Childhood asthma is associated with mutations and gene expression differences of ORMDL genes that can interact. Issue 10 (20th July 2015)

• Record Type: Journal Article
• Authors: Toncheva, A. A.; Potaczek, D. P.; Schedel, M.; Gersting, S. W.; Michel, S.; Krajnov, N.; Gaertner, V. D.; Klingbeil, J. M.; Illig, T.; Franke, A.; Winkler, C.; Hohlfeld, J. M.; Vogelberg, C.; von Berg, A.; Bufe, A.; Heinzmann, A.; Laub, O.; Rietschel, E.; Simma, B.; Genuneit, J.; Muntau, A. C.; Kabesch, M.
• Is Part Of: Allergy. Volume 70:Issue 10(2015:Oct.)
• Page Start: 1288
• Page End: 1299
• Publication Date: 2015-07-20
• Subjects: Allergy -- Periodicals; 616.97
• DOI: 10.1111/all.12652
• Languages: English
• ISSNs: 0105-4538

Abstract

<abstract abstract-type="main" id="all12652-abs-0001"> <title>Abstract</title> <sec id="all12652-sec-0001" sec-type="section"> <title>Background</title> <p>Genomewide association studies identified <italic>ORMDL3</italic> 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 <italic>ORMDL</italic> genes and ORMDL protein conservation among different species suggest that they may have shared functions. We hypothesized that if single nucleotide polymorphisms (SNPs) in <italic>ORMDL3</italic> alter its gene expression and play a role in asthma, variants in <italic>ORMDL1</italic> and <italic>ORMDL2</italic> might also be associated with asthma.</p> </sec> <sec id="all12652-sec-0002" sec-type="section"> <title>Methods</title> <p>Asthma associations of 44 genotyped SNPs were determined in at least 1303 subjects (651 asthmatics). <italic>ORMDL</italic> expression was evaluated in peripheral blood mononuclear cells (PBMC) from 55 subjects (eight asthmatics) before and after allergen stimulation, and in blood (<italic>n </italic>=<italic> </italic>60, 5 asthmatics). Allele‐specific <italic>cis</italic>‐effects on <italic>ORMDL</italic> expression were assessed. Interactions between human ORMDL proteins were determined in living cells.</p> </sec> <sec id="all12652-sec-0003" sec-type="section"> <title>Results</title> <p>Sixteen SNPs in all three <italic>ORMDL</italic>s were associated with asthma (14 in <italic>ORMDL3</italic>). Baseline expression of <italic>ORMDL1</italic> (<italic>P </italic>=<italic> </italic>1.7 × 10<sup>−6</sup>) and <italic>ORMDL2</italic> (<italic>P </italic>=<italic> </italic>4.9 × 10<sup>−5</sup>) was significantly higher in PBMC from asthmatics, while induction of <italic>ORMDL</italic>s upon stimulation was stronger in nonasthmatics. Disease‐associated alleles (rs8079416, rs4795405, rs3902920) alter <italic>ORMDL3</italic> expression. ORMDL proteins formed homo‐ and heterooligomers and displayed similar patterns of interaction with SERCA2 and SPT1.</p> </sec> <sec id="all12652-sec-0004" sec-type="section"> <title>Conclusions</title> <p>Polymorphisms in <italic>ORMDL</italic> genes are associated with asthma. Asthmatics exhibit increased <italic>ORMDL</italic> levels, suggesting that <italic>ORMDL</italic>s 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.</p> </sec> </abstract>