Association of IL12B promoter polymorphism with severity of atopic and non-atopic asthma in children.
BACKGROUND
Severe asthma is a frequent cause of hospital admission, especially among children. The main environmental triggers of airway inflammation in asthma are viruses and aeroallergens. These agents elicit reciprocal immune responses, characterised by production of T helper 1 and T helper 2 cytokines, respectively. There is no genetic explanation for how hyper-responsiveness to these disparate environmental stimuli develops among individuals with asthma. Our aim was to assess relation between an IL12B promoter polymorphism and asthma.


METHODS
We did a cohort study in which we initially genotyped 411 6-year olds for the IL12B promoter polymorphism. We then assessed the relation between this polymorphism and asthma severity. A further 85 asthmatic children in an additional sample of 433 children from the same cohort were then assessed to confirm these findings. We also examined in-vitro interleukin-12 responses in a subgroup of individuals.


RESULTS
Heterozygosity for the IL12B promoter polymorphism was observed in 76% (16) of atopic and non-atopic individuals with severe asthma in the initial sample. By comparison, heterozygotes comprised only 31% (17) of the moderate asthma group, and 48% (20) of individuals with mild asthma were heterozygous, as were unaffected controls. These findings were confirmed in the second sample (overall p<0.0001). Our data suggest that IL12B promoter heterozygosity contributes to asthma severity rather than susceptibility per se. The severity-predisposing genotype was associated with reduced interleukin 12 p40 gene transcription and decreased interleukin 12 p70 secretion.


CONCLUSIONS
Interleukin 12 plays a key part in antagonism of T helper 2 differentiation, and in induction of antiviral host defense. Genetically determined attenuation of interleukin-12 response capacity would, therefore, provide a plausible common immunological pathway to disease severity for the two major forms of asthma.
Morahan
Grant
G
The Walter and Eliza Hall Institute of Medical Research, PO Royal Melbourne Hospital, Victoria 3050, Australia.
Huang
Dexing
D
Wu
Mark
M
Holt
Barbara J
BJ
White
Gregory P
GP
Kendall
Garth E
GE
Sly
Peter D
PD
Holt
Patrick G
PG
D001249:Asthma / Q000235:genetics*; D002648:Child; D006579:Heterozygote; D006801:Humans; D018664:Interleukin-12 / Q000235:genetics*; D053762:Interleukin-12 Subunit p40; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012130:Respiratory Hypersensitivity / Q000235:genetics*; D012720:Severity of Illness Index
C500879:IL12B protein, human; D053762:Interleukin-12 Subunit p40; D018664:Interleukin-12