rs3816183 — HAAO Ile37Val

HAAO Ile37Val — When the Sleep Pathway Tips Toward Neurotoxicity

Your body uses the amino acid tryptophan three ways: to make serotonin and melatonin (the sleep hormones), to fuel energy metabolism as NAD+, and — when inflammation is present — to produce quinolinic acid, a potent excitotoxin that keeps the brain in a state of heightened arousal. The enzyme HAAO (3-hydroxyanthranilate 3,4-dioxygenase) sits at the critical branch point that decides how much of your tryptophan ends up as quinolinic acid. The rs3816183 Ile37Val variant alters this enzyme's function, skewing the pathway in ways that raise insomnia risk.

The Mechanism

In the kynurenine pathway, most dietary tryptophan (~95%) is metabolized through kynurenine¹¹ through kynurenine
rather than the 1-2% that becomes serotonin. At the HAAO step, 3-hydroxyanthranilic acid (3-HAA) is converted by HAAO into a semialdehyde intermediate that spontaneously cyclizes into quinolinic acid (QUIN)²² quinolinic acid (QUIN)
a potent NMDA receptor agonist with excitotoxic properties. QUIN is then metabolized to NAD+, but this conversion is easily overwhelmed: the neuronal enzyme that degrades QUIN (QPRT) becomes saturated at concentrations around 300 nM, allowing excess QUIN to accumulate and continuously stimulate NMDA receptors.

The Ile37Val substitution (p.Ile37Val) changes a bulky isoleucine to the smaller valine at position 37, near the active site of this iron-dependent dioxygenase. While detailed kinetic studies on this specific variant are limited, population genetics clearly signals functional impact: the T allele (encoding Val37) has been independently identified in two types of studies — as an insomnia risk locus in the landmark 2019 insomnia GWAS, and as a hypospadias risk factor, consistent with altered quinolinic acid synthesis affecting embryonic development pathways.

Critically, inflammation amplifies this genetic susceptibility. Pro-inflammatory cytokines upregulate the upstream enzyme IDO1, dramatically increasing flux through the entire kynurenine pathway. With an already-altered HAAO, more tryptophan is shunted toward quinolinic acid production instead of toward serotonin and its downstream conversion to melatonin.

The Evidence

The primary genetic evidence comes from a massive insomnia GWAS: Jansen et al. (2019) in Nature Genetics³³ Jansen et al. (2019) in Nature Genetics
Genome-wide analysis of insomnia in 1,331,010 individuals identifies new risk loci and functional pathways identified 202 genome-wide significant loci and performed pathway enrichment analysis that highlighted kynurenine pathway genes — HAAO, KYNU, QPRT, and ACMSD — as a convergent insomnia risk cluster. This is mechanistically coherent: all four encode enzymes in the same metabolic branch responsible for determining the kynurenic acid to quinolinic acid ratio.

The metabolic link to sleep quality is directly demonstrated in human data: Cho et al. (2017)⁴⁴ Cho et al. (2017)
Sleep disturbance and kynurenine metabolism in depression. Journal of Psychosomatic Research found that sleep disturbance was significantly associated with a reduced kynurenic acid/quinolinic acid (KynA/QA) ratio — meaning a shift toward neurotoxic quinolinic acid dominance.

The mechanistic pathway from QUIN elevation to disrupted sleep is established in experimental models: Pocivavsek et al. (2018)⁵⁵ Pocivavsek et al. (2018)
Acute kynurenine challenge disrupts sleep-wake architecture in rats demonstrated that elevated kynurenine (which feeds HAAO to produce QUIN) reduced total REM duration, delayed REM onset, and increased wakefulness, with EEG evidence of impaired theta power during REM — a signature of hippocampal arousal. The mechanism is NMDA receptor hyperactivation and antagonism of α7 nicotinic acetylcholine receptors.

Finally, the NAD+ connection provides a second route to intervention: Weiss (2026)⁶⁶ Weiss (2026)
Vitamin B3 ameliorates sleep duration and quality reviewed clinical evidence that nicotinamide riboside (NR) supplementation — which bypasses HAAO to replenish NAD+ — improves sleep efficiency in individuals with insomnia and supports circadian clock gene function (BMAL1, PER2).

Practical Actions

For T-allele carriers, two complementary strategies address the underlying mechanism: (1) reducing inflammation to limit IDO1 induction and the resulting kynurenine flood through HAAO, and (2) supporting NAD+ levels via a pathway that bypasses HAAO entirely. Timing of tryptophan intake also matters — consuming tryptophan-rich foods in the evening rather than splitting intake evenly across the day preferentially supports serotonin/melatonin synthesis while the liver's kynurenine pathway activity is lower.

Interactions

HAAO Ile37Val acts within a broader kynurenine pathway context. The upstream enzyme KMO (kynurenine 3-monooxygenase) and downstream enzyme QPRT both have functional variants that modulate the same neurotoxic/neuroprotective balance. TT carriers may benefit from looking at their KMO and QPRT variants to understand the full picture of their kynurenine pathway function.

The COMT gene (rs4680) interacts with this pathway indirectly: COMT metabolizes catecholamines that modulate hypothalamic arousal, and individuals with both HAAO TT and COMT AA (low dopamine clearance) may experience compounded sleep-onset difficulty via both NMDA hyperactivation and elevated dopaminergic arousal.