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

Eric M. Schauberger, Susan L. Ewart*, Syed H. Arshad, Marianne Huebner, Wilfried Karmaus, John W. Holloway, Karen H. Friderici, Julie T. Ziegler, Hongmei Zhang, Matthew J. Rose-Zerilli, Sheila J. Barton, Stephen T. Holgate, Jeffrey R. Kilpatrick, John B. Harley, Stephane Lajoie-Kadoch, Isaac T.W. Harley, Qutayba Hamid, Ramesh J. Kurukulaaratchy, Max A. Seibold, Pedro C. AvilaWilliam Rodriguez-Cintrón, Jose R. Rodriguez-Santana, Donglei Hu, Christopher Gignoux, Isabelle Romieu, Stephanie J. London, Esteban G. Burchard, Carl D. Langefeld, Marsha Wills-Karp

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)753-760.e11
JournalJournal of Allergy and Clinical Immunology
Volume128
Issue number4
DOIs
StatePublished - Oct 2011

Keywords

  • ATPAF1
  • Asthma
  • SNP
  • children
  • gene
  • genetic
  • genome-wide association
  • purinergic
  • respiratory
  • single nucleotide polymorphism

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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