Identification of ATPAF1 as a novel candidate gene for asthma in children

Authors

• Eric M. Schauberger, Michigan State University
• Susan L. Ewart, Michigan State University
• Syed H. Arshad, David Hide Asthma and Allergy Research CentreFollow
• Marianne Huebner, Michigan State University
• Wilfried Karmaus, University of South Carolina
• John W. Holloway, University of Southampton, Faculty of Medicine
• Karen H. Friderici, Michigan State University
• Julie T. Ziegler, Wake Forest School of Medicine
• Hongmei Zhang, University of South CarolinaFollow
• Matthew J. Rose-Zerilli, University of Southampton, Faculty of Medicine
• Sheila J. Barton, University of Southampton, Faculty of Medicine
• Stephen T. Holgate, University of Southampton, Faculty of Medicine
• Jeffrey R. Kilpatrick, JKA Genomics
• John B. Harley, JKA Genomics
• Stephane Lajoie-Kadoch, Cincinnati Children's Hospital
• Isaac T.W. Harley, Cincinnati Children's Hospital
• Qutayba Hamid, Meakins-Christie Laboratories
• Ramesh J. Kurukulaaratchy, David Hide Asthma and Allergy Research CentreFollow
• Max A. Seibold, National Jewish Health
• Pedro C. Avila, Northwestern University Feinberg School of Medicine
• William Rodriguez-Cintrón, San Juan VA Medical Center
• Jose R. Rodriguez-Santana, CSP
• Donglei Hu, University of California, San Francisco
• Christopher Gignoux, University of California, San Francisco
• Isabelle Romieu, Instituto Nacional de Salud Pública. México
• Stephanie J. London, National Institute of Environmental Health Sciences (NIEHS)
• Esteban G. Burchard, University of California, San Francisco
• Carl D. Langefeld, Wake Forest School of Medicine
• Marsha Wills-Karp, Cincinnati Children's Hospital

Abstract

Background: Asthma is a common disease of children with a complex genetic origin. Understanding the genetic basis of asthma susceptibility will allow disease prediction and risk stratification. Objective: We sought to identify asthma susceptibility genes in children. Methods: A nested case-control genetic association study of children of Caucasian European ancestry from a birth cohort was conducted. Single nucleotide polymorphisms (SNPs, n = 116,024) were genotyped in pools of DNA samples from cohort children with physician-diagnosed asthma (n = 112) and normal controls (n = 165). A genomic region containing the ATPAF1 gene was found to be significantly associated with asthma. Additional SNPs within this region were genotyped in individual samples from the same children and in 8 independent study populations of Caucasian, African American, Hispanic, or other ancestries. SNPs were also genotyped or imputed in 2 consortia control populations. ATPAF1 expression was measured in bronchial biopsies from asthmatic patients and controls. Results: Asthma was found to be associated with a cluster of SNPs and SNP haplotypes containing the ATPAF1 gene, with 2 SNPs achieving significance at a genome-wide level (P = 2.26 × 10-5 to 2.2 × 10-8). Asthma severity was also found to be associated with SNPs and SNP haplotypes in the primary population. SNP and/or gene-level associations were confirmed in the 4 non-Hispanic populations. Haplotype associations were also confirmed in the non-Hispanic populations (P =.045-.0009). ATPAF1 total RNA expression was significantly (P <.01) higher in bronchial biopsies from asthmatic patients than from controls. Conclusion: Genetic variation in the ATPAF1 gene predisposes children of different ancestries to asthma. © 2011 American Academy of Allergy, Asthma & Immunology.

Publication Title

Journal of Allergy and Clinical Immunology

Recommended Citation

Schauberger, E., Ewart, S., Arshad, S., Huebner, M., Karmaus, W., Holloway, J., Friderici, K., Ziegler, J., Zhang, H., Rose-Zerilli, M., Barton, S., Holgate, S., Kilpatrick, J., Harley, J., Lajoie-Kadoch, S., Harley, I., Hamid, Q., Kurukulaaratchy, R., Seibold, M., Avila, P., Rodriguez-Cintrón, W., Rodriguez-Santana, J., Hu, D., Gignoux, C., Romieu, I., London, S., Burchard, E., Langefeld, C., & Wills-Karp, M. (2011). Identification of ATPAF1 as a novel candidate gene for asthma in children. Journal of Allergy and Clinical Immunology, 128 (4) https://doi.org/10.1016/j.jaci.2011.04.058