ALOX5AP and LTA4H polymorphisms modify augmentation of bronchodilator responsiveness by leukotriene modifiers in Latinos

Article Outline

• Abstract
• Methods
  • Study participants
  • Clinical data collection
  • Genetic analysis
  • Statistical analysis
• Results
  • Participant characteristics
  • Leukotriene modifiers and bronchodilator responsiveness
  • Effects of ALOX5AP and LTA4H polymorphisms
  • Interactions between ALOX5AP and LTA4H
• Discussion
• Acknowledgment
• References
• Copyright

Background

Understanding the effects of interactions between multiple genes and asthma medications may aid in the understanding of the heterogeneous response to asthma therapies.

Objective

To identify modulating effects of arachidonate 5-lipoxygenase-activating protein (ALOX5AP) and leukotriene A₄ hydrolase (LTA4H) gene polymorphisms on the drug-drug interaction between leukotriene modifiers and albuterol in Mexicans and Puerto Ricans.

Methods

In a cross-sectional study of 293 Mexicans and 356 Puerto Ricans with asthma, ALOX5AP and LTA4H genes were sequenced, and interactions between gene polymorphisms and bronchodilator responsiveness to albuterol were compared between leukotriene modifier users and nonusers.

Results

In heterozygotes and homozygotes for the minor allele at LTA4H single nucleotide polymorphism (SNP) rs2540491 and heterozygotes for the major allele at LTA4H SNP rs2540487, leukotriene modifier use was associated with a clinically significant increase in percent change in FEV₁ after albuterol administration of 7.10% (P = .002), 10.06% (P = .001), and 10.03% (P < .001), respectively. Presence of the major allele at ALOX5AP SNP rs10507391 or the minor allele at ALOX5AP SNP rs9551963 augmented this response. When stratified by ethnicity, these findings held true for Puerto Ricans but not Mexicans.

Conclusion

LTA4H and ALOX5AP gene polymorphisms modify the augmentation of bronchodilator responsiveness by leukotriene modifiers in Puerto Ricans but not Mexicans with asthma.

Key words: Asthma, leukotriene, leukotriene modifier, Latino, albuterol, drug responsiveness, association study, genetic polymorphism

Abbreviations used: ALOX5AP, Arachidonate 5-lipoxygenase-activating protein, BMI, Body mass index, %ΔFEV₁, Percent change in FEV₁, GALA, Genetics of Asthma in Latino Americans, LTA4H, Leukotriene A₄ hydrolase, LTB₄, Leukotriene B₄, SNP, Single nucleotide polymorphism

The identification of pharmacogenetic effects on an individual's responsiveness to asthma medications is important for the potential targeted use of specific medications in populations that are most likely to derive clinical benefit from their use. This is particularly important in ethnic minorities because they are underrepresented in clinical studies¹, ² yet they disproportionately experience poor asthma outcomes.³, ⁴

Leukotrienes play an important role in the pathophysiology of asthma by mediating bronchoconstriction, mucus production, and airway edema.⁵ Leukotriene synthesis is initiated in airway leukocytes in response to a number of stimuli including allergens,⁶ and leukotriene synthesis begins with arachidonate 5-lipoxygenase, which catalyzes the synthesis of leukotriene A₄ from arachidonic acid, an activity facilitated by arachidonate 5-lipoxygenase-activating protein (ALOX5AP). This precursor to the biologically active leukotrienes is acted on by leukotriene A₄ hydrolase (LTA4H) to form leukotriene B₄ (LTB₄) and leukotriene C₄ synthase to produce the cysteinyl leukotrienes. These leukotrienes then act on their specific receptors on various target cells within the respiratory tract that propagate their biologic activity. The production and activity of these leukotrienes are modulated by 5-lipoxygenase inhibitors (zileuton) and cysteinyl leukotriene antagonists (montelukast, zafirlukast, pranlukast), respectively.

Previous genetic association studies have evaluated the role of some leukotriene-related genes, such as arachidonate 5-lipoxygenase and leukotriene C₄ synthase⁷; however, there are few reports on the effects of the ALOX5AP and LTA4H genes. The activities of these gene products are necessary in the biological pathway leading to leukotriene production, and recent reports have identified these genes as important determinants of asthma susceptibility and the expression of asthma-related traits. In the Genetics of Asthma in Latino Americans (GALA) study, we recently reported that polymorphisms within both the ALOX5AP and LTA4H genes were protective for asthma in Latinos and associated with baseline lung function.⁸ Importantly, the effects of the polymorphisms were varied between the Puerto Rican and Mexican participants. Holloway et al⁹ previously reported similar associations for other polymorphisms with the same genes in white subjects.

