Functional Variant in the Autophagy-Related 5 Gene Promotor is Associated with Childhood Asthma

Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, United States of America.
PLoS ONE (Impact Factor: 3.23). 04/2012; 7(4):e33454. DOI: 10.1371/journal.pone.0033454
Source: PubMed


Autophagy is a cellular process directed at eliminating or recycling cellular proteins. Recently, the autophagy pathway has been implicated in immune dysfunction, the pathogenesis of inflammatory disorders, and response to viral infection. Associations between two genes in the autophagy pathway, ATG5 and ATG7, with childhood asthma were investigated.
Using genetic and experimental approaches, we examined the association of 13 HapMap-derived tagging SNPs in ATG5 and ATG7 with childhood asthma in 312 asthmatic and 246 non-allergic control children. We confirmed our findings by using independent cohorts and imputation analysis. Finally, we evaluated the functional relevance of a disease associated SNP.
We demonstrated that ATG5 single nucleotide polymorphisms rs12201458 and rs510432 were associated with asthma (p = 0.00085 and 0.0025, respectively). In three independent cohorts, additional variants in ATG5 in the same LD block were associated with asthma (p<0.05). We found that rs510432 was functionally relevant and conferred significantly increased promotor activity. Furthermore, Atg5 expression was increased in nasal epithelium of acute asthmatics compared to stable asthmatics and non-asthmatic controls.
Genetic variants in ATG5, including a functional promotor variant, are associated with childhood asthma. These results provide novel evidence for a role for ATG5 in childhood asthma.

Download full-text


Available from: Jocelyn Biagini Myers,
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Purpose of review: Asthma is a common worldwide respiratory illness with significant morbidity and mortality. The disease is characterized by airway inflammation with involvement of multiple biological pathways. Genetic predisposition and increased susceptibility to severe respiratory viral infections are well known clinical features of asthma. Autophagy is an evolutionarily conserved cellular degradation process with significant impact on immunity and antiviral response. In this review we have described the role of autophagy in immune cell survival, proliferation and function. Autophagy has complex effects on immune response involved in inflammation, specifically Th2 immune response. Common respiratory viruses are associated with increased morbidity and mortality in asthmatic patients. Recent findings: We describe recent studies showing the effect of autophagy on replication and immune response to common respiratory viruses. The role of autophagy in asthma has recently been investigated. Two studies have been published describing the association of autophagy with asthma. Genetic polymorphism in specific autophagy genes is associated with asthma and influences gene expression in an experimental in-vivo model. Summary: These studies provide us with a window into the possible role of autophagy in asthma and offer new clues to pathogenesis. Modulation of autophagy has the potential to develop into a new therapeutic avenue to treat this common respiratory ailment.
    Current opinion in pulmonary medicine 11/2012; 19(1). DOI:10.1097/MCP.0b013e32835b1150 · 2.76 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Majority of PD are sporadic, for which genetic causes remain largely unknown. Alpha-synuclein, the main component of Lewy bodies, plays a central role in the PD pathogenesis. Macroautophagy is a highly conserved cellular process that digests dysfunctional macromolecules and damaged organelles. Accumulating evidence indicates that macroautophagy (hereafter referred to as autophagy) is involved in alpha-synuclein degradation. Dysregulation of autophagy has been observed in the brain tissues from PD patients and animal models. We hypothesized that change expression levels of autophagy-related genes (ATG), including ATG5, may contribute to PD. In this study, we genetically and functionally analyzed the ATG5 gene promoter in groups of sporadic PD patients and ethic-matched healthy controls. A novel heterozygous variant, 106774459T>A, was identified in one female patient, but in none of controls, which significantly enhanced transcriptional activities of the ATG5 gene promoter. Furthermore, ATG5 gene expression level in the PD patient was significantly elevated than that in controls. Four novel heterozygous variants, 106774423C>A, 106774418C>A, 106774382C>A and 106774206G>A, were only found in controls. The variant, 106774464C>T, and SNP-106774030A>G (rs510432) were found in PD patients and controls with similar frequencies. Collectively, the variant identified in PD patient may change ATG5 protein levels and alter autophagy activities, contributing to PD onset as a risk factor.
    Neuroscience Letters 02/2013; 538. DOI:10.1016/j.neulet.2013.01.044 · 2.03 Impact Factor
  • Source

    New England Journal of Medicine 02/2013; 368(7):651-62. DOI:10.1056/NEJMra1205406 · 55.87 Impact Factor
Show more