of the expected size and differentiated between individual mEPHX genotypes in the study populations (figure). In the control group the slow allele was three times more common than the fast variant-13 (6%) of 203 individuals were homozygous for the exon-3 mutation (slow) and 99 (49%) were heterozygous. In comparison, the exon-4 polymorphism (fast) was detected in only 56 (28%) individuals, and only three individuals were homozygous for this variant (table 1).

The

Discussion

Our demonstration of an association between genetically defined polymorphisms in mEPHX activity and susceptibility to COPD and emphysema suggests that highly reactive epoxide intermediates may have a role in the initiation and progression of the characteristic tissue abnormalities seen in emphysema. The very slow phenotype was four to five times more common in both the COPD and emphysema groups than in controls. Also, the proportions of the emphysema group with normal and fast mEPHX phenotypes

References (21)

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