VIP Variant in ALOX5
The ALOX5 repeat promoter polymorphism is the most widely studied polymorphism in the ALOX5 gene. The alleles are formed by a tandem repeat polymorphism of the nucleotide sequence 5'GGGCGG3'. Specifically, the polymorphism is located at positions \-176 to \-147 from the ATG start site of ALOX5. This region of the ALOX5 gene is thought to act as a transcription binding factor site for both Sp1 and Egr-1 zinc-finger transcription factors in the promoter region of ALOX5 [Article:9698605]. The most common (wild-type) allele has 5 repeats in this region. The variant alleles are determined by variant numbers of repeats occurring in the region, which can range from 3 to 8 in humans. The most common allele contains 5 repeats, and the three most common variants have a 6-base-pair (1 repeat) deletion, a 12-base-pair (2 repeats) deletion or a 6-base-pair addition, respectively. In vitro data from In et al. reveal reduced expression of a reporter gene when under the control of ALOX5 promoter variant alleles [Article:9062372]. In addition, lower levels of ALOX5 mRNA in cultured eosinophils from asthmatics were found in carriers of two variant alleles as compared to subjects with two wild-type alleles [Article:16364163].
The allele frequencies of ALOX5 promoter variants vary considerably between subject groups. The variant allele frequencies are reported here as overall frequencies for all variants since most studies have grouped subjects with variant alleles either as variant carriers or as homozygous variants rather than by specific genotype. Dwyer et al. [Article:14702425] reported the variant frequency in a healthy population to be 0.18 overall, whereas the genotype frequency of carriers of two variant alleles was 0.06. However, race differences in allele frequency were found. Specifically, in African Americans the variant frequency was 0.24, which is considerably higher than the variant allele frequency for the entire population. Further, the variant frequency was 0.19 in Asian and Pacific Islanders. In contrast, a study by Drazen et al. in asthma subjects reported a 0.25 overall variant allele frequency [Article:10369259]. In accordance with the previous study 6% of these asthma subjects did not carry the common, five-repeat allele. Lima et al. also found a large difference in the variant allele frequency between racial groups, where in Caucasians the frequency of carriers of two variant alleles was 0.036 and was 0.25 in African Americans [Article:16293801] (see Phenotype Dataset).
Phenotypically, variants in the ALOX5 promoter region are associated most prominently with asthma and atherosclerosis [Articles:15876305, 14702425]. Specifically, Kim et al. found that aspirin-intolerant\- asthma patients carrying a variant allele showed increased airway hyper-responsiveness in response to methacholine challenge as compared to aspirin-intolerant-asthma patients with wild-type genotype [Article:15876305]. Further, in terms of pharmacogenomics, variants have been associated with diminished response to an experimental 5-lipoxygenase inhibitor treatment [Article:10369259]. However, conflicting results have also been published. In a primarily Caucasian population, Fowler et al. found no difference in the response of asthmatics to a leukotriene D4 antagonist, montelukast, between carriers of variant alleles and wild-type homozygous subjects as measured by various lung function tests [Article:12107604]. However, Lima et al. reported that subjects who were carriers of at least one variant allele had a 73% reduction in risk of having one or more asthma exacerbations while taking montelukast [Article:16293801].
ALOX5 promoter variants have also been associated with increased risk for the development and progression of atherosclerosis as compared to patients with wild-type alleles. In particular, Dwyer et al. found that the promoter variants are associated with an increased risk for atherosclerosis [Article:14702425], as measured by carotid intima-media thickness differences in a healthy population. Furthermore, dietary intake of 5-lipoxygenase substrates such as arachidonic acid is associated with increased atherosclerosis whereas intake of marine n-3 fatty acids are associated with reduced atherosclerosis [Article:14702425]. Pharmacogenomic studies relating atherosclerosis treatments and the ALOX5 promoter polymorphism have not been reported.
| Key Publications: | |
|---|---|
| Drugs / Other Molecules |
Drug (1)
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| Diseases | aspirin-induced asthma 2 Coronary Artery Disease 3 4 |
| Phenotype Datasets | Outcomes in Asthmatics taking montelukast |
Appendix
Genomic Variant & GenBank ID: (GGGCGG)5 > (GGGCGG)3-8 at 34399 on AL731567 http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=nucleotide&val=21537524
GoldenPath Position: chr10:45,189,558 - 45,189,587 (hg18) (for wild-type allele)
Connected Diseases
| Evidence | Disease |
|---|---|
| aspirin-induced asthma | |
| Coronary Artery Disease |