<i>ORMDL3</i> Gene Is Associated with Asthma in Three Ethnically Diverse Populations

Galanter, Joshua; Choudhry, Shweta; Eng, Celeste; Nazario, Sylvette; Rodríguez‐Santana, José; Casal, Jesus; Torres-Palacios, Alfonso; Salas, Jorge; Chapela, Rocío; Watson, H. Geoffrey; Meade, Kelley; LeNoir, Michael A.; Rodríguez-Cintrón, William; Avila, Pedro C.; Burchard, Esteban G.

doi:10.1164/rccm.200711-1644oc

Cited by 240 publications

(198 citation statements)

References 34 publications

(27 reference statements)

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“…However, after adjusting for the effect of rs7216389-T, association with other markers was nonsignificant. Two recent studies found no significant association of rs7216389-T with asthma in African-American patients, 10,42 which, given the difference in LD structure in European and African Americans, suggests that rs7216389-T is not the causal variant itself and that the causal variant is in lower LD with rs7216389-T in African Americans. Recently, other SNPs highly correlated with rs7216389 were found to be associated with Crohn's disease (rs2872507) 43 and type I diabetes (rs2290400), 44 indicating that sequence variants at the 17q21 locus may be involved in mechanisms regulating immune responses.…”

Section: Discussionmentioning

confidence: 99%

A sequence variant on 17q21 is associated with age at onset and severity of asthma

et al. 2010

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A sequence variant (rs7216389-T) near the ORMDL3 gene on chromosome 17q21 was recently found to be associated with childhood asthma. We sought to evaluate the effect of rs7216389-T on asthma subphenotypes and its correlation with expression levels of neighboring genes. The association of rs7216389-T with asthma was replicated in six European and one Asian study cohort (N¼4917 cases N¼34 589 controls). In addition, we found that the association of rs7216389-T was confined to cases with early onset of asthma, particularly in early childhood (age: 0-5 years OR¼1.51, P¼6.89 . 10 À9 ) and adolescence (age: 14-17 years OR¼1.71, P¼5.47 . 10 À9 ). A weaker association was observed for onset between 6 and 13 years of age (OR¼1.17, P¼0.035), but none for adult-onset asthma (OR¼1.07, P¼0.12). Cases were further stratified by sex, asthma severity and atopy status. An association with greater asthma severity was observed among early-onset asthma cases (P¼0.0012), but no association with sex or atopy status was observed among the asthma cases. An association between sequence variants and the expression of genes in the 17q21 region was assessed in white blood cell RNA samples collected from Icelandic individuals (n¼743). rs7216389 associated with the expression of GSDMB and ORMDL3 genes. However, other sequence variants showing a weaker association with asthma compared with that of rs7216389 were more strongly associated with the expression of both genes. Thus, the contribution of rs7216389-T to the development of asthma is unlikely to operate only through an impact on the expression of ORMDL3 or GSDMB genes.

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Section: Discussionmentioning

confidence: 99%

A sequence variant on 17q21 is associated with age at onset and severity of asthma

et al. 2010

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“…macrophage | eosinophil M offatt et al (1) were the first to report in 2007 a genomewide association study (GWAS) of asthma, which demonstrated that multiple markers on chromosome 17q21 (linked to the gene orosomucoid like 3; ORMDL3) were strongly and reproducibly associated with asthma in three different asthma cohorts. The identification of ORMDL3 as an asthma-associated gene has been confirmed in additional GWAS studies and in genetic association studies in populations of diverse ethnic backgrounds (2)(3)(4). In addition to the association of ORMDL3 with asthma, it is also associated with childhood onset of asthma (1) and exposure of children with asthma to environmental tobacco smoke (2).…”

mentioning

confidence: 83%

ORMDL3 is an inducible lung epithelial gene regulating metalloproteases, chemokines, OAS, and ATF6

