rs12598836 — HMOX2

Intronic variant near heme oxygenase 2 (HMOX2) associated with migraine-with-aura susceptibility; the G allele (GRCh38 reference) tags a regulatory effect on constitutive CO production in cerebral vessels, modulating cerebrovascular reactivity relevant to aura pathophysiology

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HMOX2 — Heme Oxygenase 2 and Migraine with Aura

Heme oxygenase 2 (HMOX2) is the constitutive enzyme responsible for breaking down free heme in the brain. Unlike its inducible sibling HMOX1, HMOX2 is always switched on — particularly in cerebral blood vessels, neurons, and astrocytes — producing three products at baseline: biliverdin11 biliverdin
converted rapidly to the antioxidant bilirubin by biliverdin reductase, iron, and carbon monoxide (CO)22 carbon monoxide (CO)
a gasotransmitter: a small molecule gas with defined signalling functions in cells, analogous to nitric oxide. That constitutive CO is not merely a metabolic byproduct — it is an active vasosignalling molecule that sets the baseline tone of cerebral arterioles and interacts continuously with the nitric oxide (NO) system.

rs12598836 is an intronic variant within HMOX2 on chromosome 16p13.3. The G allele (the GRCh38 reference) is the migraine risk allele. It is carried at approximately 30% frequency in Europeans but 80% in Africans, making it one of the more population-stratified migraine risk variants identified to date.

The Mechanism

CO produced by HO-2 acts as a tonic vasoregulator33 tonic vasoregulator
a continuous background signal that holds vascular tone within a narrow physiological range, distinct from acute vasoactive responses in cerebral microvessels. It competes directly with nitric oxide synthase (NOS): CO inhibits NOS by binding to the enzyme's heme prosthetic group, reducing NO output. When HO-2 activity is experimentally blocked, cerebral arterioles dilate — an effect reversed by adding CO back or blocking NOS. This CO-NO balance is precisely the type of vascular regulation relevant to migraine-with-aura pathophysiology.

Cortical spreading depression (CSD)44 Cortical spreading depression (CSD)
the electrophysiological wave of neuronal depolarisation and suppression that underlies migraine aura, propagating at 3–5 mm/minute across the cortex alters cerebral blood flow in a characteristic triphasic pattern — initial hyperaemia, then oligaemia, then sustained hypoperfusion. The HMOX2/CO system, by setting baseline cerebrovascular tone and interacting with NO, is positioned mechanistically at exactly this interface between neurovascular coupling and aura. The rs12598836 G allele presumably tags a regulatory change in HMOX2 expression or splicing that shifts this CO-NO balance in a direction that lowers the threshold for CSD initiation or sustains the oligaemic phase that produces aura symptoms.

The Evidence

The primary evidence comes from Hautakangas et al. 202255 Hautakangas et al. 2022
Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles. Nature Genetics, the largest migraine GWAS conducted to date. Among 123 genome-wide significant loci, the HMOX2 locus (rs12598836-G) was one of only three variants with subtype-specific effects exclusive to migraine with aura (14,624 MA cases vs 703,852 controls). The overall migraine odds ratio per G allele is modest — 1.038 (p = 2×10⁻¹⁰) — but the specificity for the MA subtype implicates an aura mechanism rather than the shared migraine headache pathway.

The mechanistic case rests on dedicated HO-2 neurophysiology research. Parfenova and Leffler 200866 Parfenova and Leffler 2008
Cerebroprotective functions of HO-2. Antioxidants & Redox Signaling documented that HO-2 maintains cerebral blood flow during seizures and hypoxia through rapid CO production — without requiring new enzyme synthesis. Ishikawa et al. 200577 Ishikawa et al. 2005
Microcirculation showed that HO-2-derived CO tonically antagonises NO-mediated vasodilation in rat cerebral arterioles, establishing CO from this enzyme as a moment-to-moment cerebrovascular regulator. The link to CSD is supported by Nimura et al. 199688 Nimura et al. 1996
Journal of Cerebral Blood Flow and Metabolism, who showed that prolonged spreading depression induces HO-1 in cortical glia via AP-1 activation — the heme oxygenase pathway responds to and is activated by CSD waves.

