rs10509679 — CYP2C9

Intronic CYP2C9 haplotype tag associated with increased ischemic stroke risk in Asian populations, acting through altered epoxyeicosatrienoic acid (EET) production and impaired cerebrovascular tone regulation

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CYP2C9 and Stroke Risk — When a Drug-Metabolism Gene Affects the Brain's Blood Supply

CYP2C9 is best known as the liver enzyme that metabolizes warfarin, ibuprofen, and dozens of other common medications. But CYP2C9 is also an epoxygenase — it converts arachidonic acid11 arachidonic acid
A 20-carbon omega-6 fatty acid released from cell membranes during inflammation and stress; the precursor for a broad array of signaling lipids including prostaglandins, leukotrienes, and epoxyeicosatrienoic acids into epoxyeicosatrienoic acids (EETs), a family of lipid mediators that relax blood vessel walls, suppress inflammation, and actively protect brain tissue during ischemic episodes. rs10509679 is an intronic variant within CYP2C9 that tags a haplotype associated with increased susceptibility to ischemic stroke, most clearly documented in Chinese Han populations.

The Mechanism

EETs are produced in vascular endothelium and neurons by the epoxygenase branch of the arachidonic acid cascade — a pathway in which CYP2C8 and CYP2C9 are the dominant enzymes in human cerebral vessels. Once synthesized, EETs act as endothelium-derived hyperpolarizing factors: they open smooth muscle potassium channels, reduce intracellular calcium, and relax arterial tone. In the brain, EETs also suppress NF-κB-driven neuroinflammation and trigger preconditioning responses that limit infarct size during transient ischemia. The pathway's clinical relevance was established by Donnelly et al. 201522 Donnelly et al. 2015
Donnelly MK et al. Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage. J Cereb Blood Flow Metab. 2015;35(2):267-76, who showed in 363 subarachnoid hemorrhage patients that genetic variants reducing EET biosynthesis worsened outcomes: CYP2C8*4 carriers showed 44% and 36% lower CSF EET levels and 2.2- to 2.5-fold higher rates of delayed cerebral ischemia and neurologic deterioration. Conversely, carrying a favorable CYP2C9 variant (g.816G) was associated with better long-term recovery. This was the first clinical demonstration that EET pathway genetics directly shapes cerebrovascular outcomes in humans.

rs10509679 sits 530 nucleotides into an intron of CYP2C9 (c.642+530, GRCh38 chr10:94,948,469). As an intronic variant, it does not change the CYP2C9 protein sequence directly. Its most likely mechanism is regulatory: intronic variants frequently influence mRNA splicing efficiency, pre-mRNA secondary structure, or binding affinity for intronic regulatory elements. In Asian populations — where the A allele frequency reaches 30% compared to 4% in African populations — this locus may tag a regional haplotype that modifies CYP2C9 expression in the brain vasculature, reducing EET output and thereby narrowing the window between normal cerebrovascular tone and ischemic injury.

The Evidence

The primary association evidence comes from Zhang et al. 202533 Zhang et al. 2025
Zhang J et al. CYP2C9 polymorphism is associated with susceptibility to ischemic stroke in a Chinese population. Ann Med. 2025;57(1):2506839, a matched case-control study of 643 ischemic stroke patients and 643 healthy controls from Inner Mongolia Medical University. Among four CYP2C9 intronic SNPs tested (rs10509679, rs1934967, rs1934968, rs9332220), only rs10509679 reached individual statistical significance: OR=1.48 (95% CI 1.05-2.09, p=0.024). A haplotype combining the risk alleles at all four loci — A(rs10509679)-C(rs1934967)-G(rs1934968)-G(rs9332220) — showed further elevated stroke risk, suggesting that the four intronic variants collectively tag a functional haplotype block. The study was limited to one ethnic group and a single centre, and the individual OR of 1.48 is modest; independent replication in larger, multi-ethnic cohorts is needed before this variant can be assigned a higher evidence grade.

The broader picture of CYP2C9 and stroke is reinforced by two large Taiwan Biobank analyses: Peng et al. 202144 Peng et al. 2021
Peng JW et al. Interactive association between CYP2C9 rs2860905 polymorphism and atrial fibrillation on ischemic stroke in Taiwan Biobank participants. Pharmacogenomics Pers Med. 2021;14:1199-1212 found that the CYP2C9 rs2860905 GG genotype enhanced stroke risk and interacted multiplicatively with atrial fibrillation (combined OR=4.68 vs 3.70 for AF alone, 17,726 participants). A companion study by Peng et al. 202255 Peng et al. 2022
Peng JW et al. Independent and interactive effects of sex and CYP2C9 variant rs4918758 on ischemic stroke risk. Int J Gen Med. 2022;15:3771-3780 demonstrated sex-stratified stroke risk for another CYP2C9 intronic variant, with significantly elevated risk in men (OR=1.32) but not women. Together, these studies establish a consistent, if still emerging, pattern linking CYP2C9 intronic variation to ischemic stroke susceptibility in East and South Asian populations, likely via EET pathway effects on cerebrovascular reactivity.

