Genetic Basis for Personalized Medicine in Asthma

5-lipoxygenase (ALOX5)

5-lipoxygenase catalyzes the conversion of arachidonic acid to LTA₄. The ALOX5 gene has been mapped to chromosome 10q11.2, which spans approximately 82 kb and is composed of 14 exons and 13 introns. Extensive evidence suggests that polymorphisms spanning the ALOX5 gene influence clinical responses to LTRAs and LTSIs; most notably, a functional Sp1 repeat polymorphism in the promoter region of the gene associated with altered gene transcription was associated with response to the LTSI, ABT-761. More recently, studies have included multiple polymorphisms and larger cohorts looking at both LTRA and LTSI responses. Tantisira and colleagues identified an association between ALOX5 intronic SNPs; rs892690, rs2029253 and rs2115819, and change in FEV₁ postzileuton treatment, in a cohort of 577 asthma patients. Importantly, the rs2115819 SNP was also a predictor of response to montelukast in a previous study of 252 asthma subjects using percentage change in FEV₁ as the primary outcome. In both cases the GG versus GA or AA had the greatest improvement in FEV₁ – for example, change in FEV₁ % predicted postmontelukast GG = 30%, GA = 4.4% and AA = 2.0% (p = 0.017). The potential lack of signal for the rs892690 and rs2029253 SNPs in the montelukast study may be due to the reduced power of this study compared with the zileuton study. The functional significance of these intronic SNPs remains to be resolved. Klotsman and colleagues identified two ALOX5 SNPs (rs4987105 [synonymous Thr120Thr] and rs4986832 (5'-region)) that were associated with improvements in peak expiratory flow on treatment with montelukast in a 12 week study in 174 asthma patients – for example, rs4987105: CC = 33.7 (n = 110), CT = 55.3 (n = 42) and TT = 94.8 (n = 10).