The evidence level for the GWAS association is moderate: the study is large and well-powered, but the HMOX2 subtype-specific finding has not yet been independently replicated in a separate MA-specific meta-analysis. The overall migraine association (p = 2×10⁻¹⁰) is genome-wide significant, but the MA-specific effect merits further confirmation.

Practical Actions

For G allele carriers, the modestly elevated migraine-with-aura susceptibility points to the importance of managing triggers that destabilise neurovascular coupling — particularly those that alter the CO-NO balance acutely. The G allele's effect size is small (OR 1.038), meaning it is one of many genetic contributors to MA risk rather than a dominant determinant. For GG homozygotes with diagnosed MA, discussing vasoconstrictor triptans (which target serotonin 5-HT1B/D receptors on cerebral vessels and are the most effective acute MA treatments) with a neurologist is appropriate given the cerebrovascular mechanism involved.

Interactions

The three MA-specific loci identified in Hautakangas 2022 — HMOX2, CACNA1A, and MPPED2 — are worth considering together. CACNA1A encodes the voltage-gated calcium channel P/Q subunit, variants in which cause familial hemiplegic migraine; calcium channel dysregulation lowers the CSD threshold independently of the vascular mechanism. HMOX2 and CACNA1A likely act through distinct pathways (neurovascular vs neuronal excitability), so co-inheritance of risk variants in both genes could have an additive effect on MA susceptibility.

rs10166942 (TRPM8) is an established migraine risk SNP in the same neurology-cognition category; TRPM8 mediates cold-triggered pain sensitivity and cerebrovascular responses, representing a distinct pathway to migraine susceptibility from the HO-2/CO axis.

Genotype Interpretations

What each possible genotype means for this variant.

AA Normal

No HMOX2 risk alleles — typical heme oxygenase 2 activity and migraine-with-aura susceptibility

You carry two copies of the A allele at rs12598836, the non-risk genotype at this locus. Approximately 31% of people globally share this genotype, and it is the most common genotype among Europeans (about 49% of Europeans are AA). You do not carry the G allele that was associated with migraine-with-aura susceptibility in the Hautakangas 2022 GWAS. This variant does not contribute to your migraine risk; other genetic and environmental factors remain relevant.

AG Intermediate

One HMOX2 risk allele — mildly elevated migraine-with-aura susceptibility

The HMOX2 protein is a constitutive heme oxygenase that produces carbon monoxide (CO) in cerebral blood vessels. CO from HO-2 tonically modulates nitric oxide (NO) signalling, setting baseline cerebrovascular tone. The rs12598836 G allele tags a regulatory effect in HMOX2 that likely shifts this CO-NO balance in cerebral vessels, modifying susceptibility to cortical spreading depression — the electrophysiological event that produces the visual and sensory aura phenomena preceding migraine headache.

The HMOX2 locus is specifically enriched for MA (migraine with aura) rather than migraine without aura, pointing to a mechanism operating at the aura phase rather than the shared headache phase. If you experience migraines without aura, this variant is less likely to be a contributing factor.

GG High Risk

Two HMOX2 risk alleles — elevated migraine-with-aura susceptibility via cerebrovascular CO pathway

HMOX2 encodes heme oxygenase 2, the constitutive enzyme that produces carbon monoxide (CO) in neurons and cerebral blood vessels. CO from HO-2 competes with nitric oxide (NO) at the level of NOS enzyme binding and downstream guanylyl cyclase signalling, acting as a tonic brake on NO-mediated vasodilation. This CO-NO balance governs cerebrovascular reactivity moment to moment.

Cortical spreading depression (CSD) — the slow wave of neuronal depolarisation underlying migraine aura — is exquisitely sensitive to this balance. The oligaemic phase of CSD (sustained hypoperfusion following initial hyperaemia) is partly mediated through NO and vascular signalling. A shifted CO-NO ratio from altered HMOX2 function could lower the CSD threshold or prolong the oligaemic phase, explaining why the HMOX2 locus shows specificity for MA rather than migraine without aura.

HO-2 also produces biliverdin (rapidly converted to the potent antioxidant bilirubin) and iron. Bilirubin at physiological concentrations protects neurons from oxidative stress — a protective role relevant during the metabolic demands imposed by CSD. Altered HMOX2 function therefore potentially affects both the vascular and the neuroprotective arms of the cortical spreading depression response.