Parental Smoking Modifies the Relation between Genetic Variation in Tumor Necrosis Factor-α (TNF) and Childhood Asthma Hao Wu,1 Isabelle Romieu,2 Juan-Jose Sienra-Monge,3 Blanca Estela del Rio-Navarro,3 Daniel M. Anderson,1 Erin W. Dunn,1 Lori L. Steiner,4 Irma del Carmen Lara-Sanchez,2 and Stephanie J. London1,5 1Laboratory of Respiratory Biology, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA; 2National Institute of Public Health, Cuernavaca, Morelos, Mexico; 3Hospital Infantil de Mexico Federico Gomez, Mexico City, Mexico; 4Department of Human Genetics, Roche Molecular Systems, Alameda, California, USA; 5Epidemiology Branch, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA Abstract Background: Polymorphisms in the proinflammatory cytokine genes tumor necrosis factor-α (TNF) and lymphotoxin-α (LTA, also called TNF-β) have been associated with asthma and atopy in some studies. Parental smoking is a consistent risk factor for childhood asthma. Secondhand smoke and ozone both stimulate TNF production. Objectives: Our goal was to investigate whether genetic variation in TNF and LTA is associated with asthma and atopy and whether the association is modified by parental smoking in a Mexican population with high ozone exposure. Methods: We genotyped six tagging single nucleotide polymorphisms (SNPs) in TNF and LTA, including functional variants, in 596 nuclear families consisting of asthmatics 4–17 years of age and their parents in Mexico City. Atopy was determined by skin prick tests. Results: The A allele of the TNF-308 SNP was associated with increased risk of asthma [relative risk (RR) = 1.54 ; 95% confidence interval (CI) , 1.04–2.28], especially among children of nonsmoking parents (RR = 2.06 ; 95% CI, 1.19–3.55 ; p for interaction = 0.09) . Similarly, the A allele of the TNF-238 SNP was associated with increased asthma risk among children of nonsmoking parents (RR = 2.21 ; 95% CI, 1.14–4.30 ; p for interaction = 0.01) . LTA SNPs were not associated with asthma. Haplotype analyses reflected the single SNP findings in magnitude and direction. TNF and LTA SNPs were not associated with the degree of atopy. Conclusions: Our results suggest that genetic variation in TNF may contribute to childhood asthma and that associations may be modified by parental smoking. Key words: allergy, asthma, atopy, environmental tobacco smoke, genetic predisposition to disease, lymphotoxin-α (LTA) , ozone, secondhand smoke, single nucleotide polymorphism (SNP) , tumor necrosis factor-α(TNF) . Environ Health Perspect 115:616–622 (2007) . doi:10.1289/ehp.9740 available via http://dx.doi.org/ [Online 16 January 2007] Address correspondence to S.J. London, NIEHS, PO Box 12233, MD A3-05, Research Triangle Park, NC 27709 USA. Telephone: (919) 541-5772. Fax: (919) 541-2511. E-mail: london2@niehs.nih.gov Supplemental Material is available online at http://www.ehponline.org/docs/2007/9740/suppl.pdf We thank the children and parents who participated in this study ; S. Chanock, National Cancer Institute, for determination of short tandem repeats for parentage testing ; G. Chiu for data management and analysis ; S. Baker, S. Lein, and S. McReynolds for specimen handling ; and D. Ramirez for participation in the fieldwork. This work was funded by Z01 ES49019 from the Division of Intramural Research, NIEHS, NIH, DHHS, and grant 26206-M from CONACYT, Mexico. I.R. is supported by the National Center for Environmental Health at the Centers for Disease Control and Prevention. L.L.S. is employed by Roche Molecular Systems ; genotyping reagents for some analyses were provided by Roche Molecular Systems at no cost under a research collaboration agreement. The authors declare they have no competing financial interests. Received 19 September 2006 ; accepted 16 January 2007. The full version of this article is available for free in HTML or PDF formats. |