{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nORMDL3 has emerged as a prominent susceptibility gene in asthma and several immune‐mediated disorders. Large‐scale genome‐wide association studies and subsequent replication efforts have consistently linked common variants at the 17q21 locus—including those affecting ORMDL3—to early‐onset asthma, ulcerative colitis, Crohn’s disease, and allergic rhinitis. These studies demonstrate that risk alleles are associated with increased ORMDL3 transcript levels in lymphoblastoid, airway epithelial, and immune cells, while allele‐specific regulatory mechanisms and epigenetic modifications further modulate its expression. Such genetic regulation strongly implicates ORMDL3 in the control of inflammatory pathways and airway responsiveness."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, ORMDL3 encodes an endoplasmic reticulum–resident transmembrane protein that plays a central role in maintaining cellular homeostasis. Functional studies have shown that ORMDL3 directly modulates ER Ca²⁺ homeostasis by binding and inhibiting the sarco-endoplasmic reticulum Ca²⁺ ATPase (SERCA), thereby dampening Ca²⁺ signaling and facilitating activation of the unfolded protein response (UPR) via the ATF6 pathway. In parallel, the yeast homologs (Orm1/2) and mammalian studies have revealed that ORMDL3 forms stable complexes with serine palmitoyltransferase (SPT)—the enzyme that catalyzes the rate-limiting step in de novo sphingolipid biosynthesis—even though overexpression models suggest a complex relationship with sphingolipid production. Recent high-resolution cryo-electron microscopy further delineates the architecture of the ORMDL3-SPT complex, underscoring its role as a molecular scaffold in lipid metabolic regulation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "30"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its roles in ER homeostasis and lipid metabolism, ORMDL3 influences immune cell function and airway physiology. In T lymphocytes, ORMDL3 negatively modulates store-operated Ca²⁺ entry, thereby impacting downstream nuclear factor activation and cytokine production. In airway epithelial cells, its expression is rapidly induced by allergens and Th2 cytokines (IL-4 and IL-13) through a STAT6-dependent mechanism, resulting in enhanced production of chemokines, metalloproteases, and factors that promote autophagy and airway remodeling. Moreover, ORMDL3 has been implicated in modulating host responses during viral infections—including effects on rhinovirus replication—and in regulating autophagy in immune cells, which may further contribute to the chronicity and severity of inflammatory airway diseases."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "31", "end_ref": "40"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Miriam F Moffatt, Michael Kabesch, Liming Liang, et al. 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