rs10889160 — CYP2J2

Intronic CYP2J2 tag SNP; the C allele marks a haplotype associated with reduced epoxyeicosatrienoic acid (EET) production and increased myocardial infarction risk through impaired cardioprotective vasodilation

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CYP2J2 and the EET Shield — When the Heart's Own Vasodilator Falls Short

Deep within cardiomyocytes and the endothelial cells lining coronary arteries, an enzyme quietly converts arachidonic acid into a family of potent lipid mediators called epoxyeicosatrienoic acids (EETs)11 epoxyeicosatrienoic acids (EETs)
four regioisomers produced by CYP2J2 from arachidonic acid: 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET — each with vasodilatory and anti-inflammatory properties. CYP2J2 (cytochrome P450 family 2, subfamily J, member 2) is the primary arachidonic acid epoxygenase expressed in the heart, where it serves as the body's endogenous vasodilator, anti-fibrotic, and anti-arrhythmic system. Variants that reduce CYP2J2 expression or activity lower EET production, weakening this protective shield precisely when it matters most — under metabolic stress, ischemia, and inflammatory challenge.

The Mechanism

rs10889160 is an intronic variant in CYP2J2 on chromosome 1 (GRCh38 position 59,896,449). It does not change the CYP2J2 protein sequence directly — it is a tag SNP marking a genomic haplotype that influences CYP2J2 expression levels. Marciante et al. (2008)22 Marciante et al. (2008) identified rs10889160 as one of two intronic CYP2J2 variants significantly associated with myocardial infarction risk in a large population-based study.

The functional consequence runs through EETs. Spiecker et al. (2004)33 Spiecker et al. (2004) demonstrated that individuals with loss-of-function CYP2J2 promoter variants have significantly lower plasma EET metabolite concentrations (p=0.028) and showed a 48% reduction in CYP2J2 promoter activity in cell reporter assays. EETs normally activate endothelial potassium channels, hyperpolarizing vascular smooth muscle and causing vasodilation of coronary arteries — an effect critical for matching myocardial oxygen supply to demand. EETs also suppress NF-κB-driven inflammation in cardiomyocytes, inhibit cardiac fibrosis, reduce cardiomyocyte apoptosis, and have direct antiarrhythmic properties.

The link between reduced CYP2J2 and heart disease pathology is further supported by Evangelista et al. (2020)44 Evangelista et al. (2020), who found that CYP2J2 protein levels were significantly lower in cardiac tissue from patients with non-ischemic cardiomyopathy compared to healthy controls. Silencing CYP2J2 in cultured human cardiomyocytes dysregulated approximately 1,100 genes, with enrichment in ion channel and metabolic pathways — a pattern consistent with EET loss as a driver of electrical instability and metabolic dysfunction.

The Evidence

The primary population-genetic evidence comes from Marciante et al., Pharmacogenetics and Genomics 200855 Marciante et al., Pharmacogenetics and Genomics 2008, a case-control study within the Group Health cohort comparing 856 incident nonfatal MI cases to 2,688 controls. Among 30 tag-SNPs across three CYP epoxygenase genes, rs10889160 emerged as one of two CYP2J2 intronic variants significantly associated with MI risk: OR=1.24 (95% CI 1.07–1.43; p=0.004; q=0.090). The companion intronic variant rs11572325 showed similar direction (OR=1.27; 95% CI 1.08–1.51; p=0.006). No association was found with ischemic stroke.

The broader mechanistic case is strengthened by evidence from the functionally characterized CYP2J2*7 variant (G-50T promoter, rs890293). Spiecker et al., Circulation 200466 Spiecker et al., Circulation 2004 found OR=2.23 (95% CI 1.04–4.79) for CAD in 289 patients vs 255 controls, with direct measurement of reduced plasma EET metabolites. A parallel study by Liu et al., Atherosclerosis 200777 Liu et al., Atherosclerosis 2007 in a Taiwanese cohort found the CYP2J2*7 T allele conferred OR=1.78 for premature MI (under age 45), rising to a synergistic 6.7-fold risk in smokers — consistent with smoking's known ability to suppress EET production.

The evidence is graded moderate: the rs10889160 association has not been independently replicated in a second large cohort, the functional mechanism of this specific intronic variant is not characterized (it is a tag SNP, not proven causal), and the q-value (0.090) reflects modest multiple-testing survival. The broader pathway biology is well-established through the CYP2J2 gene family and EET physiology literature.

