Correction of bronchial challenge data for age and size may affect the results of genetic association studies in children

Abstract

Meaningful studies of asthma genetics require careful definition of airway hyperresponsiveness (AHR). In children, several studies have emphasized the need for correction of bronchial challenge data for baseline parameters, such as age, gender, lung function and atopic status, when undertaking airway responsiveness measurements. However, few studies have suggested how this should be performed in practice. This study describes a method for the correction of dose-response slopes (DRS) and PC20 values for baseline parameters in children, and illustrates the effect of such corrections on the association of AHR with the glutathione S-transferase GSTP1 Ile105Val polymorphism in children. Skin prick and methacholine challenge testing, measurement of total serum IgE concentration and GSTP1 genotyping were performed in 145 unrelated British children aged 7-18 years. Correction of bronchial challenge results, expressed as both DRS and PC20 values, for age, gender, baseline lung function and atopic status was performed using linear regression and discriminant analysis, respectively. Adjusting bronchial challenge results for the age and size of the child altered AHR status, defined as a PC20 methacholine <8 mg/ml, in 37% of children. Correction for baseline parameters also resulted in a significant reduction in mean DRS (original uncorrected DRS 83.6, corrected DRSc 27.4). This had a marked effect on the results of the association study, unmasking a previously unidentified association between the GSTP1 genotype and AHR in children. Age and size adjustment of bronchial challenge data has a significant effect on AHR status and may influence the results of genetic association studies in children.

Maternal glutathione S‐transferase GSTP1 genotype is a specific predictor of phenotype in children with asthma

“…In a population of asthmatic families from North Staffordshire we have demonstrated a protective effect of child and maternal GSTP1 Val 105 /Val 105 genotype on measures of corrected AHR (17). Paternal GSTP1 Val 105 /Val 105 genotype did not influence offspring corrected AHR, and the effects of maternal GSTP1 genotype appeared independent of transmission to the offspring.…”

“…This genotype has been shown to protect against the asthma phenotypes of airway hyperresponsiveness (AHR) and atopy in adults (13, 14). Moreover, variations in GSTP1 also appear to influence susceptibility to childhood respiratory illness (15; Val 105 /Val 105 being protective), childhood lung function growth (16), atopic status and corrected AHR (17). A further polymorphism is present at codon 114 in exon 6.…”

“…It has been proposed that these differences in enzymatic efficiency may result in differences of asthma risk and phenotype (14). In Caucasian populations 10–15% of individuals are homozygous for the Val 105 /Val 105 genotype (13–17). This genotype has been shown to protect against the asthma phenotypes of airway hyperresponsiveness (AHR) and atopy in adults (13, 14).…”

The genetics of asthma – are the glutathione S‐transferases serious players?

“…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].…”

“…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 increased oxidative stress [6] and that polymorphism in GSTs may influence susceptibility to asthma, atopy and airway hyperresponsiveness (AHR) [7][8][9][10][11][12].…”