Am. J. Respir. Crit. Care Med., Volume 161, Number 5, May 2000, 1437-1442

Polymorphism at the Glutathione S-transferase GSTP1 Locus
A New Marker for Bronchial Hyperresponsiveness and Asthma

ANTHONY A. FRYER, ANDREA BIANCO, MICHAEL HEPPLE, PETER W. JONES, RICHARD C. STRANGE, and MONICA A. SPITERI

Department of Respiratory Medicine and Clinical Biochemistry Research Laboratory, Centre for Cell and Molecular Medicine, North Staffordshire Hospital, Keele University, and Department of Mathematics, Keele University, Staffordshire, United Kingdom

Most genetic studies of asthma have concentrated on genes on chromosomes 11q and 5q and their association with the key asthma-related phenotypes of bronchial hyperresponsiveness (BHR) and atopy. Although asthma is characterized by airway inflammation, a critical component of which is oxidative stress, few data exist on genes involved in protecting against this insult. We describe an association study designed to examine whether allelic variation at the glutathione-S-transferase GSTP1 locus influences expression of the BHR and atopy phenotypes in asthma. The enzyme encoded by GSTP1 utilizes a variety of lipid and DNA products of oxidative stress, and polymorphic variants of this gene are associated with altered catalytic function of this enzyme. We found that the frequency of GSTP1 Val¹⁰⁵/Val¹⁰⁵ was significantly lower in asthmatic than in control subjects. Indeed, the presence of this genotype conferred a sixfold lower risk of asthma than did GSTP1 Ile¹⁰⁵/Ile¹⁰⁵. Remarkably, asthma risk in Val¹⁰⁵ homozygotes was further reduced (by ninefold) after correction for atopic indices, age, and gender. Trend analysis after stratification according to the degree of bronchial reactivity/obstruction showed that the frequency of GSTP1 Val¹⁰⁵/Val¹⁰⁵ correlates with decreasing severity of airway dysfunction. Furthermore, subjects with GSTP1 Val¹⁰⁵/Val¹⁰⁵ have four- and 10-fold lower risks, respectively, of exhibiting atopy defined by skin test positivity and IgE level. These data show that GSTP1 polymorphism is strongly associated with asthma and related phenotypes, and provide an alternative explanation for the linkage of chromosome 11q13 with BHR and atopy.

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