Practical Actions

For C-allele carriers, the most mechanism-specific intervention is increasing substrate availability for whatever CYP2J2 activity remains. CYP2J2 also metabolizes EPA and DHA from omega-3 fatty acids into 17,18-epoxy-EPA and 19,20-epoxy-DHA — compounds with potent antiarrhythmic properties in cardiomyocytes88 potent antiarrhythmic properties in cardiomyocytes. These EPA- and DHA-derived epoxides share many of the cardioprotective properties of arachidonic acid-derived EETs, and dietary omega-3 supplementation profoundly shifts the cardiac eicosanoid profile toward these protective metabolites.

Monitoring cardiac inflammatory biomarkers — particularly high-sensitivity CRP and erythrocyte membrane EET ratios where available — provides downstream visibility into whether EET-dependent anti-inflammatory signaling is functioning adequately. The smoking interaction documented for CYP2J2*7 variants is particularly relevant for C-allele carriers given shared pathway biology.

Interactions

rs10889160 and rs11572325 are the two intronic tag-SNPs within CYP2J2 identified by Marciante et al. (2008). Their combined haplotype context likely determines the degree of expression-level effect. The functionally characterized promoter variant rs890293 (CYP2J2*7) provides a causal anchor for the pathway biology; rs10889160 appears to tag a related expression haplotype by LD.

Interaction with smoking is biologically plausible and supported by the Liu et al. (2007) synergistic data on the CYP2J2*7 variant — smoking reduces EET production, and reduced CYP2J2 capacity from the C allele compounds this deficit. CYP2J2 metabolizes both arachidonic acid and omega-3 fatty acids; reduced activity impairs the cardioprotective benefit of dietary EPA/DHA supplementation by limiting conversion to epoxy-EPA and epoxy-DHA metabolites.

Nutrient Interactions

EPA (eicosapentaenoic acid) altered_metabolism
DHA (docosahexaenoic acid) altered_metabolism

Genotype Interpretations

What each possible genotype means for this variant.

TT Normal

Your CYP2J2 genotype is associated with normal cardiac EET production capacity

You carry two copies of the T allele at rs10889160, the most common genotype globally (found in approximately 60% of people) and in about 72% of people of European descent. This genotype is outside the CYP2J2 MI-risk haplotype identified by Marciante et al. (2008) and is associated with normal baseline EET production in the heart and vasculature. Your CYP2J2-mediated vasodilatory and anti-inflammatory protection appears genetically intact at this locus.

CT Intermediate

One copy of the CYP2J2 MI-risk allele — moderately reduced EET-mediated cardiac protection

CYP2J2 is the heart's primary epoxygenase, producing EETs that relax coronary arteries, suppress cardiomyocyte inflammation, inhibit fibrosis, and stabilize cardiac electrical conduction. The C allele at rs10889160 tags a haplotype associated with lower EET output. With one copy, the impact is partial — your other allele continues to support CYP2J2 expression. The clinical significance is modest at the individual level but measurable at the population level.

Omega-3 fatty acids (EPA, DHA) are alternative substrates for CYP2J2. The enzyme converts EPA into 17,18-epoxy-EPA and DHA into 19,20-epoxy-DHA, which have antiarrhythmic and anti-inflammatory properties overlapping with EETs. Increasing omega-3 intake gives your CYP2J2 more protective substrate to work with, a mechanism-specific intervention for C-allele carriers.

CC High Risk

Two copies of the CYP2J2 MI-risk allele — reduced EET-mediated cardiac protection requires targeted intervention

CYP2J2 normally converts arachidonic acid into EETs at high rates in cardiomyocytes and coronary endothelial cells. EETs activate large-conductance calcium-activated potassium channels in vascular smooth muscle — the primary molecular mechanism for coronary vasodilation. They also suppress NF-κB activation in cardiomyocytes, reducing inflammatory cytokine production in response to ischemic stress. In animal models, CYP2J2 overexpression reduces infarct size, limits post-MI fibrosis, preserves systolic function, and prevents electrical remodeling that predisposes to arrhythmia.

Evangelista et al. (2020) found significantly reduced CYP2J2 protein in human cardiomyopathy tissue, establishing the link between CYP2J2 deficit and actual human heart disease. Spiecker et al. (2004) showed directly measured EET metabolite reductions in individuals with CYP2J2 promoter variants. The CC genotype at rs10889160 likely tags a haplotype with the most severe expression deficit in this intronic regulatory region.

EPA and DHA from omega-3 fatty acids are alternative CYP2J2 substrates. The enzyme generates 17,18-epoxy-EPA from EPA — a compound with potent antiarrhythmic activity in neonatal cardiomyocyte studies. Dietary omega-3 supplementation causes a profound shift of the cardiac CYP-eicosanoid profile toward these EPA- and DHA-derived protective epoxides, providing a partially compensatory cardioprotective effect independent of EET production.