ORIGINAL ARTICLE Interaction between early maternal smoking and variants in TNF and GSTP1 in childhood wheezing S. Panasevich 1 , C. Lindgren 2 , J. Kere 3,4,5 , M. Wickman 1,6,7 , G. Pershagen 1,8 , F. Nyberg 1,9 and E. Mel´ en 1,7,10 1 Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden, 2 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, 3 Clinical Research Centre, Karolinska University Hospital, Huddinge, Sweden, 4 Department of Medical Genetics, University of Helsinki, Helsinki, Finland, 5 Department of Biosciences at Novum, Karolinska Institutet, Huddinge, Sweden, 6 Sachs Children’s Hospital, Stockholm, Sweden, 7 Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden, 8 Department of Community Medicine, Karolinska University Hospital, Stockholm, Sweden, 9 AstraZeneca R&D M ¨ olndal, M ¨ olndal, Sweden and 10 Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden Clinical & Experimental Allergy Correspondence: S. Panasevich, Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE-171 77, Stockholm, Sweden. E-mail: sviatlana.panasevich@ki.se Cite this as: S. Panasevich, C. Lindgren, J. Kere, M. Wickman, G. Pershagen, F. Nyberg and E. Mel´ en, Clinical & Experimental Allergy , 2010 (40) 458–467. Summary Background Children exposed to tobacco smoke early in life have a higher risk of wheeze. Individual susceptibility may depend on genetic factors. Objective We studied whether variations in single nucleotide polymorphisms (SNPs) in the TNF, glutathione S transferase P1 (GSTP1) and b2-adrenoreceptor (ADRB2) genes modify the effect of early maternal smoking on the development of childhood asthma, wheeze and allergic sensitization. Methods In the Swedish prospective birth cohort BAMSE (Children, Allergy, Milieu, Stockholm, Epidemiological Survey) (n = 4089), data collection included questionnaires to measure tobacco smoke exposure and clinical outcomes up to age 4 and medical examinations with blood sampling for specific IgE measurements and genotyping. We defined early maternal smoking as daily smoking by the mother during pregnancy and/or postnatally. We investigated five TNF, six GSTP1 and three ADRB2 SNPs in 982 selected wheezers and non-wheezers. Results An interaction with early maternal smoking was found for three TNF SNPs (857C/T, Intron 1, Intron 3) with respect to early wheeze (up to 2 years of age). For example, the odds ratio (OR) for developing early wheeze related to early maternal smoking was 2.4 [95% confidence interval (CI) 1.6–3.7] in children with a wild-type CC homozygote genotype of the TNF 857 SNP, while no tobacco-related risk was seen in children carrying the rare T allele. A clear dose response was observed in children with the CC genotype, with an OR of 1.3 (95% CI 1.1–1.5) per each additional pack per week smoked by the mother during pregnancy. A suggestive interaction with early maternal smoking was also seen for three GSTP1 SNPs (Intron 5, Intron 6 and Ile105Val) with respect to transient wheeze, but not for ADRB2 and wheeze phenotypes. No effect modifications were observed for allergic sensitization. Conclusion Our results suggest that the risk of early childhood wheeze associated with early maternal smoking may be modified by TNF and GSTP1 polymorphisms. Keywords Asthma, children, environmental tobacco smoke, gene–environment interaction, TNF, wheeze Submitted 4 June 2009; revised 16 October 2009; accepted 7 December 2009 Introduction Exposure to tobacco smoke in utero and early in life leads to oxidative stress, as indicated in blood analysis in newborns and children at 3 months of age [1, 2]. Reactive oxygen species may induce inflammation. Tobacco- exposed children have on average lower birth weight, impaired lung function and changed immune function parameters as well as a higher risk of developing wheeze and asthma [3–5]. The mechanisms leading to these effects are not fully clarified. Applying methods of genetic epidemiology may help in understanding the pathological Epidemiology of Allergic Disease doi: 10.1111/j.1365-2222.2010.03452.x Clinical & Experimental Allergy, 40, 458–467  c 2010 Blackwell Publishing Ltd