Pharmacogenetic association between ALOX5 promoter genotype ...

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2Abbott. Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA. 3Genset Corporation, 875 Prospect Street, La Jolla, California 92037, USA.
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© 1999 Nature America Inc. • http://genetics.nature.com

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

© 1999 Nature America Inc. • http://genetics.nature.com

Jeffrey M. Drazen1, Chandri N. Yandava1, Louise Dubé2, Natalie Szczerback2, Richard Hippensteel2, Antonino Pillari1, Elliot Israel1, Nicholas Schork3, Eric S. Silverman1, David A. Katz2 & Jeffrey Drajesk2

Clinically similar asthma patients may develop airway obstruction by different mechanisms1,2. Asthma treatments that specifically interfere with the 5-lipoxygenase (ALOX5) pathway3−5 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 ALOX5pathway 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 culture6,7. Because expression of ALOX5 is in part transcriptionally regulated8, 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.

We examined the results of two identical clinical trials with ABT761, a potent and selective inhibitor of ALOX5, stratified by genotype at the ALOX5 locus, which contains 3−6 tandem repeats of the Sp1-binding motif GGGCGG. We designated an individual homozygous for the most commonly occurring allele (with five tandem Sp1-binding motifs) as wild type, an individual having one wild-type allele and one mutant allele (that is, ALOX5 with three, four, or six tandem Sp1-binding motifs) as a heterozygote and an individual with no wild-type alleles as a mutant. Our reasoning for this allele grouping is that in human cells in vitro, alleles containing other than five tandem Sp1 repeats have diminished activity in promoter-reporter constructs6. Table 1 • Distribution of genotypes among study subjects Genotypea

Patient count

Genotype frequency

33 35 44 45 46 55 56 66 total

3 11 7 60 2 133 4 1 221

0.014 0.050 0.032 0.272 0.009 0.602 0.016 0.005

The clinical trials of the efficacy of ABT-761 for asthma were closed before the projected enrollment was completed, because an interim analysis failed to show an improvement in the event rate of abnormal liver function tests with ABT-761 compared with its parent compound, zileuton9,10. At the time of trial closure, 902 patients had entered the double-blind phase of the protocol and 325 individuals had completed the entire protocol. Although the projected enrollment was not reached, enough patients were enrolled to demonstrate superior efficacy, using the forced expiratory volume in the first second (FEV1) as the outcome indicator, for the high dose of ABT-761 compared with either low dose or placebo (P