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

Research output: Contribution to journalArticlepeer-review

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
Externally publishedYes

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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