Polymorphisms at the glutathione S-transferase, GSTP1 locus: a novel mechanism for susceptibility and development of atopic airway inflammation

A common feature of environmental irritants is their ability to cause local inflammation which could alter airway function. The principal targets of s uch injury are the epithelial cells lining the airway passages and the lowe r respiratory gas-exchange areas. While host atopy is a recognized risk fac tor for airway inflammation, atopy alone cannot cause asthma. We hypothesiz e that susceptibility to persistent airway inflammation in atopic individua ls is characterized by an inherited deficiency in the effectiveness of deto xification of inhaled irritants and products of oxidative stress such as re active oxygen species (ROS). Our case-control studies show that polymorphis ms at the glutathione S-transferase, GSTP1, locus on chromosome 11q13 may a ccount for variation in host response to oxidative stress, a key component of airway inflammation. Frequency of the GSTP1 Val/Val genotype is reduced in atopic subjects compared with nonatopic subjects. Trend analysis also sh ows a significant decrease of GSTP1 Val/Val (with parallel increase of GSTP 1 Ile/Ile) genotype frequency with increasing severity of airflow obstructi on/bronchial hyperresponsiveness. The implication of specific polymorphisms at the GSTP1 locus in airway inflammation is entirely novel: however, GST are recognized as a supergene family of enzymes critical in 1) cell protect ion from the toxic products of ROS-mediated reactions, 2) modulation of eic osanoid synthesis.