Polymorphism at the glutathione S-transferase GSTP1 locus - A new marker for bronchial hyperresponsiveness and asthma

Most genetic studies of asthma have concentrated on genes on chromosomes 11 q and 5q and their association with the key asthma-related phenotypes of br onchial hyperresponsiveness (BHR) and atopy. Although asthma is characteriz ed by airway inflammation, a critical component of which is oxidative stres s, few data exist on genes involved in protecting against this insult. We d escribe an association study designed to examine whether allelic variation at the glutathione-S-transferase GSTP1 locus influences expression of the B HR and atopy phenotypes in asthma. The enzyme encoded by GSTP1 utilizes a v ariety of lipid and DNA products of oxidative stress, and polymorphic varia nts of this gene are associated with altered catalytic function of this enz yme. We found that the frequency of CSTP1 Val(105)/Va(105) was significantl y lower in asthmatic than in control subjects. Indeed, the presence of this genotype conferred a sixfold lower risk of asthma than did GSTP1 Ile(105)/ Ile(105). Remarkably, asthma risk in Va(105) homozygotes was further reduce d (by ninefold) after correction for atopic indices, age, and gender. Trend analysis after stratification according to the degree of bronchial reactiv ity/obstruction showed that the frequency of GSTP1 Val(105)/Va(105) correla tes with decreasing severity of airway dysfunction. Furthermore, subjects w ith GSTP1 Val(105)/Val(105) have four- and 10-fold lower risks, respectivel y, of exhibiting atopy defined by skin test positivity and IgE level. These data show that CSTP1 polymorphism is strongly associated with asthma and r elated phenotypes, and provide an alternative explanation for the linkage o f chromosome 11q13 with BHR and atopy.