rs11572325 — CYP2J2

CYP2J2 rs11572325 — A Cardiac Epoxygenase Variant and MI Risk

Your heart produces its own endogenous cardioprotective molecules. CYP2J2 is a cytochrome P450 enzyme expressed predominantly in cardiomyocytes and vascular endothelial cells, where it converts arachidonic acid into epoxyeicosatrienoic acids (EETs)¹¹ epoxyeicosatrienoic acids (EETs)
Biologically active lipid mediators produced by cytochrome P450 epoxygenases; they dilate coronary arteries, reduce vascular inflammation, inhibit platelet aggregation, and protect cardiac tissue from ischemic injury. The intronic variant rs11572325 sits within an intron of CYP2J2 on chromosome 1 and forms part of a haplotype block with the promoter variant rs890293 (CYP2J2*7) and the neighboring intronic SNP rs2280275 — all three of which tag the same reduced-CYP2J2-expression signal. Population studies have linked the rs11572325 T allele to both myocardial infarction risk and female-specific essential hypertension.

The Mechanism

CYP2J2 converts arachidonic acid into four EET regioisomers (5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET). These lipid mediators activate K⁺ channels in vascular smooth muscle to cause vasodilation, suppress nuclear factor-κB signaling to reduce endothelial inflammation, inhibit platelet aggregation, and reduce cardiomyocyte apoptosis after ischemic stress. [| Lai & Chen 2021 (PMID 33716791): EETs from CYP2J2 protect against cardiac hypertrophy, fibrosis, and apoptosis; raising EET levels via CYP2J2 overexpression or sEH inhibition reproducibly reduces myocardial injury in experimental models]. The rs11572325 T allele is in strong [linkage disequilibrium | LD means two alleles are inherited together so frequently that one allele predicts the other across the population] with the CYP2J2*7 promoter variant (rs890293), which disrupts an Sp1 transcription factor binding site and reduces CYP2J2 promoter activity by approximately 50%. T-allele carriers show measurably lower circulating EET metabolite concentrations (14,15-DHET), attenuating the vasodilatory and anti-inflammatory signaling that normally protects the coronary vasculature.

CYP2J2 also preferentially metabolizes omega-3 fatty acids EPA and DHA into 17,18-EEQ and 19,20-EDP²² 17,18-EEQ and 19,20-EDP
Omega-3 epoxides with antiarrhythmic and vasodilatory properties; EPA is metabolized by CYP2J2 at approximately 17-fold higher efficiency than arachidonic acid. This substrate competition means that high dietary omega-3 intake can shift eicosanoid output toward cardioprotective mediators even when EET-generating capacity is reduced.

The Evidence

Myocardial infarction risk: The best-powered study comes from a population-based case-control analysis³³ population-based case-control analysis
Marciante et al. Common variation in cytochrome P450 epoxygenase genes and MI risk. Pharmacogenet Genomics, 2008 of 856 incident MI cases and 2,688 controls. The rs11572325 T allele was associated with increased MI risk (OR 1.27, 95% CI 1.08–1.51, P=0.006, Benjamini-Hochberg q=0.090), surviving multiple-testing correction in a panel of 30 tag-SNPs across three CYP epoxygenase genes. Notably, the companion CYP2J2 variant rs10889160 showed an independent association (OR 1.24, 95% CI 1.07–1.43, P=0.004), while neither CYP2C8 nor CYP2C9 variants reached significance — pointing specifically to CYP2J2 as the locus driving cardiovascular EET risk. No association with ischemic stroke was observed.

Hypertension — female-specific effect: A comprehensive Russian population study⁴⁴ comprehensive Russian population study
Polonikov et al. 2019, n=2,314 (discovery + replication cohorts) genotyped eight CYP2J2 SNPs including rs11572325. The T allele was associated with essential hypertension in women (OR 1.89, 95% CI 1.22–2.95) in the discovery cohort, with directional replication in an independent Belgorod cohort. Critically, no association was detected in men, and haplotype analysis placed rs11572325 within the highest-risk female haplotype (T–T–G–C–C–C–T–A across eight CYP2J2 SNPs). This sex-dependent effect likely reflects estrogen's modulatory role in arachidonic acid metabolism and CYP2J2 transcriptional sensitivity.

Functional EET reduction: The CYP2J2*7 promoter variant (rs890293), in strong LD with rs11572325, was shown to [reduce promoter activity by ~50% | Liu et al. 2007 (PMID 17126841): CYP2J2*7 T carriers had lower plasma EET metabolites; smoking synergistically increased MI risk 6.7-fold] and produce lower circulating EET concentrations. Smokers carrying the T allele exhibited a 6.7-fold amplification of MI risk relative to non-smoking wild-type carriers (P=0.01 for interaction) — highlighting that environmental exposures compound the genetic EET deficit.

Practical Actions

The most specific actionable intervention is dietary: because CYP2J2 metabolizes EPA and DHA into cardioprotective omega-3 epoxides at far higher efficiency than arachidonic acid, supplementing with concentrated fish oil or algae-based EPA/DHA shifts eicosanoid output toward 17,18-EEQ and 19,20-EDP even when EET-generating capacity is reduced. Cardiovascular monitoring is also warranted, particularly in women, given the replicated hypertension signal. Smoking dramatically amplifies the EET-reduction risk and represents the highest-leverage modifiable factor for carriers.

Interactions

rs11572325 is part of the CYP2J2 haplotype block that includes the promoter variant rs890293 (CYP2J2*7) and the intronic variant rs2280275. Studies of all three variants consistently find similar effect directions — they tag the same reduced-expression signal. The companion MI-associated variant rs10889160 showed an independent association in the same Marciante 2008 study, suggesting the two intronic variants may contribute additively to cardiovascular risk through distinct LD blocks within CYP2J2. The soluble epoxide hydrolase variant rs751141 (EPHX2) modulates EET degradation downstream: reduced EPHX2 activity raises EET levels, potentially offsetting reduced CYP2J2 production. The CYP2C8 epoxygenase variant rs1058932 contributes to the same vascular EET pool via a different gene — together, variants in CYP2J2 and CYP2C8 define an individual's total coronary EET production capacity.