The effects of an insertion in the 5'UTR of the AMCase on gene expression and pulmonary functions.

Background: Studies regarding the physiological role of acidic mammalian chitinase (AMCase) and the effects of its genetic variants on asthma have produced conflicting results.

Objectives: We aimed to determine the genetic variants in the AMCase gene that could regulate the gene expression and thus influence disease severity.

Methods: Genetic variants of the AMCase gene were determined by sequencing of asthmatics and healthy controls in up to -1 kb in the promoter region and exon 1 and 2. In an association study, a population of asthmatic (n = 504) and healthy Turkish children (n = 188) were genotyped for the observed SNPs. A replication study was performed in a North American adult population of patients with mild (n = 317) and severe (n = 145) asthma. The functional properties of the insertion were determined by promoter reporter assay, electromobility shift assay and transcription factor ELISA experiments.

Results: Of the identified SNPs, only a ten base pair insertion (CAATCTAGGC) in the 5'UTR region of exon 2 was significantly associated with lower FEV(1) (β = -14.63 SE = 6.241, P = 0.019) in Turkish children with asthma. However, in the adult population, the same insertion showed a trend toward higher FEV(1). The insertion was shown to have enhancer activity and the mutant probe possessing the insertion had higher binding affinity for the nuclear extracts.

Conclusion: Our study shows that a ten base pair insertion in the 5'UTR region of AMCase gene may modify gene expression and thus may affect the severity of asthma. However, its effects appear to be different in different populations.