ORMDL3

MEDIUM

ORM1-like protein 3

Chromosome: 17q21

Gene Overview

ORMDL3 encodes a transmembrane protein anchored in the endoplasmic reticulum (ER) membrane that acts as a negative regulator of serine palmitoyltransferase (SPT), the rate-limiting enzyme in de novo sphingolipid biosynthesis. By inhibiting SPT, ORMDL3 modulates cellular ceramide levels and downstream sphingolipid metabolites. Overexpression of ORMDL3, as seen in carriers of asthma-risk alleles at 17q21, leads to reduced ceramide synthesis, altered sphingolipid homeostasis, and activation of the unfolded protein response (UPR) in the ER. The 17q21 locus was the first childhood asthma susceptibility locus identified by GWAS and remains one of the most replicated. ORMDL3 expression is upregulated by inflammatory cytokines and allergen exposure, and its dysregulation contributes to airway hyperresponsiveness and remodeling through ER stress-mediated pathways.

Molecular Function

  • sphingolipid biosynthesis regulation
  • ER stress response
  • serine palmitoyltransferase inhibition

Protein class: transmembrane protein

Regulatory Annotation

Promoter activity: ORMDL3 promoter is responsive to NF-κB and inflammatory cytokines; IL-4 and IL-13 upregulate ORMDL3 expression in bronchial epithelial cells.

Enhancer associations: Asthma-associated SNPs (e.g., rs8076131, rs12936231) at 17q21 act as cis-regulatory variants modulating ORMDL3 transcription; chromatin interaction data show enhancer-promoter looping in lymphoblastoid cell lines.

eQTL tissues: lung, bronchial epithelium, lymphoblastoid cell lines

Tissue Expression Context

bronchial epitheliumTPM range: 15–50GTEx vv8
lungTPM range: 8–30GTEx vv8
lymphoblastoid cell linesTPM range: 20–60GTEx vv8

Pathways

Linked Diseases & Exposures

Diseases

  • asthma— GWAS, strength 0.85
  • copd— GWAS, strength 0.45

Exposures

Mechanistic Hypotheses

ORMDL3 variants alter ceramide/sphingolipid metabolism, increasing ER stress in bronchial epithelial cells under inflammatory conditions. Carriers of asthma-risk alleles at 17q21 show elevated ORMDL3 expression, which suppresses serine palmitoyltransferase activity and disrupts sphingolipid homeostasis, triggering the unfolded protein response and amplifying airway inflammation.

Cantero-Recasens et al. demonstrated that ORMDL3 overexpression activates the UPR and ATF6 pathway; Moffatt et al. established the 17q21 GWAS association; eQTL analyses confirm genotype-dependent ORMDL3 expression in lung tissue.

MEDIUM

Confidence Rating

Overall evidence confidence for this gene entry: MEDIUM

Ancestry Context

17q21 risk haplotype frequency varies substantially: ~50% European, ~20% African-ancestry. Effect size attenuated in non-European populations.

Cross-ancestry eQTL replication: Yes

References

  1. 1.Moffatt MF, et al. (2010). Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. New England Journal of Medicine. doi:10.1056/NEJMoa0906312
  2. 2.Verlaan DJ, et al. (2009). Allele-specific chromatin remodeling in the ZPBP2/GSDMB/ORMDL3 locus associated with the risk of asthma and autoimmune disease. Nature Genetics. doi:10.1038/ng.381
  3. 3.Cantero-Recasens G, et al. (2010). ORMDL3 modulates ceramide levels and the unfolded protein response in the endoplasmic reticulum. Human Molecular Genetics. doi:10.1093/hmg/ddp555