rs17222842 — ALOX5AP ALOX5AP variant (SG13S32)

Intronic ALOX5AP haplotype tag; the common G allele marks the HapB cardiovascular risk haplotype via elevated leukotriene production, while the rare A allele confers partial protection against coronary heart disease and myocardial infarction

See your personal result for ALOX5AP

Upload your DNA data to find out which genotype you carry and what it means for you.

Upload your DNA data

Works with 23andMe, AncestryDNA, and other DNA test exports. Results in under 60 seconds.

The Leukotriene Switch: ALOX5AP, Inflammation, and Heart Attack Risk

A genetic variant in the ALOX5AP gene — encoding the 5-lipoxygenase-activating protein (FLAP) — tags a risk haplotype that has been linked to myocardial infarction and stroke across multiple European cohorts. FLAP is the membrane scaffold that enables 5-lipoxygenase (5-LOX) to process arachidonic acid into pro-inflammatory leukotrienes, particularly leukotriene B4 (LTB4)11 leukotriene B4 (LTB4)
a potent lipid mediator that recruits neutrophils, activates macrophages, and promotes atherosclerotic plaque formation. Without FLAP, 5-LOX cannot dock on the nuclear membrane and remains catalytically inactive.

The Mechanism

rs17222842 is an intronic tag SNP — a marker, not a functional mutation — that travels with the four-SNP HapB haplotype (rs17216473A–rs10507391A–rs9315050A–rs17222842*G*). Carriers of this haplotype show evidence of increased leukotriene pathway activity, which promotes:

  • Macrophage activation and foam-cell formation in arterial plaques
  • Endothelial dysfunction via LTB4-driven oxidative stress
  • Platelet aggregation and vasospasm through cysteinyl leukotrienes
  • Systemic low-grade inflammation measurable as elevated hs-CRP

The minor A allele at rs17222842 is absent from HapB and correlates with reduced haplotype burden — i.e., the A allele tags the absence of the full risk haplotype. Carriers of the A allele therefore represent a genetically lower-risk subgroup.

The Evidence

The story begins with the landmark Helgadottir et al. 2004 Nature Genetics paper22 Helgadottir et al. 2004 Nature Genetics paper
"The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke", which identified ALOX5AP haplotypes as conferring approximately twice the risk of MI and stroke in Icelandic and British populations. A 2005 Scottish replication study33 2005 Scottish replication study
Helgadottir A et al., Am J Hum Genet, 2005 confirmed HapA's stroke association (RR 1.36, P=0.007) in 450 stroke patients vs 710 controls.

For HapB specifically — the haplotype defined by the rs17222842 G allele — evidence has accumulated across multiple cohorts:

Importantly, the A allele itself shows a directly protective signal: Oosterveer et al. 200988 Oosterveer et al. 2009 found the A allele at rs17222842 was protective against tendon xanthomas in 945 FH patients (OR 0.62, 95% CI 0.43–0.90, P=0.01), consistent with reduced inflammatory drive.

However, effect sizes vary across populations and some prospective studies in non-European cohorts found no association, highlighting that this is a moderate-evidence haplotype marker rather than a high-penetrance causal variant.

Practical Actions

For individuals carrying GG (the common genotype, without the protective A allele), strategies that reduce leukotriene-driven inflammation are most relevant:

  • Omega-3 fatty acids (EPA/DHA): EPA competes with arachidonic acid for 5-LOX, directly reducing the substrate available for leukotriene synthesis
  • Monitoring cardiovascular inflammatory biomarkers (hs-CRP, Lp-PLA2): more informative than standard lipid panels for leukotriene-pathway risk
  • Targeted anti-inflammatory diet: reducing dietary arachidonic acid (red meat, high-fat dairy) limits leukotriene precursor availability

For A allele carriers (AG or AA), the protective signal at this locus is reassuring, though it does not override other cardiovascular risk factors.

Interactions

rs17222842 is one of four tag SNPs constituting the ALOX5AP HapB haplotype. The full haplotype is defined by: rs17216473 (A allele) + rs10507391 (A allele) + rs9315050 (A allele) + rs17222842 (G allele). Haplotype carriers who also carry high-LDL variants (e.g. LDLR, APOB, PCSK9) face compounded risk — the Oosterveer/van der Net FH cohorts showed the strongest effects in high-LDL subgroups, suggesting leukotriene- driven inflammation and lipid accumulation act synergistically in plaque development. Interaction with COX-2 (PTGS2) pathway variants may also modulate net eicosanoid balance in favor of or against resolution of arterial inflammation.

Genotype Interpretations

What each possible genotype means for this variant.

GG G/G — Baseline Risk Normal

Common genotype — standard ALOX5AP leukotriene haplotype burden

You carry two copies of the G allele at rs17222842 (GG genotype), which is the most common genotype in people of European descent — shared by approximately 82% of this population. The G allele tags the ALOX5AP HapB cardiovascular risk haplotype, but since GG represents the population majority, it also represents the baseline reference risk level for cardiovascular disease in this genetic context. You do not carry the rare protective A allele that is associated with reduced leukotriene-driven inflammation. Your ALOX5AP-related cardiovascular risk is at the population average.

AA A/A — Protective Genotype Beneficial

Rare protective genotype — lowest HapB leukotriene haplotype burden

The AA genotype means neither of your chromosomes carries the HapB haplotype allele at rs17222842. Since rs17222842 G is the defining tag for HapB (rs17216473A + rs10507391A + rs9315050A + rs17222842G), the AA genotype is genetically inconsistent with HapB carriage at this locus. Observational data from 945 familial hypercholesterolemia patients found the A allele protective against xanthomas (OR 0.62, 95% CI 0.43–0.90) — consistent with reduced leukotriene inflammatory drive. This genetic advantage does not offset other cardiovascular risk factors (LDL, blood pressure, smoking, diabetes), but it does indicate a naturally lower burden from this specific inflammatory pathway.

AG A/G — Partial Risk Intermediate

One copy of the HapB risk allele — mildly elevated leukotriene-pathway inflammatory signal

The AG genotype indicates partial HapB haplotype burden. The G allele travels with the complete HapB four-SNP signature (defined by Huang et al. 2010 as: rs17216473A–rs10507391A–rs9315050A–rs17222842G), which has been associated with CHD across multiple European cohorts: Girelli et al. 2007 (OR 1.67 angiography- confirmed CAD in 1,431 patients), van der Net et al. 2009 (HR 1.48 in 1,817 FH patients), Tsai et al. 2009 (adjusted OR 2.05 for premature CAD). The biological mechanism involves elevated leukotriene B4 (LTB4) production — LTB4 recruits neutrophils, activates macrophages, and promotes foam-cell formation in arterial plaques. Note that association strength varies between cohorts and that not all prospective or non-European studies replicate the effect; this is moderate-strength evidence.