EDITORIAL Clinical and Experimental Allergy The genetics of asthma – are the glutathione S-transferases serious players? W. Lenney and A. A. Fryer Human Disease and Genomics Research Group, Institute for Science and Technology in Medicine, Keele University School of Medicine, University Hospital of North Staffordshire, Stoke-on-Trent, Staffordshire, UK The inheritable nature of allergic disease has been known for nearly a century and is well supported by family studies and studies on twins [1, 2]. Asthma as a complex disease is multifactorial, with many candidate genes suspected as being important in its development and outcome. Several candidate genes for asthma are to be found in chromosomal areas that have also been identified by asthma linkage studies. One of the strongest linkages for asthma and atopy is with the b-adrenergic receptor and the cytokine cluster on 5q. Recent exciting associa- tions have been identified with the discovery of a disin- tegrin and metalloprotease (ADAM 33) and linkage on chromosome 20p13 [3]. Also on chromosome 11q13 can be found the high affinity IgE receptor, the clara cell protein, and glutathione-S-transferase P1 (GSTP1), the latter being a candidate gene due to its role in protection against oxidative stress [4]. At the cellular level and under physiological condi- tions, energy-containing molecules released by the mito- chondria combine with oxygen to produce reactive oxygen species (ROS), which are metabolized by glu- tathione peroxidase, catalase and superoxide dismutase. ROS are toxic products that can damage lipids, protein and DNA in airway cells [5]; hence an effective and efficient detoxification process is imperative. The GSTs are a supergene family of enzymes that are essential to the detoxication of these products of oxidative stress. There is increasing evidence that asthma is associated with in- creased oxidative stress [6] and that polymorphism in GSTs may influence susceptibility to asthma, atopy and airway hyperresponsiveness (AHR) [7–12]. In this issue, Mak et al. [13] carried out a case–control study in Hong Kong to test the hypothesis that common genetic variants in members of the GST supergene family and total plasma GST activity affect susceptibility to asthma development in Chinese atopic adults. Their re- sults provide a valuable contribution to the current literature, much of which is derived from western popula- tions. Perhaps the most studied of the GSTs in the context of asthma and lung function is the pi class gene, GSTP1. Fryer et al. [7] first identified that homozygosity of the Val 105 variant was associated with reduced risk of asthma and AHR in a UK adult population, supporting the hypothesis of a role for this gene in protection against oxidative stress. Subsequently, this has been confirmed by Anyacioglu et al. [8], who showed a threefold lower risk of asthma in Val 105 homozygotes compared with the wild- type genotype in a Turkish adult population. Other studies had also confirmed the protective effect of GSTP1 Val 105 homozygosity on asthma phenotypes: in Italian patients with occupational asthma [9], in children with asthma from Taiwan [10], UK [11] and Tunisia [12]. Furthermore, this genotype has been linked to improved lung function in children [14] and in Japanese patients with COPD [15]. However, not all studies support these findings. In addi- tion to the article by Mak et al. in this issue, Brasch- Andersen et al. [16] and Nickel et al. [17] failed to identify a significant association in Danish and German patients, respectively, while Oh et al. [18] did not show any significant associations in both aspirin-tolerant and aspirin-intolerant patients with asthma from Korea. Tamer et al. [19] demonstrated an opposite effect, with Val 105 homozygosity conferring a fourfold increased risk of asthma in a Turkish adult cohort. Despite these contrasting findings, GSTP1 remains a strong candidate for lung growth and lung function in asthma. Its role in lung extends beyond its role as a detoxifying enzyme, with studies showing that the protein product has significant effects on apoptosis and prolifera- tion [4, 20]. Furthermore, Wolf et al. [21] showed that the lungs of GSTP null mice are twice the size of those from wild-type animals. Data from Child et al. [22] and Carroll et al. [23] support a hypothesis of an in utero effect of GSTP1 on lung function by showing that the maternal Correspondence: Prof. Warren Lenney, Academic Department of Paediatrics, Uni- versity Hospital of North Staffordshire, Stoke-on-Trent, Stafford- shire, ST4 6QG UK. E-mail: warren.lenney@uhns.nhs.uk doi: 10.1111/j.1365-2222.2007.02772.x Clinical and Experimental Allergy, 37, 1124–1126  c 2007 The Authors Journal compilation  c 2007 Blackwell Publishing Ltd