rs12598836 — HMOX2

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.