Promoter polymorphism in the 5‐lipoxygenase (ALOX5) and 5‐lipoxygenase‐activating protein (ALOX5AP) genes and asthma susceptibility in a Caucasian population

Sayers, Ian; Barton, Sheila J.; Rorke, Steuart; Sawyer, J. E.; Peng, Qiuju; Beghè, Bianca; Ye, S.; Keith, Tim P.; Clough, Joanne; Holloway, John W.; Sampson, Anthony P.; Holgate, Stephen T.

doi:10.1046/j.1365-2222.2003.01733.x

Cited by 52 publications

(52 citation statements)

References 26 publications

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“…When collapsed into three genotypes based on the wild-type (n ϭ 5) and the mutant form X (n ϶ 5), significant racial differences were observed. The distribution of genotypes in whites in our study was similar to those published previously (12,(37)(38)(39). Figure E1R (see online supplement) shows LD between ALOX5 SNPs.…”

Section: Allele Frequencies Hwe and Ldsupporting

confidence: 88%

Influence of Leukotriene Pathway Polymorphisms on Response to Montelukast in Asthma

Lima

Zhang

Grant

et al. 2006

Am J Respir Crit Care Med

212

226

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Rationale: Interpatient variability in montelukast response may be related to variation in leukotriene pathway candidate genes. Objective: To determine associations between polymorphisms in leukotriene pathway candidate genes with outcomes in patients with asthma receiving montelukast for 6 mo who participated in a clinical trial. Methods: Polymorphisms were typed using Sequenom matrixassisted laser desorption/ionization time-of-flight (MALDI-TOF) mass array spectrometry and published methods; haplotypes were imputed using single nucleotide polymorphism-expectation maximization (SNP-EM). Analysis of variance and logistic regression models were used to test for changes in outcomes by genotype. In addition, 2 and likelihood ratio tests were used to test for differences between groups. Case-control comparisons were analyzed using the SNP-EM Omnibus likelihood ratio test. Measurements: Outcomes were asthma exacerbation rate and changes in FEV 1 compared with baseline. Results: DNA was collected from 252 participants: 69% were white, 26% were African American. Twenty-eight SNPs in the ALOX5, LTA4H, LTC4S, MRP1, and cysLT1R genes, and an ALOX5 repeat polymorphism were successfully typed. There were racial disparities in allele frequencies in 17 SNPs and in the repeat polymorphism. Association analyses were performed in 61 whites. Associations were found between genotypes of SNPs in the ALOX5 (rs2115819) and MRP1 (rs119774) genes and changes in FEV 1 (p Ͻ 0.05), and between two SNPs in LTC4S (rs730012) and in LTA4H (rs2660845) genes for exacerbation rates. Mutant ALOX5 repeat polymorphism was associated with decreased exacerbation rates. There was strong linkage disequilibrium between ALOX5 SNPs. Associations between ALOX5 haplotypes and risk of exacerbations were found. Conclusions: Genetic variation in leukotriene pathway candidate genes contributes to variability in montelukast response. Keywords: antiinflammatory; montelukast; pharmacodynamic; pharmacogeneticMontelukast is a selective cysteinyl leukotriene 1 (cysLT 1 ) receptor antagonist (1). Montelukast is recommended as an alternative to low-dose inhaled corticosteroids for patients with mild persis- tent asthma and recommended as alternative add-on (to inhaled corticosteroids) treatment in patients with moderate persistent (step 3) and severe persistent (step 4) asthma (2). Numerous clinical trials in adults and children with asthma have established the efficacy and safety of montelukast (3, 4). However, interpatient variability in response to montelukast in both children and adults with asthma is significant, with 35 to 78% of patients receiving montelukast being classified as nonresponders (5-7). The mechanisms underlying interpatient variability in response are not clear but are believed to be due, in part, to genetic variability (8-11). Indeed, several studies have reported that promoter polymorphisms in the ALOX5 (12) and the LTC 4 synthase (LTC4S) genes contribute to variability in response to LT modifiers and LT selective antagonists (13)(14)(15)(16).Cy...