In addition to the effects of the ALOX5AP and LTA4H genes on asthma outcomes, we also recently identified that leukotriene modifier use is associated with improved bronchodilator responsiveness to albuterol among Puerto Rican but not Mexican American children with asthma.¹⁰ These leukotriene modifiers are active in the biologic pathways leading to the production and activity of leukotrienes, in which ALOX5AP and LTA4H are integral participants, and inhibition of leukotriene activity is known to lead to sustained bronchodilation.

Because Puerto Ricans and Mexicans in the GALA study experience differing clinical outcomes both from polymorphisms of the ALOX5AP and LTA4H genes and with the use of leukotriene modifiers that modulate the biologic pathways in which these genes are key players, we reasoned that distinct pharmacogenetic outcomes may exist in these 2 populations.

The current study aims to identify modulating effects of genetic variants in the ALOX5AP and LTA4H genes on the drug-drug interaction between leukotriene modifiers and albuterol in Latinos recruited in the GALA study. We hypothesized that polymorphisms within each of the genes would account for the augmentation of bronchodilator responsiveness by leukotriene modifiers that is present in Puerto Rican participants but absent in Mexican participants in the GALA study. Characterizing these complex interactions may help us to understand the heterogeneity in the response to leukotriene-modifying medications within and between different ethnic groups.

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Methods 

Study participants 

Six hundred forty-nine Latino individuals with asthma from the GALA study were analyzed in the current study. This sample includes 293 individuals of Mexican origin, recruited in Mexico City and the San Francisco Bay Area, and 356 individuals of Puerto Rican origin, recruited in Puerto Rico and New York City. Pertinent clinical and demographic characteristics of these samples are shown in Table I. Ethnicity was defined by all 4 grandparents being of Mexican or Puerto Rican origin. Further details on these samples have been previously published.⁶ Individuals were recruited if they had a diagnosis of asthma and either were taking a medication for asthma or had 2 or more asthma-related symptoms (wheezing, coughing, and/or dyspnea).¹¹ All subjects or legal guardians provided written informed consent, and local institutional review boards approved the study.

Table I. Clinical and demographic characteristics of participants, stratified by leukotriene modifier use and ethnicity

LT, Leukotriene; MX, Mexicans; PR, Puerto Ricans.

Data are given as median (25th-75th percentiles) unless otherwise indicated.

Clinical data collection 

After obtaining age-appropriate informed consent and assent, a trained interviewer administered the modified version of the 1978 American Thoracic Society-Division of Lung Diseases Epidemiology Questionnaire,¹² as previously described.¹¹ The medications montelukast, zafirlukast, and zileuton were all categorized as leukotriene modifiers and were not distinguished.

Pulmonary function was evaluated by using spirometry performed to American Thoracic Society standards¹³ before and 15 minutes after the administration of albuterol, as previously described.¹¹ Briefly, albuterol was administered through a 5-cm plastic mouthpiece from a standard metered-dose inhaler at a dose of 2 puffs (180 μg) for participants age <16 years and 4 puffs (360 μg) for participants age ≥16 years. Baseline FEV₁ is reported as pre-FEV₁, and postbronchodilator FEV₁ is reported as post-FEV₁. Bronchodilator responsiveness is reported as percent change in FEV₁ (%ΔFEV₁):

Spirometric reference values from Hankinson et al¹⁴ were used to determine percent predicted values. The reference values generated for Mexicans were also used for the Puerto Rican subjects because no reference values were available for this ethnic group. Subjects were classified as having either intermittent or persistent asthma on the basis of data gathered from the 1978 American Thoracic Society-Division of Lung Diseases Epidemiology Questionnaire and pulmonary function testing, as previously described.¹⁰

Genetic analysis 

Genetic information on 6 single nucleotide polymorphisms (SNPs) was collected for all individuals. Four markers in the LTA4H gene and 2 in the ALOX5AP were selected to cover most of the gene regions while minimizing the number of comparisons. Markers with a minor allele frequency higher than 5%, low degree of linkage disequilibrium with other markers (r² < 0.80), and minor allele involved in haplotypes with a frequency higher than 10% were included in the analyses. Exact details on selection criteria and genotyping procedures have been previously described.⁸ Marker location and allelic and genotypic frequencies of the different SNPs are detailed in Table II. All SNPs were in Hardy-Weinberg equilibrium after stratification by ethnicity (P > .05).

Table II. Genotype and allele frequencies of analyzed SNPs in the LTA4H and ALOX5AP genes

A, Common allele; a, minor allele; GALA, all subjects in GALA study; MAF, minor allele frequency; MX, Mexicans; PR, Puerto Ricans; 5′UTR, 5′ untranslated region.

