Background: The first and well replicated childhood asthma susceptibility locus identified by genome-wide association was 17q21. ORMDL3 , located near the top association signal, belongs to the ORMDL gene family including ORMDL1, -2 and -3 . ORMDL proteins participate in the sphingolipid metabolism and maintain the ceramide homeostasis.ORMDL3 regulates the intracellular Ca 2+ levels, cellular stress responses and lymphocyte activation. Strong sequence homology between ORMDL s and protein conservation among different species suggest that they may have shared functions. Objectives: We hypothesized that single nucleotide polymorphisms (SNPs) in ORMDL genesare associated with asthma and that expression of ORMDL s correlates with asthma. Methods: Associations of 44 genotyped SNPs (Illumina HumanHap300Chip, MALDI-TOF MS) were assessed in 1,303 subjects (651 asthmatics) from MAGIC and ISAAC II studies. Expression in: (1) peripheral blood mononuclear cells (PBMC) (n=55, 8 asthmatics) before and after (48h) allergen stimulation; and (2) blood (n=60, 5 asthmatics) was determined. Allele-specific effects on the ORMDL s expression were evaluated. Results: Sixteen SNPs in all three ORMDL genes were associated with asthma (most in ORMDL3 ). Baseline expression in PBMC was significantly higher in asthmatics for ORMDL1 ( p =1.7*10 -6 ) and -2 ( p =4.9*10 -5 ) while induction of ORMDL s upon stimulation was stronger in unaffected subjects. Asthma associated rs8079416 and rs8076131 influenced ORMDL3 expression in allele-specific manner. Conclusions: SNPs in all three ORMDL s are associated with asthma. Asthmatics exhibit increased ORMDL levels, suggesting that ORMDL s contribute to asthma development. These authors contributed equally: Antoaneta Toncheva, Daniel Potaczek and Michaela Schedel.
Toncheva et al. (Mon,) studied this question.