rs2280275 — CYP2J2

CYP2J2 — The Heart's Epoxygenase and Its Cardiovascular Signaling

Your heart produces its own protective signaling molecules. CYP2J2 is a cytochrome P450 enzyme expressed primarily in cardiac myocytes and vascular endothelial cells, where it converts arachidonic acid into epoxyeicosatrienoic acids (EETs)¹¹ epoxyeicosatrienoic acids (EETs)
Biologically active lipid mediators with vasodilatory, anti-inflammatory, and cardioprotective properties. These EETs — particularly 11,12-EET and 14,15-EET — relax blood vessel walls, suppress vascular inflammation, inhibit platelet aggregation, and protect cardiac tissue from ischemic injury. When CYP2J2 activity is reduced, EET levels fall and this local cardioprotective system is compromised.

rs2280275 is an intronic variant in CYP2J2 that lies in strong linkage disequilibrium²² linkage disequilibrium
Alleles in LD are inherited together so frequently that one can serve as a proxy for the other, even without a direct functional role with the promoter variant rs890293 (CYP2J2*7). That promoter variant disrupts a Sp1 transcription factor binding site and reduces CYP2J2 promoter activity by approximately 50%, leading to measurably lower plasma EET concentrations. rs2280275 is therefore a marker for — and likely a contributing modifier of — reduced CYP2J2-mediated EET biosynthesis.

The Mechanism

CYP2J2 sits at the intersection of two metabolic programmes. Its primary endogenous role is epoxygenating polyunsaturated fatty acids: arachidonic acid yields EETs, EPA yields epoxyeicosatetraenoic acids (EEQs)³³ epoxyeicosatetraenoic acids (EEQs)
17,18-EEQ is the predominant omega-3 epoxide from EPA metabolism by CYP2J2, with potent antiarrhythmic properties, and DHA yields epoxydocosapentaenoic acids (EDPs). These omega-3-derived epoxides are actually preferred CYP2J2 substrates — EPA is metabolized at roughly 17-fold higher efficiency than arachidonic acid. This substrate competition means that dietary omega-3 intake can partially compensate for reduced CYP2J2 activity by flooding the enzyme with alternative substrates and shifting the eicosanoid profile toward cardioprotective mediators. Its secondary role is xenobiotic metabolism: CYP2J2 metabolizes antihistamines including astemizole, ebastine, and terfenadine in the heart.

The Evidence

The landmark 2004 Spiecker et al. Circulation study⁴⁴ 2004 Spiecker et al. Circulation study
Risk of coronary artery disease associated with polymorphism of the cytochrome P450 epoxygenase CYP2J2 established that the CYP2J2*7 (rs890293) promoter variant, which is in strong LD with rs2280275, was present in 17.3% of CAD patients versus 10.6% of controls (OR 2.23, 95%CI 1.04–4.79) in a cohort of 289 CAD patients and 255 controls. Carriers had significantly lower plasma EET metabolite concentrations.

rs2280275 itself has been directly studied in several populations. A 2013 Chinese study of 336 Uygur CAD patients⁵⁵ 2013 Chinese study of 336 Uygur CAD patients
Zhu et al. A novel polymorphism of the CYP2J2 gene is associated with coronary artery disease found that the CC genotype (plus-strand T/T) was protective against CAD in men (dominant model OR 0.28, P=0.001), with the C allele (plus-strand C) showing a sex-specific risk pattern. A 2019 Russian study of 2,314 subjects⁶⁶ 2019 Russian study of 2,314 subjects
Polonikov et al. A comprehensive study revealed SNP-SNP interactions and sex-dependent relationship found rs2280275 associated with essential hypertension in women specifically (OR 1.59, 95%CI 1.10–2.37), replicated in an independent cohort. Notably, no association was found in men, underscoring a pronounced sex-dependent effect. Results differ across populations: Uygur and Russian studies show directionally opposite effects of the T allele (papers' notation) in hypertension versus CAD contexts, likely reflecting population differences in LD structure and modifier genes.

Practical Actions

The most actionable implication concerns dietary omega-3 intake. CYP2J2 processes EPA and DHA from fish oil more efficiently than it processes arachidonic acid, generating cardioprotective 17,18-EEQ and 19,20-EDP⁷⁷ cardioprotective 17,18-EEQ and 19,20-EDP
Antiarrhythmic omega-3 epoxides that activate cardiac potassium channels and reduce calcium-dependent arrhythmia triggers. Individuals carrying the C allele, whose EET-producing capacity may be reduced, have the most to gain from shifting the substrate pool toward omega-3 fatty acids through supplementation. Cardiovascular monitoring is also relevant: elevated blood pressure and standard lipid panel tracking are supported by the hypertension and CAD associations found across multiple populations.

Interactions

rs2280275 is in strong linkage disequilibrium with the CYP2J2 promoter variant rs890293 (CYP2J2*7). Studies of these two variants frequently find similar effect directions and magnitudes, and haplotype analyses suggest they tag the same underlying reduced-expression signal. The neighboring intronic SNP rs11572325 shows similar associations in the same Russian hypertension dataset, and all three variants appeared in the highest-risk female haplotype (T-T-G-C-C-C-T-A). The soluble epoxide hydrolase variant rs751141 (EPHX2) modulates the downstream degradation of EETs: reduced EPHX2 activity raises EET levels, which can partially offset reduced CYP2J2 production. The combined genotype pattern of rs2280275 and rs751141 has been examined in the context of diabetic nephropathy — their net effect on EET tone may be relevant when considering renal and cardiovascular risk together.