Statistical analysis 

Participants were stratified on the basis of the use of leukotriene modifiers. Then demographic and clinical characteristics were compared with the unpaired 2-tailed t test (continuous variables) or the χ² test (categorical variables).

The primary endpoint was the effect of LTA4H and ALOX5AP gene polymorphisms on the association between leukotriene modifier use and bronchodilator responsiveness to albuterol. The association between leukotriene modifier use and bronchodilator responsiveness was evaluated by comparing mean %ΔFEV₁ (as described in the “Clinical data collection” section) of participants using leukotriene modifiers with mean %ΔFEV₁ of those not using leukotriene modifiers (%ΔFEV₁ of leukotriene modifier users – %ΔFEV₁ of leukotriene modifier nonusers), and this difference was described as the difference in mean %ΔFEV₁.

Analyses were performed with multiple linear regression with inclusion of variables specific to each analysis (relevant gene polymorphisms and an interaction term between leukotriene modifier use and relevant polymorphisms), variables previously found to have a significant effect on the model evaluating the effects of leukotriene modifiers on bronchodilator responsiveness (pre-FEV₁ and an interaction term between leukotriene modifier use and FEV₁),¹⁰ and variables included for face validity (age, sex, and genetic admixture). Individual genetic admixture estimates were obtained using a set of 106 ancestry-informative markers as previously described¹⁵ and were included in the analyses to account for the potential presence of population stratification in these populations. The following variables were previously found not to have significant effects on the model evaluating the effects of leukotriene modifiers on bronchodilator responsiveness¹⁰ and were therefore not included in the analyses: asthma duration, plasma IgE level, allergic rhinitis, family history of atopy, tobacco smoke exposure, asthma medications other than leukotriene modifiers, and interaction terms between specific medications and pre-FEV₁. All analyses were repeated with the inclusion of body mass index (BMI) as a predictor variable because there was a statistically significant difference in BMI between Mexican and Puerto Ricans, but this did not affect outcomes and was therefore not included in the final analyses. Each SNP was analyzed as a multilevel categorical predictor variable; therefore, Wald tests were performed for each regression analysis to assess for overall statistical significance of the effects of the polymorphisms on the model (ie, to account for multiple pairwise calculations). In models identifying significant effects from LTA4H and ALOX5AP genes, the statistical analyses were repeated after stratifying by ethnicity.

As a secondary endpoint, gene-gene interactions were investigated between LTA4H and ALOX5AP by including 3-way interaction terms between relevant LTA4H polymorphisms, ALOX5AP polymorphisms, and leukotriene modifier use. Because of the multiple testing and subsequent inflated risk of making a type 1 error, Holm correction was used to establish a more conservative P ≤.008 for the secondary endpoints. STATA V.9.1 software (STATA, College Station, Tex) was used for the statistical analyses.

Because this study involved secondary data analysis, sample size calculations were performed to ensure that the study was adequately powered to detect the primary endpoint: a clinically meaningful difference in mean %ΔFEV₁ between subjects with different alleles of each gene. With the sample sizes and 95% CIs reported, the study was capable of identifying a 5% difference in mean %ΔFEV₁ with α = .05 and power of 0.8.

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Results 

Participant characteristics 

Participants using leukotriene modifiers and those not using leukotriene modifiers were similar for all characteristics except that a higher percentage of leukotriene modifiers users had persistent asthma (Table I). Mexicans and Puerto Ricans differed in that Mexicans were older, had a higher BMI, and had a higher baseline FEV₁ than Puerto Ricans. The frequencies of the different alleles for each SNP are detailed in Table II.

Leukotriene modifiers and bronchodilator responsiveness 

The difference in mean (95% CI) %ΔFEV₁ between participants using leukotriene modifiers and those not using leukotriene modifiers was 5.04 (1.99-8.08; P = .001), indicating that subjects using leukotriene modifiers had a 5.04% greater improvement in FEV₁ after administration of a bronchodilator than did subjects not using this class of medication.

Effects of ALOX5AP and LTA4H polymorphisms 

Neither of the 2 ALOX5AP SNPs had an effect on the association between leukotriene modifier use and bronchodilator responsiveness. The F test statistic (numerator degrees of freedom, denominator degrees of freedom) was F(2,568) = 0.25 (P = .776) for the rs10507391 SNP and F(2,568) = 0.18 (P = .835) for the rs9551963 SNP.

