Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment

Clinically similar asthma patients may develop airway obstruction by different mechanisms(1,2). Asthma treatments that specifically interfere with the 5-lipoxygenase (ALOX5) pathway(3-5) provide a method to identify those patients in whom the products of the ALOX5 pathway (that is, the leukotrienes) contribute to the expression of the asthma phenotype. Failure of an asthma,patient to respond to treatment with ALOX5-pathway modifiers indicates that leukotrienes are not critical to the expression of the asthmatic phenotype in that patient. We previously defined a family of DNA sequence variants in the core promoter of the gene ALOX5 (on chromosome 10q11.2) associated with diminished promoter-reporter activity in tissue culture(6,7) 7. Because expression of ALOX5 is in part transcriptionally regulated(8), we reasoned that patients with these sequence variants may have diminished gene transcription, and therefore decreased ALOX5 product production and a diminished clinical response to treatment with a drug targeting this pathway. Such an effect indicates an interaction between gene promoter sequence variants and. drug-treatment responses, that is, a pharmacogenetic effect of a promoter sequence on treatment responses.