Childhood asthma is associated with mutations and gene expression differences of ORMDL genes that can interact

Allergy. 2015 Oct;70(10):1288-99. doi: 10.1111/all.12652. Epub 2015 Jul 20.

Abstract

Background: Genomewide association studies identified ORMDL3 as a plausible asthma candidate gene. ORMDL proteins regulate sphingolipid metabolism and ceramide homeostasis and participate in lymphocyte activation and eosinophil recruitment. Strong sequence homology between the three ORMDL genes and ORMDL protein conservation among different species suggest that they may have shared functions. We hypothesized that if single nucleotide polymorphisms (SNPs) in ORMDL3 alter its gene expression and play a role in asthma, variants in ORMDL1 and ORMDL2 might also be associated with asthma.

Methods: Asthma associations of 44 genotyped SNPs were determined in at least 1303 subjects (651 asthmatics). ORMDL expression was evaluated in peripheral blood mononuclear cells (PBMC) from 55 subjects (eight asthmatics) before and after allergen stimulation, and in blood (n = 60, 5 asthmatics). Allele-specific cis-effects on ORMDL expression were assessed. Interactions between human ORMDL proteins were determined in living cells.

Results: Sixteen SNPs in all three ORMDLs were associated with asthma (14 in ORMDL3). Baseline expression of ORMDL1 (P = 1.7 × 10(-6) ) and ORMDL2 (P = 4.9 × 10(-5) ) was significantly higher in PBMC from asthmatics, while induction of ORMDLs upon stimulation was stronger in nonasthmatics. Disease-associated alleles (rs8079416, rs4795405, rs3902920) alter ORMDL3 expression. ORMDL proteins formed homo- and heterooligomers and displayed similar patterns of interaction with SERCA2 and SPT1.

Conclusions: Polymorphisms in ORMDL genes are associated with asthma. Asthmatics exhibit increased ORMDL levels, suggesting that ORMDLs contribute to asthma. Formation of heterooligomers and similar interaction patterns with proteins involved in calcium homeostasis and sphingolipid metabolism could indicate shared biological roles of ORMDLs, influencing airway remodeling and hyperresponsiveness.

Keywords: bioluminescence energy transfer; childhood asthma; peripheral blood mononuclear cells; protein-protein interaction; single nucleotide polymorphism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Alleles
  • Asthma / genetics*
  • Asthma / immunology
  • Asthma / metabolism
  • Case-Control Studies
  • Chromosome Mapping
  • Epistasis, Genetic
  • Female
  • Gene Expression Regulation*
  • Genetic Association Studies*
  • Genetic Predisposition to Disease*
  • Genotype
  • Humans
  • Linkage Disequilibrium
  • Male
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Multigene Family
  • Mutation*
  • Odds Ratio
  • Polymorphism, Single Nucleotide
  • Protein Binding

Substances

  • Membrane Proteins
  • ORMDL1 protein, human
  • ORMDL2 protein, human
  • ORMDL3 protein, human