Practical Actions

For carriers of the A allele, the two most actionable levers are: (1) supporting EET production upstream by ensuring adequate omega-6 precursor handling via EPA/DHA competition — high omega-3 intake shifts arachidonic acid metabolism away from pro-inflammatory pathways and toward protective eicosanoids; and (2) monitoring for established stroke risk factors that compound the genetic vulnerability — particularly atrial fibrillation, which the Taiwan Biobank data suggest interacts with CYP2C9 variants to multiply stroke risk several-fold. Ibuprofen and other NSAIDs that compete for CYP2C9 enzyme activity may transiently reduce EET production; this is worth discussing with a prescriber for A/A homozygotes on regular NSAID regimens.

Interactions

rs10509679 resides in a four-SNP haplotype block with rs1934967, rs1934968, and rs9332220 within CYP2C9. The rs1934967 variant is independently catalogued in the pharmacogenomics section (also CYP2C9, chr10) and is associated with warfarin sensitivity and NSAID metabolism in Asian populations. Carrying risk alleles at both rs10509679 and rs1934967 places someone on the stroke-risk haplotype identified in the Zhang 2025 study. Both variants are informative for the same CYP2C9 functional domain and may compound.

Genotype Interpretations

What each possible genotype means for this variant.

GG Reference Haplotype Normal

Common G/G genotype — no elevated stroke risk from this CYP2C9 locus

You carry two copies of the G allele at rs10509679, the reference genotype found in approximately 74% of people globally. The G allele at this locus is not associated with altered ischemic stroke risk. Your CYP2C9 epoxygenase activity and EET production are not impaired by this particular intronic variant. About 74% of people share this genotype globally, though the distribution varies substantially by ancestry: approximately 72% of Europeans, 44% of East Asians, and 92% of Africans carry the G/G genotype.

AG Haplotype Tag Carrier Intermediate

One A allele — modestly increased ischemic stroke risk, particularly in Asian ancestry

CYP2C9 synthesizes epoxyeicosatrienoic acids (EETs) from arachidonic acid in vascular endothelium. EETs relax arterial walls, suppress vascular inflammation, and provide neuroprotection during ischemic episodes. Intronic variants like rs10509679 may reduce CYP2C9 expression or alter mRNA processing in cerebrovascular tissue, narrowing the EET-mediated protection against transient reductions in cerebral blood flow. The four-SNP haplotype (A at rs10509679, C at rs1934967, G at rs1934968, G at rs9332220) collectively tagged a higher-risk group in the Zhang 2025 study. If you also carry the risk alleles at the other three haplotype members, your stroke risk may be further elevated.

AA Homozygous Risk Haplotype High Risk

Two A alleles — highest CYP2C9 haplotype-associated stroke risk from this locus

EETs (epoxyeicosatrienoic acids) produced by CYP2C9 in vascular endothelium are among the strongest endogenous cerebrovascular vasodilators. They open potassium channels in smooth muscle, lower intracellular calcium, and reduce vasomotor tone — giving cerebral arteries a larger buffer before a flow-limiting obstruction triggers ischemia. When CYP2C9 expression or activity is reduced by an intronic regulatory variant, this buffer narrows. In subarachnoid hemorrhage patients, lower CYP2C8- mediated CSF EET levels (the closest studied analogue) were associated with 2.5-fold higher rates of delayed cerebral ischemia. For A/A carriers of rs10509679, the practical implication is that cerebrovascular EET reserve may be reduced, making proactive stroke risk factor management particularly important.

The four-SNP CYP2C9 haplotype (A-C-G-G across rs10509679, rs1934967, rs1934968, rs9332220) was identified as a unit in the Zhang 2025 study; A/A homozygotes at rs10509679 likely also carry the other haplotype-defining alleles, amplifying any functional consequence. Atrial fibrillation is an especially important risk modifier: Taiwan Biobank data showed CYP2C9 variant carriers with AF had OR=4.68 for stroke vs OR=3.70 for AF alone — indicating a multiplicative, not merely additive, effect.