Miller

Tam²,

Cho³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

173

264

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Orosomucoid like 3 (ORMDL3) has been strongly linked with asthma in genetic association studies, but its function in asthma is unknown. We demonstrate that in mice ORMDL3 is an allergen and cytokine (IL-4 or IL-13) inducible endoplasmic reticulum (ER) gene expressed predominantly in airway epithelial cells. Allergen challenge induces a 127-fold increase in ORMDL3 mRNA in bronchial epithelium in WT mice, with lesser 15-fold increases in ORMDL-2 and no changes in ORMDL-1. Studies of STAT-6–deficient mice demonstrated that ORMDL3 mRNA induction highly depends on STAT-6. Transfection of ORMDL3 in human bronchial epithelial cells in vitro induced expression of metalloproteases (MMP-9, ADAM-8), CC chemokines (CCL-20), CXC chemokines (IL-8, CXCL-10, CXCL-11), oligoadenylate synthetases (OAS) genes, and selectively activated activating transcription factor 6 (ATF6), an unfolded protein response (UPR) pathway transcription factor. siRNA knockdown of ATF-6α in lung epithelial cells inhibited expression of SERCA2b, which has been implicated in airway remodeling in asthma. In addition, transfection of ORMDL3 in lung epithelial cells activated ATF6α and induced SERCA2b. These studies provide evidence of the inducible nature of ORMDL3 ER expression in particular in bronchial epithelial cells and suggest an ER UPR pathway through which ORMDL3 may be linked to asthma.

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“…Furthermore, it has been found that polymorphisms in all three ORMDL genes are associated with asthma and that asthmatics exhibit increased ORMDL levels (25). The findings on the role of ORMDL3 in asthma were replicated in studies from different populations (26)(27)(28) (Table 1). Further analyses supported the conclusion that genetic elements regulating ORMDL3 expression (Table 2) may contribute to asthma development (7,13,22,25,(29)(30)(31)(32)(33)(34).…”

Section: Association Of Ormdl3 With Asthma and Other Pathologiesmentioning

confidence: 88%

“…Yu and coworkers found that in Chinese population rs7216389 asthmatic children exhibit increased levels of IgE (38). On the other hand, several other studies examining different populations found no significant differences in the IgE levels between patients with asthma and healthy controls (28,39,40).…”

Section: Association Of Ormdl3 With Asthma and Other Pathologiesmentioning

confidence: 98%

The role of ORMDL proteins, guardians of cellular sphingolipids, in asthma

Paulenda

Dráber

2016

Allergy

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To cite this article: Paulenda T, Draber P. The role of ORMDL proteins, guardians of cellular sphingolipids, in asthma. AbstractA family of widely expressed ORM-like (ORMDL) proteins has been recently linked to asthma in genomewide association studies in humans and extensively explored in in vivo studies in mice. ORMDL proteins are key regulators of serine palmitoyltransferase, an enzyme catalyzing the initial step of sphingolipid biosynthesis. Sphingolipids play prominent roles in cell signaling and response to stress, and they affect the mechanistic properties of cellular membranes. Deregulation of sphingolipid biosynthesis and their recycling has been proven to support and even cause several diseases including allergy, inflammation, and asthma. ORMDL3, the most extensively studied member of the ORMDL family, has been shown to be important for endoplasmic reticulum homeostasis by regulating the unfolded protein response and calcium response. In immune cells, ORMDL3 is involved in migration and in the production of proinflammatory cytokines. Furthermore, changes in the expression level of ORMDL3 are important in allergen-induced asthma pathologies. This review focuses on functional aspects of the ORMDL family proteins, which may serve as new therapeutic targets for the treatment of asthma and some other life-threatening diseases.

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ORMDL3 Gene Is Associated with Asthma in Three Ethnically Diverse Populations

Abstract: Our results confirm that the ORMDL3 locus is a risk factor for asthma in ethnically diverse populations. However, inconsistent SNP-level results suggest that further studies will be needed to determine the mechanism by which ORMDL3 predisposes to asthma.

Cited by 240 publications

References 34 publications

A sequence variant on 17q21 is associated with age at onset and severity of asthma

A sequence variant on 17q21 is associated with age at onset and severity of asthma

ORMDL3 is an inducible lung epithelial gene regulating metalloproteases, chemokines, OAS, and ATF6

The role of ORMDL proteins, guardians of cellular sphingolipids, in asthma

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