Of the LTA4H SNPs, rs2540491 and rs2540487 had a significant effect on the association between leukotriene modifier use and bronchodilator responsiveness, with F(2,570) = 4.84 (P = .008) and F(2,551) = 3.43 (P = .033), respectively. The rs17525488 and rs2540493 SNPs did not have a significant effect on the model, with F(2,545) = 0.42 (P = .655) and F(2,567) = 1.28 (P = .279), respectively.

In heterozygotes and homozygotes for the minor allele at the rs2540491 SNP, the use of a leukotriene modifier was associated with an augmentation of bronchodilator responsiveness, with a difference in mean %ΔFEV₁ of 7.10 (2.61-11.59; P = .002) and 10.06 (4.29-15.82; P = .001), respectively. In homozygotes for the major allele, leukotriene modifier use had no effect on bronchodilator responsiveness, with a difference in mean %ΔFEV₁ of –0.31 (−4.91 to 4.29; P = .896). When stratified by ethnicity, Puerto Rican participants followed the same pattern in augmentation of bronchodilator responsiveness by leukotriene modifiers, but the Mexican participants did not, regardless of which allele was present at the rs2540491 SNP (Fig 1, A).

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• Fig 1. 

  Difference in mean %ΔFEV₁ between leukotriene modifier users and nonusers stratified by LTA4H genotype and ethnicity. Results for markers rs2540491 (A) and rs2540487 (B) are shown. ALL, All participants; MX, Mexicans; PR, Puerto Ricans.

At the rs2540487 SNP, heterozygotes demonstrated an augmentation of bronchodilator responsiveness with leukotriene modifier use (difference in mean %ΔFEV₁ of 10.03 [5.23-14.83; P < .001]) whereas homozygotes for either the major or minor alleles showed no association between leukotriene modifier use and bronchodilator responsiveness (difference in mean %ΔFEV₁ of 2.52 [–1.16 to 6.20; P = .180] and 2.54 [–9.48 to 14.56; P = .679], respectively). When stratified by ethnicity, a similar pattern again held true for the Puerto Rican participants with no association evident in Mexican participants regardless of which allele was present (Fig 1, B). Because the frequency of subjects homozygous for the minor allele of rs2540487 was low, further analysis was performed comparing carriers of the minor allele (Aa or aa) to homozygotes for the major allele (AA) to determine whether carrying at least 1 copy of the minor allele was associated with augmented bronchodilator responsiveness in leukotriene modifier users. The use of a leukotriene modifier was associated with an augmentation of bronchodilator responsiveness in minor allele carriers in Puerto Rican participants but not Mexican participants (difference in mean %ΔFEV₁ of 4.93 [0.11 to 9.74; P = .045] and –3.77 [–10.03 to 2.48; P = .236], respectively).

Because participants were recruited from different sites in the United States or their country of origin and different environmental exposures in the various locations could account for some of the observed findings, the regression analyses were repeated with inclusion of variables for birth location and recruitment site. Adjustment of the analyses for these variables had no effect on the reported differences in mean %ΔFEV₁, with the largest measured effect on any of the above reported significant outcomes a change in the magnitude of the difference in mean %ΔFEV₁ of 0.17. Likewise, the outcomes were not significantly affected in the analyses stratified by ethnicity.

Interactions between ALOX5AP and LTA4H 

Because ALOX5AP and LTA4H are in same enzymatic pathway for the production of the proinflammatory leukotriene B₄, gene-gene interactions were sought that altered the effects of LTA4H SNPs on the augmentation of bronchodilator responsiveness by leukotriene modifiers. Only those LTA4H SNPs found to have a significant effect in the primary analysis were analyzed for the presence of interactions with ALOX5AP. The number of participants homozygous for the minor alleles at the LTA4H SNPs was small; therefore, homozygotes for the minor alleles and heterozygotes were combined to identify a dominant effect of the minor allele.

For LTA4H SNPs rs2540491 and rs2540487, only participants with genotypes containing the minor allele demonstrated augmentation of bronchodilator responsiveness by leukotriene modifiers, and both ALOX5AP SNPs interacted with the LTA4H SNP's effects (Table III). For the ALOX5AP rs10507391 SNP, only participants with genotypes containing the major allele demonstrated augmentation of bronchodilator responsiveness by leukotriene modifiers, suggesting a dominant effect of the major allele. For the ALOX5AP rs9551963 SNP, only participants with genotypes containing the minor allele demonstrated augmentation of bronchodilator responsiveness by leukotriene modifiers, suggesting a dominant effect of the minor allele. When stratified by ethnicity, these findings held true for Puerto Ricans but not for Mexicans.

Table III. Interactions between LTA4H and ALOX5AP SNPs and their effect on the augmentation of bronchodilator responsiveness by leukotriene modifiers

A, Common allele; a, minor allele.

