Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment.
Clinically similar asthma patients may develop airway obstruction by different mechanisms. Asthma treatments that specifically interfere with the 5-lipoxygenase (ALOX5) pathway 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. Because expression of ALOX5 is in part transcriptionally regulated, 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.
Drazen
J M
JM
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. jdrazen@rics.bwh.harvard.edu
Yandava
C N
CN
Dubé
L
L
Szczerback
N
N
Hippensteel
R
R
Pillari
A
A
Israel
E
E
Schork
N
N
Silverman
E S
ES
Katz
D A
DA
Drajesk
J
J
D000483:Alleles; D018927:Anti-Asthmatic Agents / Q000627:therapeutic use*; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics*; D001249:Asthma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D005787:Gene Frequency; D014644:Genetic Variation; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016859:Lipoxygenase Inhibitors / Q000627:therapeutic use; D010641:Phenotype; D011401:Promoter Regions, Genetic; D016896:Treatment Outcome
D018927:Anti-Asthmatic Agents; D016859:Lipoxygenase Inhibitors; D001094:Arachidonate 5-Lipoxygenase; C096921:atreleuton; D006918:Hydroxyurea