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October 13, 2026Frontiers in GeneticsOpen Access

Revisiting the genetic support of leukotriene pathway drug targets in atherosclerotic cardiovascular disease

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Why the study?

Prior genetic association studies linking ALOX5 and ALOX5AP to ASCVD motivated clinical trials of 5-LO inhibitors, but the effect of 5-LO inhibition on ASCVD clinical outcomes remains unclear.

Does genetic variation in the leukotriene pathway genes ALOX5 and ALOX5AP influence the risk of atherosclerotic cardiovascular disease outcomes in a large multi-ancestry cohort?

Key Points

To re-evaluate previously reported genetic associations of leukotriene pathway genes ALOX5 and ALOX5AP with atherosclerotic cardiovascular disease risk and inflammatory biomarkers across diverse ancestries.
Conducted a multi-ancestry meta-analysis using genetic and hospitalization record data from 378,962 participants in the UK Biobank.
Tested the effects of ALOX5 promoter Sp1 repeat counts and ALOX5AP HapA haplotype variants on cardiovascular outcomes (myocardial infarction, ischemic stroke, revascularization) and biomarkers (cIMT, CRP, LDL-C, omega-6).
Continuous dosage of ALOX5 Sp1 repeats was significantly associated with plasma omega-6 levels (p = 8.90 × 10 −5) but was not associated with cIMT, CRP, LDL-C, or any clinical ASCVD outcome.

Study Design

Type

Cohort (n=378,962)

Multicenter

Yes

Structured PICO

Does genetic variation in the leukotriene pathway genes ALOX5 and ALOX5AP influence the risk of atherosclerotic cardiovascular disease outcomes in a large multi-ancestry cohort?

P

Population

378,962 unrelated participants across four genetically predicted ancestry groups (European, African, South Asian, and East Asian) in the UK Biobank cohort evaluated for genetic associations with ASCVD.

E

Exposure

Naturally occurring genetic variation in leukotriene pathway drug target genes: ALOX5 promoter Sp1 tandem repeat polymorphisms (homozygous non-5 repeats model and ancestry-specific continuous dosage model), ALOX5AP four-SNP HapA haplotype (recessive, dominant, and additive models), regional common variants, rare variants, and genetically predicted gene expression of 18 leukotriene pathway genes.

C

Comparator

Reference genotype/haplotype carriers (homozygous 5-repeat carriers or ancestry-specific mode of 8 repeats in African and 10 repeats in other ancestries for ALOX5; non-carriers or single-copy carriers for ALOX5AP HapA).

O

Outcome

Atherosclerotic cardiovascular disease (ASCVD) clinical outcomes algorithmically defined from hospitalization and surgical records, including myocardial infarction (MI), ischemic stroke (IS), and coronary revascularization procedures (percutaneous coronary intervention [PCI] or coronary artery bypass graft [CABG]).hard clinical

Limitations

Absence of certain ancestry groups not available through self-reporting (e.g., Middle Eastern)
Lack of leukotriene pathway-specific molecular markers (e.g., circulating leukotriene metabolites) to serve as direct proxies for 5-LO and ALOX5AP activity
Does not rule out gene-gene or nutrient-gene interactions (such as arachidonic acid availability)
TWAS approaches using bulk gene expression atlases may lack resolution to detect highly localized effects within the atherosclerotic plaque environment
Absence of some ancestry groups not available through UK Biobank self-reporting (e.g., Middle Eastern)
Lack of direct circulating leukotriene metabolite measurements in the UK Biobank to serve as molecular proxies for 5-LO and ALOX5AP activity
Inability to rule out complex gene-gene or nutrient-gene interactions involving arachidonic acid metabolism
Limited spatial and cellular resolution of TWAS relying on bulk tissue gene expression atlases to detect localized plaque effects

Ask about this paper

Answers are grounded in this paper and cite their sources.

Implication

Large-scale multi-ancestry genetic analyses fail to replicate prior links between ALOX5 or ALOX5AP variants and ASCVD, suggesting prior associations were likely confounded by population stratification and casting doubt on human genetic support for 5-LO pathway inhibition in ASCVD.

Abstract

Arachidonate 5-lipoxygenase (5-LO) and its activating protein, encoded by ALOX5 and ALOX5AP respectively, are two leukotriene pathway proteins suspected to play a role in atherosclerotic cardiovascular disease (ASCVD) through inflammatory mechanisms. Prior genetic association studies linking ALOX5 and ALOX5AP to ASCVD have motivated clinical trials of 5-LO inhibitors, such as atreleuton, which was associated with reduced atherosclerotic plaque progression in patients with a recent acute coronary syndrome in a phase II trial. However, the effect of 5-LO inhibition on ASCVD clinical outcomes remains unclear. Using data from the UK Biobank, we revisit previously reported genetic associations of ALOX5 and ALOX5AP with ASCVD using a multi-ancestry meta-analysis including data from 378,962 participants. We characterize ancestral differences in previously studied ALOX5 and ALOX5AP polymorphisms which could have led to population stratification. When adequately accounting for ancestry, these previous associations were not replicated. In addition to our replication efforts, we used association scans and transcriptome-wide association studies to test the involvement of leukotriene pathway genes with ASCVD. Overall, our results do not support a role for genetic variation in ALOX5 or its activating protein in ASCVD risk.

Discussion

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Cite This Study

St-Laurent et al. (2026) conducted a cohort in Atherosclerotic cardiovascular disease (ASCVD) (n=378,962). Genetic variants in ALOX5 (Sp1 promoter motif repeats) and ALOX5AP (HapA haplotype) vs. Ancestry-specific reference alleles or non-carriers of variant alleles/haplotypes was evaluated on Atherosclerotic cardiovascular disease outcomes (myocardial infarction, ischemic stroke, and revascularization procedures).

synapsesocial.com/papers/6aee6b6871a7594806220933 https://doi.org/10.3389/fgene.2026.1812905

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