5-lipoxygenase pharmacogenetics in asthma: overlap with Cys-leukotriene receptor antagonist loci.
The two classes of leukotriene modifiers work by inhibiting different portions of the same pathway. We hypothesized that single nucleotide polymorphisms (SNPs) in genes associated with response to montelukast (a cys-leukotriene receptor antagonist) would also be associated with response to zileuton (a 5-lipoxygenase inhibitor). We genotyped 26 SNPs that had previously been interrogated for association with montelukast response in five candidate genes (ABCC1, ALOX5, CYSLTR1, LTA4H, LTC4S) in a population of 577 asthmatics who participated in a clinical trial comparing intermittent and continuous-release zileuton to placebo. After adjusting for age and sex, six SNPs in three genes were associated with longitudinal forced expiratory volume at 1 s in response to zileuton (P values 0.005-0.05). After adjusting for age and sex, six SNPs in three genes were associated with longitudinal forced expiratory volume at 1 s in response to zileuton (P values 0.005-0.05), including two SNPs (ALOX5 rs2115819 and ABCC1 rs119774) that we had previously reported as associated with FEV1 response to montelukast. Thus, the lung function response to zileuton is modulated by several of the loci that also influence montelukast response.
Tantisira
Kelan G
KG
Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. kelan.tantisira@channing.havard.edu
Lima
John
J
Sylvia
Jody
J
Klanderman
Barbara
B
Weiss
Scott T
ST
D000085:Acetates / Q000008:administration & dosage / Q000627:therapeutic use*; D000328:Adult; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D003521:Cyclopropanes; D003545:Cysteine / Q000378:metabolism; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects / Q000235:genetics; D005838:Genotype; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D020024:Leukotriene Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D016859:Lipoxygenase Inhibitors; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011804:Quinolines / Q000008:administration & dosage / Q000627:therapeutic use*; D018077:Receptors, Leukotriene / Q000378:metabolism; D013440:Sulfides
D000085:Acetates; D018927:Anti-Asthmatic Agents; D003521:Cyclopropanes; D020024:Leukotriene Antagonists; D016859:Lipoxygenase Inhibitors; D011804:Quinolines; D018077:Receptors, Leukotriene; D013440:Sulfides; D003545:Cysteine; C093875:montelukast; C063449:zileuton; D006918:Hydroxyurea