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 such injury are the epithelial cells lining the airway passages and the lower respiratory gas-exchange areas. While host atopy is a recognized risk factor for airway inflammation, atopy alone cannot cause asthma. We hypothesize that susceptibility to persistent airway inflammation in atopic individuals is characterized by an inherited deficiency in the effectiveness of detoxification of inhaled irritants and products of oxidative stress such as reactive oxygen species (ROS). Our case-control studies show that polymorphisms at the glutathione S-transferase, GSTP1, locus on chromosome 11q13 may account 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 shows a significant decrease of GSTP1 Val/Val (with parallel increase of GSTP1 Ile/Ile) genotype frequency with increasing severity of airflow obstruction/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 protection from the toxic products of ROS-mediated reactions, 2) modulation of eicosanoid synthesis.
Spiteri
M A
MA
Department of Respiratory Medicine, Keele University, Staffordshire, UK. m.spiteri@virgin.net
Bianco
A
A
Strange
R C
RC
Fryer
A A
AA
D016535:Bronchial Hyperreactivity / Q000235:genetics* / Q000503:physiopathology; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000503:physiopathology; D011110:Polymorphism, Genetic / Q000235:genetics*; D012130:Respiratory Hypersensitivity / Q000235:genetics* / Q000503:physiopathology
D005982:Glutathione Transferase