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Section: Allele Frequencies Hwe and Ldsupporting

confidence: 88%

Influence of Leukotriene Pathway Polymorphisms on Response to Montelukast in Asthma

Lima

Zhang

Grant

et al. 2006

Am J Respir Crit Care Med

212

226

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“…Odds ratios and 95% confidence intervals (95% CI) for genotypes were estimated using unconditional logistic regression models. The ALOX5 VNTR polymorphism was categorized (31,32). For the ALOX5AP poly(A) microsatellite, unlike the biallelic distribution in previous reports (31, 33), we found this microsatellite included continuous variation ranging from 15A to 26A, with most alleles being 23A or 19A.…”

Section: Methodscontrasting

confidence: 82%

5-Lipoxygenase and 5-Lipoxygenase-Activating Protein Gene Polymorphisms, Dietary Linoleic Acid, and Risk for Breast Cancer

Wang

John

Ingles

2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

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The n-6 polyunsaturated fatty acid 5-lipoxygenase pathway has been shown to play a role in the carcinogenesis of breast cancer. We conducted a population-based case-control study among Latina, African-American, and White women from the San Francisco Bay area to examine the association of the 5-lipoxygenase gene (ALOX5) and 5-lipoxygenaseactivating protein gene (ALOX5AP) with breast cancer risk. Three ALOX5AP polymorphisms [poly(A) microsatellite, À4900 A>G (rs4076128), and À3472 A>G (rs4073259)] and three ALOX5 polymorphisms [Sp1-binding site (-GGGCGG-) variable number of tandem repeat polymorphism, À1279 G>T (rs6593482), and 760 G>A (rs2228065)] were genotyped in 802 cases and 888 controls. We did not find significant main effects of ALOX5 and ALOX5AP genotypes on breast cancer risk that were consistent across race or ethnicity; however, there was a significant interaction between the ALOX5AP À4900 A>G polymorphism and dietary linoleic acid intake (P = 0.03). Among women consuming a diet high in linoleic acid (top quartile of intake, >17.4 g/d), carrying the AA genotype was associated with higher breast cancer risk (age-and race-adjusted odds ratio, 1.8; 95% confidence interval, 1.2-2.9) compared with carrying genotypes AG or GG. Among women consuming V17.4 g/d of linoleic acid, ALOX5AP À4900 genotype was not associated with breast cancer risk (age-and race-adjusted odds ratio, 0.9; 95% confidence interval, 0.7-1.2). These results support a role for n-6 polyunsaturated fatty acids in breast carcinogenesis and suggest that epidemiologic studies on dietary fat and breast cancer should take into account genetic predisposition related to n-6 polyunsaturated fatty acid metabolism. (Cancer Epidemiol Biomarkers Prev 2008;17(10):2748 -54)

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“…Mutations of the Sp1 repeat in the promoter are associated with airway hyperresponsiveness, but not asthma susceptibility (105,106). Using 341 asthma enriched families, no association between the ALOX5 Sp1 polymorphism and asthma or asthma-related phenotypes was identified (107). However, the Sp1 polymorphism has been suggested as a predictor of disease severity (108).…”

Section: Alox5 and Alox5apmentioning

confidence: 99%

“…Two polymorphisms have been identified in the ALOX5AP promoter, a )336 (G>A) and a poly(A) repeat at position )169 to )146 yielding 19A and 23A alleles (107). No associations were observed with asthma in a Caucasian cohort of 341 asthma families or basal transcription levels in a promoter reporter analysis (107).…”

