engleski

Polymorphisms in region 20p13-p12 and their interaction with environmental tobacco smoke exposure in relation to asthma severity

ADAM33 is the first asthma gene identified by positional cloning. Since the first report, there have been a number of replications studies with diverse results. Possible explanations for the heterogeneity between the studies include the effects of other genes in the vicinity, gene-gene and gene-environment interactions. We aimed to investigate the association between genes in the 20p13-p12 region (ADAM33 and flanking genes ATRN, GFRA4, SIGLEC1 and HSPA12B) and markers of asthma severity (lung function and severe exacerbations) amongst schoolchildren with asthma. The effect of early- life environmental tobacco smoke (ETS) exposure on asthma severity in the context of genetic variants was also evaluated. Four hundred and twenty-three children with asthma aged 5–18 years were recruited into the study if the following criteria were met: (i) physician-diagnosed asthma, (ii) asthma symptoms within the previous 12 months, and (iii) use of antiasthma medication. We measured lung function (FEF50) using spirometry and extracted data on hospitalisation for severe asthma exacerbation from medical records. Early-life environmental tobacco smoke (ETS) exposure was assessed by questionnaire. We genotyped 124 single nucleotide polymorphisms (SNPs) from five genes in the 20p13-p12 region. Twentynine SNPs were significantly associated with FEF50, of which 12 (six ARTN, one ADAM33, four SIGLEC1 and one HSPA12B) remained significant after false discovery rate (FDR) correction. Two SNPs (one in ADAM33 and one in SIGLEC1) were associated with severe exacerbations. We observed a significant interaction between nine SNPs and earlylife ETS exposure in relation to FEF50, and one SNP in relation to severe exacerbations. For example, for rs512625 in ADAM33 there was significant interaction with ETS exposure in relation to severe exacerbations (Pint = 0.02) and FEF50 (Pint = 0.03) ; G-allele homozygotes had higher risk of being hospitalised [aOR 9.15, 95% CI 2.28–36.89] and had significantly poorer lung function if exposed to ETS, with no effect of ETS exposure amongst A-allele carriers. Genetic variants in 20p13-p12 region have impact on severity of disease among children with asthma and interact with early life ETS exposure in modifying asthma severity.

region 20p ; tobacco smoke exposure ; asthma

DOI: 10.1111/all.12247