rs10507391 — ALOX5AP SG13S114 intron variant

ALOX5AP SG13S114 — The Leukotriene Valve in Cardiovascular Inflammation

When a blood vessel wall becomes injured or inflamed, one of the body's first responders is the leukotriene pathway¹¹ leukotriene pathway
a branch of arachidonic acid metabolism that produces potent lipid-based inflammatory mediators from immune cells. ALOX5AP — arachidonate 5-lipoxygenase activating protein, also called FLAP (5-lipoxygenase activating protein) — is the essential scaffold protein that anchors the enzyme 5-lipoxygenase to the nuclear membrane, enabling it to convert arachidonic acid into leukotrienes. Without ALOX5AP, leukotriene biosynthesis essentially stops. Variants in ALOX5AP alter how much leukotriene the body makes when challenged by vascular stress, with downstream consequences for atherosclerosis, thrombosis, and stroke risk.

The Mechanism

rs10507391 is an intronic variant in ALOX5AP on chromosome 13q12 and is one of the four tagging SNPs that define the HapA haplotype²² HapA haplotype
a four-SNP risk haplotype in ALOX5AP first identified by deCODE Genetics in Iceland. The HapA haplotype is not a protein-coding change — it alters gene regulation and mRNA expression levels rather than the ALOX5AP protein sequence directly.

The A allele at rs10507391 has a cis-effect on ALOX5AP transcript levels and exerts trans-effects on expression of downstream pathway members ALOX5 and LTA4H in human aortic tissue samples with varying degrees of atherosclerosis. Crosslin et al., Human Genetics 2009³³ Crosslin et al., Human Genetics 2009 demonstrated that rs10507391 genotype significantly predicts expression across multiple leukotriene pathway nodes simultaneously — a signature of a regulatory hub variant influencing the entire biosynthetic axis.

The biological consequence: stimulated immune cells (neutrophils, monocytes) from A-allele carriers produce greater quantities of leukotriene B4 and cysteinyl leukotrienes. These are potent chemoattractants and vasoconstrictors that drive macrophage infiltration into atherosclerotic plaques, promote endothelial activation, and destabilize lipid cores — processes central to both plaque formation and acute thrombotic events.

The Evidence

The foundational study, Helgadottir et al., Nature Genetics 2004⁴⁴ Helgadottir et al., Nature Genetics 2004
deCODE Genetics, Iceland, identified the four-SNP ALOX5AP haplotype (HapA, which includes the rs10507391 A allele) as associated with approximately two-fold increased risk of myocardial infarction and stroke in an Icelandic population. Critically, the excess leukotriene B4 production in neutrophils was observed specifically in males carrying the at-risk haplotype, establishing a plausible sex-modulated biological mechanism.

Meta-analytic evidence for ischemic stroke has been mixed. A Caucasian-focused meta-analysis of 9 studies (4,198 cases, 3,699 controls)⁵⁵ Caucasian-focused meta-analysis of 9 studies (4,198 cases, 3,699 controls)
Li et al., Cell Mol Biol 2017 found significant association of rs10507391 with ischemic stroke risk (OR=1.18; 95% CI 1.08–1.28; P=0.0002), with the European subgroup showing OR=1.20. A larger, broader meta-analysis of 30 studies (32,782 participants)⁶⁶ broader meta-analysis of 30 studies (32,782 participants)
Zheng et al., Neuropsychiatr Dis Treat 2019 found no significant association overall (OR=1.03; 95% CI 0.93–1.14; P=0.557). This divergence likely reflects population stratification (the original Icelandic signal was ancestry-specific), haplotype-level effects not captured by single-SNP analysis, and interaction effects missed in pooled analyses.

The most mechanistically compelling validation comes from the European EUSTAR scleroderma cohort⁷⁷ European EUSTAR scleroderma cohort
Kowal-Bielecka et al., Rheumatology 2017 (977 SSc patients, 558 controls), where A-allele carriers at rs10507391 showed directly measured increases in cysteinyl leukotriene production from peripheral blood mononuclear cells. The variant associated with SSc susceptibility (OR=1.27; 95% CI 1.07–1.50) and, more strongly, with SSc-related interstitial lung disease (OR=1.45; 95% CI 1.17–1.79). This direct functional measurement of leukotriene excess provides mechanistic validation of the original Icelandic biological hypothesis.

A gene-gene interaction study in Chinese populations (Chi et al., Neuroreport 2014)⁸⁸ (Chi et al., Neuroreport 2014) found no individual effect of rs10507391 in isolation but a significant interaction with CYP3A5 A6986G that increased cerebral infarction risk nearly twofold (OR=1.80; 95% CI 1.18–2.76; P=0.006) — reinforcing the pattern that this variant's clinical impact depends heavily on genetic and environmental context.

Practical Actions

For AT heterozygotes, the primary action is monitoring inflammatory cardiovascular biomarkers — particularly high-sensitivity CRP, which integrates vascular inflammatory activity broadly and can motivate targeted lipid or anti-inflammatory therapy earlier than standard guidelines suggest.

For AA homozygotes, the evidence supports a more proactive approach: leukotriene-modulated inflammation is a distinct pathway from LDL-driven atherosclerosis, and conventional lipid management alone may not address it. Dietary shifts toward omega-3 fatty acids — specifically EPA (eicosapentaenoic acid), which competitively reduces leukotriene B4 synthesis — provide a mechanism-specific intervention. The 5-lipoxygenase pathway is also inhibited by flavonoids abundant in dark berries, quercetin-rich foods, and certain culinary herbs.

Smoking is particularly relevant here: smoking amplifies leukotriene production and synergizes with ALOX5AP genetic variation to increase atherosclerotic stroke risk in published interaction studies.

Interactions

rs10507391 is one of four tagging SNPs in the ALOX5AP HapA haplotype. The other HapA-defining SNPs (rs4769874, rs9551963, rs9315050, rs4147064) are all within ALOX5AP and collectively define the at-risk regulatory state — risk is maximal when multiple HapA alleles co-occur. HapA haplotype analysis consistently shows larger effects than any single tagging SNP analyzed alone.

A gene-gene interaction between rs10507391 and CYP3A5 rs776746 has been documented in cerebral infarction, with combined OR of ~1.80. CYP3A5 is involved in arachidonic acid metabolism, creating two-pathway convergence on leukotriene-mediated vascular inflammation. Individuals carrying risk alleles at both loci should be flagged for comprehensive cardiovascular inflammatory workup.

Pathway-level interactions with LTA4H (leukotriene A4 hydrolase, which converts the ALOX5AP product LTA4 into LTB4) and LTC4S (leukotriene C4 synthase, producing cysteinyl leukotrienes) have been documented — see related SNPs rs17222814 (LTA4H) and leukotriene receptor variants.