Title

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 Centre
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

Share

COinS