Section: Alox5 and Alox5apmentioning

confidence: 99%

Leukotriene pathway genetics and pharmacogenetics in allergy

Duroudier

Tulah

Sayers

2009

Allergy

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Leukotrienes (LT) are a family of potent eicosanoid lipid mediators with central importance in disease processes such as inflammation and proliferation most notably observed in allergic conditions like asthma (1). There are two general classes of LT according to the presence of a cysteine residue in their amino acid chain: the cysteinyl leukotrienes (CysLTs) including LTC 4 , LTD 4 and LTE 4 and the dihydroxyleukotriene LTB 4 (2). The 5-lipoxygenase pathwayLeukotrienes are produced in a multi-step enzyme pathway called the 5-lipoxygenase (5-LO) pathway, which is active in leucocytes such as neutrophils, eosinophils, mast cells and monocytes (Fig. 1). Arachidonic acid is the precursor for LT synthesis and is hydrolysed from the plasma membrane by cytosolic phospholipase A 2 (and other isoforms) (3, 4) in a calcium-dependent process (5). Upon activation, the rate-limiting enzyme 5-LO oxygenates first free arachidonic acid into the unstable intermediate 5-hydroperoxyeicosatetraenoic acid (5-HPETE) which is then either hydrolysed to 5-hydroxyeicosatetraenoic acid (5-HETE) or transformed into the unstable epoxide leukotriene A 4 (LTA 4 ) by forming a conjugated triene system through dehydration (6). 5-LO translocates from either the nucleus (in macrophages) or cyotosol (in neutrophils) to the nuclear envelope in response to cell activation (7,8). This movement occurs as 5-LO is dependent on a 5-LO activating protein (FLAP) for its function. FLAP remains associated with the nuclear membrane (9) and acts as a Ôtransfer proteinÕ presenting arachidonic acid to 5-LO, a system which allows the favourable conversion of 5-HPETE to LTA 4 compared to 5-HETE (10). Both 5-LO and FLAP are expressed in cells of myeloid lineage (11) restricting the pathway to these cell types. LTA 4 can be further metabolised to the cysteinyl leukotrienes (CysLTs) or LTB 4 . The specific glutathione S-transferase leukotriene C 4 synthase (LTC 4 S) conjugates LTA 4 to form LTC 4 which can then be rapidly converted to LTD 4 by a gammaglutamyl transpeptidase and to LTE 4 by a dipeptidase once exported out the cell by membrane transport proteins such as multi-drug related protein 1 (MRP1) (12-15). A specific zinc metallohydrolase, LTA 4 hydrolase (LTA 4 H) is responsible for the conversion of LTA 4 to LTB 4 (16). CysLTs and LTB 4 act on different G-protein coupled receptors (GPCRs). Each bind to at least two different receptors: CysLTs to CYSLTR1 and CYSLTR2 and LTB 4 to LTB 4 R1 and LTB 4 R2 (or BLT1 and BLT2) (17).Leukotrienes (LT) are biologically active lipid mediators known to be involved in allergic inflammation. Leukotrienes have been shown to mediate diverse features of allergic conditions including inflammatory cell chemotaxis/activation and smooth muscle contraction. Cysteinyl leukotrienes (LTC 4 , LTD 4 and, LTE 4 ) and the dihydroxy leukotriene LTB 4 are generated by a series of enzymes/ proteins constituting the LT synthetic pathway or 5-lipoxygenase (5-LO) pathway. Their function is mediated by interacting with multiple receptors. Leukotr...

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Promoter polymorphism in the 5‐lipoxygenase (ALOX5) and 5‐lipoxygenase‐activating protein (ALOX5AP) genes and asthma susceptibility in a Caucasian population

Abstract: Taken together, these data do not support a significant role for these polymorphisms in genetic susceptibility to asthma in the Caucasian population.

Cited by 52 publications

References 26 publications

Influence of Leukotriene Pathway Polymorphisms on Response to Montelukast in Asthma

Influence of Leukotriene Pathway Polymorphisms on Response to Montelukast in Asthma

5-Lipoxygenase and 5-Lipoxygenase-Activating Protein Gene Polymorphisms, Dietary Linoleic Acid, and Risk for Breast Cancer

Leukotriene pathway genetics and pharmacogenetics in allergy

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