rs17222814 — ALOX5AP SG13S114 (HapB tag)

ALOX5AP SG13S114 — The HapB Leukotriene Risk Haplotype

The arachidonate 5-lipoxygenase activating protein (ALOX5AP, also called FLAP — 5-Lipoxygenase Activating Protein) is an indispensable scaffold protein anchored in the nuclear and endoplasmic reticulum membranes of myeloid cells. Without FLAP, the enzyme 5-lipoxygenase cannot bind arachidonic acid efficiently enough to produce leukotrienes¹¹ leukotrienes
potent lipid mediators that drive inflammation in arterial walls, atherosclerotic plaques, and during thrombotic events. Pharmacological blockade of FLAP with compounds like MK-886 abolishes leukotriene synthesis entirely — making ALOX5AP one of the most druggable targets in the inflammatory pathway.

rs17222814 (designated SG13S114 in the original deCODE Genetics mapping work) is an intronic variant that serves as a tag for the HapB haplotype — a distinct four-marker ALOX5AP haplotype identified as an independent cardiovascular risk signal in Icelandic and UK populations. HapB is separate from the more widely studied HapA haplotype; the two tag different regulatory variations within ALOX5AP and show different population distributions and association patterns.

The Mechanism

FLAP sits at the membrane and presents arachidonic acid to 5-lipoxygenase (ALOX5), enabling the two-step oxidation of arachidonic acid to leukotriene A4 (LTA4). LTA4 is then either hydrolyzed to the potent neutrophil chemoattractant leukotriene B4 (LTB4)²² leukotriene B4 (LTB4)
acts on BLT1 and BLT2 receptors on neutrophils and macrophages; a major driver of neutrophil recruitment to atherosclerotic plaques, or conjugated with glutathione to form the cysteinyl leukotrienes (LTC4, LTD4, LTE4) that drive smooth muscle contraction in bronchi and vasculature.

In atherosclerosis, LTB4 recruits neutrophils and macrophages into vascular plaques, amplifies oxidative stress within the plaque microenvironment, and promotes the inflammatory signaling cascade that destabilizes fibrous caps — the proximate cause of acute MI and stroke. rs17222814 is intronic and does not directly change the FLAP protein sequence. As a haplotype tag, it marks a set of regulatory variants that may alter ALOX5AP expression levels or splicing efficiency in cardiovascular-relevant tissues, though the precise causal variant within the HapB haplotype block remains to be identified.

The Evidence

The foundational discovery came from deCODE Genetics (Helgadottir et al., Nature Genetics 2004)³³ deCODE Genetics (Helgadottir et al., Nature Genetics 2004)
whole-genome linkage mapping in Icelandic families followed by haplotype association in independent case-control samples from Iceland and the UK. Two distinct ALOX5AP haplotypes — HapA and HapB — each conferred approximately doubled risk of myocardial infarction. Crucially, stimulated neutrophils from MI patients carrying either haplotype produced more leukotriene B4 than those from controls, providing a direct mechanistic link between ALOX5AP variation and the leukotriene pathway in cardiovascular disease.

Replication in a Scottish stroke cohort (Helgadottir et al., AJHG 2005)⁴⁴ Replication in a Scottish stroke cohort (Helgadottir et al., AJHG 2005)
450 stroke cases and 710 controls from Aberdeenshire, independent of the Icelandic discovery cohort confirmed HapA's association with ischemic stroke (relative risk 1.36, p=0.007). HapB was overrepresented in male stroke patients, supporting the concept that the two haplotypes affect cardiovascular risk through partially distinct mechanisms. A Swedish stroke registry study (Lovkvist et al., EJHG 2008)⁵⁵ Swedish stroke registry study (Lovkvist et al., EJHG 2008)
932 ischemic stroke patients and 396 controls from a population-based register directly examined rs17222814, finding that the A allele was associated with stroke risk specifically in non-hypertensive individuals (OR=1.82, 95% CI 1.21–2.74; p=0.0039), though this did not survive correction for multiple testing.

In an Italian angiography-based CAD study (Girelli et al., EJHG 2007) of 1,431 patients, HapB was significantly overrepresented in patients with angiographically confirmed coronary artery disease⁶⁶ HapB was significantly overrepresented in patients with angiographically confirmed coronary artery disease
OR=1.67, 95% CI 1.04–2.67; p=0.032, suggesting a role in atheroma development rather than purely thrombotic events.

The evidence is not uniformly positive. A nested case-control study within the Physicians' Health Study (Zee et al., Stroke 2006)⁷⁷ nested case-control study within the Physicians' Health Study (Zee et al., Stroke 2006)
600 MI/stroke cases and 600 matched controls from a US male physician cohort found no significant association of HapB with MI or stroke (HapB OR for MI=0.62, p=0.08). A UK functional study (Maznyczka et al., Clin Sci 2007)⁸⁸ UK functional study (Maznyczka et al., Clin Sci 2007)
59 healthy subjects stratified by haplotype status, measuring LTB4 from isolated neutrophils found no difference in stimulated LTB4 production between HapA, HapB, and non-carrier groups, suggesting that if the haplotypes increase cardiovascular risk, they may do so through context-dependent mechanisms (e.g., within inflamed arterial tissue, under pro-inflammatory stimulation) rather than via a simple constitutive increase in leukotriene output. Overall, the effect of HapB is real but modest and population-heterogeneous — more robustly detected in European populations of Northern and Southern European ancestry, less consistently in North American cohorts.

Practical Actions

The A allele of rs17222814 marks a modestly elevated leukotriene-pathway activation background. The most evidence-based intervention for leukotriene pathway-associated cardiovascular risk is the competitive substrate strategy: high-dose EPA from marine or algae sources competitively displaces arachidonic acid, reducing the amount of substrate available for FLAP-mediated leukotriene production. EPA-derived leukotrienes (leukotriene B5) are substantially weaker chemoattractants than the arachidonic-acid-derived LTB4, reducing net inflammatory signaling from the pathway.

Elevated high-sensitivity CRP (hsCRP) and LTB4 urinary metabolites (urinary LTE4) can be used to gauge baseline inflammatory tone and track response to dietary or supplemental interventions. For carriers who also smoke or have hypertension, the synergistic impact on arterial inflammation merits particular attention.

Interactions

HapB (tagged by rs17222814) and HapA (tagged by rs10507391 and related SNPs) are independent haplotypes within ALOX5AP and are not simply additive — individuals can carry alleles on both haplotype blocks simultaneously. The combined effect of carrying both haplotypes has not been formally quantified in a published compound-genotype analysis, but given both haplotypes increase leukotriene-pathway activity, an additive or synergistic effect is biologically plausible.

Within the leukotriene biosynthesis cascade, ALOX5AP variants interact with downstream gene variants in LTA4H (leukotriene A4 hydrolase) and ALOX5 promoter variants. The LTA4H gene has its own cardiovascular risk haplotype (HapK), and combined pathway burden across ALOX5AP, LTA4H, and ALOX5 may confer greater risk than any single variant alone.