Annotated PGx Gene Information for ALOX5
Submitted by: Anzeela M. Schentrup, John J. Lima, Julie A. Johnson (PEAR and PAM)
Reviewed by: Reviewed
Submitted date: April 17, 2006
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| Gene HGNC Name: | ALOX5 |
|---|---|
| Gene Common Name: | Arachidonate 5-lipoxygenase |
| Introductory Information: | ALOX5 encodes arachidonate 5-lipoxygenase, a cystolic enzyme that catalyzes the two-step conversion of arachidonic acid to leukotriene A4 (LTA4). The gene was originally cloned in 1988 by both Matsumoto et al., from human lung and placenta and by Dixon et al., from human neutrophils [PMID: 2829172, 3422434]. The gene was mapped to chromosome 10 by Funk et al. using a human-hamster somatic hybrid DNA panel [PMID: 2565035]. ALOX5 is specifically located on chromosome 10q11.2. The gene consists of 14 exons encompassing 2493 nucleotides which encode a 674 amino-acid protein. The product 5-lipoxygenase is expressed exclusively in bone-marrow-derived cells, including macrophages, monocytes and primarily neutrophils. 5-lipoxygenase products are acted upon by several downstream enzymes, resulting in the formation of several leukotriene products. Together, these enzymes form the leukotriene pathway which is known to play a significant role in the inflammatory process. Furthermore, this pathway has been implicated in the pathogenesis of inflammatory diseases such as asthma and atherosclerosis. ALOX5 has one widely-studied polymorphism. The alleles of this polymorphism are formed by 3-8 tandem repeats of the nucleotide sequence 5'GGGCGG3' located in the ALOX5 promoter region. The most common (wild-type) allele has 5 repeats and all others are considered variants. These variants are associated with decreased ALOX5 promoter activity in in vitro reporter-gene models [PMID: 9062372, 16364163]. Phenotypically, variants in ALOX5 are associated with inflammatory disease, including asthma [PMID: 15876305], atherosclerosis [PMID: 14702425], and colon cancer. In particular, the ALOX5 promoter variants are associated with diminished response to leukotriene-inhibitor treatment, although these results are conflicting and these studies have not evaluated similar outcomes [PMID: 16293801, 12107604, 10369259]. In addition, a link between ALOX5 promoter variants and the development and progression of atherosclerosis has been established [PMID: 14702425, 15933245]. In addition, several other polymorphisms in ALOX5 have been reported although there is less evidence associating these variants with their phenotypes. Most prominent is a newly-identified intronic single nucleotide polymorphism (SNP) reported by Lima et al. (rs2115819), which is positively associated with increased FEV1 response to montelukast therapy. This SNP is also part of a 4-SNP haplotype associated with increased numbers of asthma exacerbations during 6 months of montelukast treatment relative to placebo [PMID: 16293801 (PA142628130)]. Further, Goodman et al. reported a significant association between 2 SNPs in the negative regulatory region of the ALOX5 promoter and a reduced risk of colon cancer, although this association was seen only in Caucasians. A haplotype which included these SNPs is also associated with reduced colon cancer risk [PMID: 15308583]. |
| Key PubMed IDs: | 2829172, 3422434, 2565035, 9062372, 16364163, 15876305, 14702425, 16293801, 12107604, 10369259, 15933245 |
| Drugs/Substrates: | montelukast [PMID: 16293801 (PA142628130)] |
| Phenotypes/Diseases: | coronary arteriosclerosis [PMID: 15933245, 14702425], colon cancer [PMID: 15308583], aspirin-induced asthma [PMID: 15876305], response to montelukast treatment in asthma [PA142628130 (PMID: 16293801)] |
| Important Variants: | tandem repeat polymorphism |