A polymorphism controlling ORMDL3 expression is associated with asthma that is poorly controlled by current medications.
BACKGROUND
The specific genetic contributions to childhood asthma have been difficult to elucidate. A recent whole-genome association study suggested that single nucleotide polymorphisms at loci controlling the expression of the ORMDL3 gene and others in the neighborhood of the NRG1 and ERO1LB genes might be important.


OBJECTIVE
We sought to replicate the associations of these genetic markers with asthma in a large population of asthmatic patients from Scotland and to assess the effect of these variants on asthma outcomes.


METHODS
Using mouthwash-derived DNA and clinical interviews and measurements, we investigated the association of 3 single nucleotide polymorphisms in the candidate genes with susceptibility to asthma in a case-control study and also exacerbations in a group of 1054 patients aged 3 to 22 years.


RESULTS
A common C/T polymorphism at a locus controlling ORMDL3 gene expression (rs7216389) was significantly associated with the risk of childhood asthma (P = 1.73 x 10(-12)), with a single copy of the T allele conferring an odds ratio of 1.50 (95% CI, 1.24-1.81) and 2 copies of the T allele conferring an odds ratio of 2.11 (95% CI, 1.71-2.61), respectively. In asthmatic patients the T allele was associated with exacerbations of the condition (P = .008). Polymorphisms at the loci of nearby genes for NRG1 (rs4512342) and ERO1LB (rs10924993) were associated with neither the occurrence of nor exacerbations of asthma.


CONCLUSIONS
A common genetic variation at a locus controlling the expression of the ORMDL3 locus increases the susceptibility to asthma and is associated with poor control of the condition in children and young adults.
Tavendale
Roger
R
Population Pharmacogenetics Group, Biomedical Research Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom.
Macgregor
Donald F
DF
Mukhopadhyay
Somnath
S
Palmer
Colin N A
CN
D000293:Adolescent; D000328:Adult; D001249:Asthma / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects / Q000276:immunology; D005819:Genetic Markers / Q000276:immunology; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000276:immunology; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D010366:Peak Expiratory Flow Rate / Q000187:drug effects / Q000276:immunology; D020641:Polymorphism, Single Nucleotide / Q000276:immunology; D012720:Severity of Illness Index; D014797:Vital Capacity / Q000187:drug effects / Q000276:immunology
D005819:Genetic Markers; D008565:Membrane Proteins; C464399:ORMDL3 protein, human