Data are presented as the difference in mean %ΔFEV₁ (95% CIs) of subjects using leukotriene modifiers compared with those not using leukotriene modifiers with each combination of LTA4H and ALOX5AP SNP genotype.

Boldface indicates P ≤ .008.

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Discussion 

This study identified interactions between gene polymorphisms in leukotriene production enzymes and the effects of leukotriene modifiers on albuterol responsiveness in Latinos with asthma. Furthermore, in subgroup analyses, these interactions were found to be present in Puerto Rican but not Mexican participants. This highlights the complex interactions underlying the heterogeneous response to asthma medications among individuals and emphasizes the importance of seeking ethnic-specific differences in gene-drug interactions.

LTB₄ and the cysteinyl leukotrienes (leukotrienes C₄, D₄, and E₄) exert their proinflammatory effects through interactions with their specific receptors on the surface of inflammatory cells. LTA4H is involved in the enzymatic pathway for the production of LTB₄, and ALOX5AP is in the common pathway for the production of both LTB₄ and the cysteinyl leukotrienes.⁵ Most leukotriene modifiers block cysteinyl leukotriene receptors but still allow LTB₄ to act through its receptor. The regulatory role that polymorphisms in the ALOX5AP and LTA4H genes play on the effect of leukotriene modifiers may be explained by the alteration of both LTB₄ and cysteinyl leukotriene production. Variants in the ALOX5AP and LTA4H genes would modify both the effects of leukotriene modifiers at the cysteinyl leukotriene receptor and the effects of LTB₄ at its receptor, thereby affecting these medications' ability to augment bronchodilator responsiveness.

The identified polymorphisms in the LTA4H gene that are associated with a greater augmentation of bronchodilator responsiveness in leukotriene modifier users do not exactly match those that were previously associated with asthma-related traits.⁸ However, the current study shows clear evidence of the involvement of LTA4H together with ALOX5AP in the effect of leukotriene modifiers on bronchodilator responsiveness. The studied polymorphisms were selected to capture most of the genetic diversity in these genes and, as previously supported, gene-based approaches are more informative than approaches at a SNP-based level.¹⁶

Our results are tempered by the limitations of cross-sectional study design, such as the inability to adjust for all potential confounders. Furthermore, the analysis of multiple gene and drug interactions limits the ability to identify small effects of each of the predictor variables; nonetheless, Wald testing confirmed the presence (and absence) of statistically significant interactions between individual gene polymorphisms and the augmentation of bronchodilator responsiveness by leukotriene modifiers in the primary analysis.

A limitation in our finding that LTA4H and ALOX5AP polymorphisms affect Puerto Rican and Mexicans differently is that there were differences in clinical characteristics between the 2 ethnic groups (ie, age, BMI, baseline FEV₁). To address these potential confounding factors, age and baseline FEV₁ were included in the statistical models, and a difference was still identified between the 2 ethnic groups. Furthermore, all the analyses were repeated with the inclusion of BMI as a predictor variable, and this had no effect on the outcomes. In addition, participants were collected in their regions of origin (Mexico and Puerto Rico) and in mainland US metropolitan regions (San Francisco Bay Area and New York City) and may have been born in a separate location than that from which they were recruited; therefore, environmental differences could explain the observed differences between populations. Although we cannot fully discard the possibility of systematic environmental differences between Mexican and Puerto Rican participants, adjustment of the statistical analyses for birth location and recruitment center had no effect on the outcomes. Furthermore, within an ethnic origin, there were no major differences between recruitment sites in the associations found. Altogether, this indicates that our conclusion that the described gene polymorphisms are associated with augmentation of bronchodilator responsiveness by leukotriene modifiers in Puerto Ricans, but not Mexicans, is both statistically and clinically significant.

Although pharmacogenetic studies evaluating the effects of specific medications on asthma outcomes have previously been reported,¹⁷, ¹⁸, ¹⁹ studies such as this one analyzing interactions between 2 genes linked in a common pathway and its effects on drug-drug interactions are only recently being investigated.²⁰ Such investigations of multiple gene-drug interactions will allow a more detailed understanding of the heterogeneous response to asthma medications and can potentially aid in the development of optimal therapeutic regimens for different individuals.

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We acknowledge the families and the patients for their participation. We also thank the numerous health care providers and community clinics for their support and participation in the GALA Study. We especially thank Jeffrey M. Drazen, MD, Scott Weiss, MD, Ed Silverman, MD, PhD, Homer A. Boushey, MD, and Jean G. Ford, MD, for all of their effort toward the creation of the GALA Study. We thank 2 anonymous reviewers for valuable comments on an earlier version of the article.

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