Elisabet Johansson1, Lisa J Martin2,3, Hua He2, Xiaoting Chen4, Matthew T Weirauch3,4,5, John W Kroner1, Gurjit K Khurana Hershey1,3, Jocelyn M Biagini1,3. 1. Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA. 2. Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA. 3. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. 4. Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA. 5. Divisions of Biomedical Informatics and Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Abstract
BACKGROUND: Second-hand smoke (SHS) exposure is associated with paediatric asthma, and oxidative stress is believed to play a role in mediating this association. The nuclear factor (erythroid-derived 2)-like 2 (NFE2L2) is important for the defence against oxidative stress. OBJECTIVE: To explore interactions between NFE2L2 genotype and SHS exposure in paediatric asthma risk. METHODS: We used a genotyped subset of patients of European ancestry (N = 669, median age at enrolment = 6.8 years) enrolled in the clinical cohort Greater Cincinnati Pediatric Clinic Repository as the study population, and a population-based paediatric cohort (N = 791) to replicate our findings. History of asthma diagnosis was obtained from medical records, and SHS exposure was obtained from questionnaires. Four NFE2L2 tagging SNPs were included in the analysis, and interactions between SHS and NFE2L2 genotype were evaluated using logistic regression. RESULTS: Three of the analysed SNPs, rs10183914, rs1806649 and rs2886161, interacted significantly with SHS exposure to increase asthma risk (p ≤ .02). The interaction was replicated in an independent cohort for rs10183914 (p = .04). Interactions between SHS exposure and NFE2L2 genotype were also associated with an increased risk of hospitalization (p = .016). In stratified analyses, NFE2L2 genotype was associated with daily asthma symptoms in children with SHS exposure (OR = 3.1; p = .048). No association was found in children without SHS exposure. Examination of publicly available chromatin immunoprecipitation followed by sequencing (ChIP-seq) data sets confirmed the presence of active histone marks and binding sites for particular transcription factors overlapping the coordinates for the significantly associated SNPs. CONCLUSIONS AND CLINICAL RELEVANCE: Our study provides evidence that NFE2L2 genotype interacts with SHS exposure to affect both asthma risk and severity in children and identifies a population of children at increased risk of asthma development.
BACKGROUND: Second-hand smoke (SHS) exposure is associated with paediatric asthma, and oxidative stress is believed to play a role in mediating this association. The nuclear factor (erythroid-derived 2)-like 2 (NFE2L2) is important for the defence against oxidative stress. OBJECTIVE: To explore interactions between NFE2L2 genotype and SHS exposure in paediatric asthma risk. METHODS: We used a genotyped subset of patients of European ancestry (N = 669, median age at enrolment = 6.8 years) enrolled in the clinical cohort Greater Cincinnati Pediatric Clinic Repository as the study population, and a population-based paediatric cohort (N = 791) to replicate our findings. History of asthma diagnosis was obtained from medical records, and SHS exposure was obtained from questionnaires. Four NFE2L2 tagging SNPs were included in the analysis, and interactions between SHS and NFE2L2 genotype were evaluated using logistic regression. RESULTS: Three of the analysed SNPs, rs10183914, rs1806649 and rs2886161, interacted significantly with SHS exposure to increase asthma risk (p ≤ .02). The interaction was replicated in an independent cohort for rs10183914 (p = .04). Interactions between SHS exposure and NFE2L2 genotype were also associated with an increased risk of hospitalization (p = .016). In stratified analyses, NFE2L2 genotype was associated with daily asthma symptoms in children with SHS exposure (OR = 3.1; p = .048). No association was found in children without SHS exposure. Examination of publicly available chromatin immunoprecipitation followed by sequencing (ChIP-seq) data sets confirmed the presence of active histone marks and binding sites for particular transcription factors overlapping the coordinates for the significantly associated SNPs. CONCLUSIONS AND CLINICAL RELEVANCE: Our study provides evidence that NFE2L2 genotype interacts with SHS exposure to affect both asthma risk and severity in children and identifies a population of children at increased risk of asthma development.
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Authors: Cassandra C Brooks; Lisa J Martin; Valentina Pilipenko; Hua He; Grace K LeMasters; James E Lockey; David I Bernstein; Patrick H Ryan; Gurjit K Khurana Hershey; Jocelyn M Biagini Myers Journal: J Asthma Date: 2019-12-06 Impact factor: 2.515
Authors: Melinda Butsch Kovacic; Jocelyn M Biagini Myers; Ning Wang; Lisa J Martin; Mark Lindsey; Mark B Ericksen; Hua He; Tia L Patterson; Tesfaye M Baye; Dara Torgerson; Lindsey A Roth; Jayanta Gupta; Umasundari Sivaprasad; Aaron M Gibson; Anna M Tsoras; Donglei Hu; Celeste Eng; Rocío Chapela; José R Rodríguez-Santana; William Rodríguez-Cintrón; Pedro C Avila; Kenneth Beckman; Max A Seibold; Chris Gignoux; Salma M Musaad; Weiguo Chen; Esteban González Burchard; Gurjit K Khurana Hershey Journal: PLoS One Date: 2011-08-30 Impact factor: 3.240