Does the EPHX2 rs751141 GG genotype increase soluble epoxide hydrolase activity and reduce protective EET signaling?

The EPHX2 gene encodes soluble epoxide hydrolase (sEH), a key enzyme regulating cardiovascular and inflammatory homeostasis through the metabolism of epoxyeicosatrienoic acids (EETs).

Mechanistic pathways of the rs751141 variant

• Structural stability and catalytic efficiency: The EPHX2 rs751141 polymorphism causes an Arg287Gln (R287Q) amino acid substitution. The wild-type G allele (Arg287) preserves a critical stabilizing salt bridge with Glu252, maintaining full catalytic efficiency.
• Genotypic differences in activity: The mutant A allele disrupts this salt bridge, altering the active site's spatial conformation and resulting in a loss-of-function variant with 25% to 58% lower catalytic activity. Because this polymorphism does not alter transcription or translation levels, individuals with the wild-type GG genotype exhibit significantly higher, uncompromised sEH activity compared to A-allele carriers.

Downstream physiological consequences

• EET degradation: Elevated sEH activity in GG homozygotes drives the rapid conversion of protective EETs into less active dihydroxyeicosatrienoic acids (DHETs), significantly reducing the functional EET/DHET ratio.
• Impaired vasodilation: Blunted EET availability limits the activation of large-conductance calcium-activated potassium ($BK_{Ca}$) channels in vascular smooth muscle cells, preventing normal hyperpolarization and endothelium-dependent vasodilation.
• Upregulated inflammatory cascades: Depleted EET levels fail to adequately suppress NF-κB signaling, leading to increased expression of vascular adhesion molecules and pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β.

Bottom line

• The EPHX2 rs751141 GG genotype is fully associated with elevated sEH catalytic activity due to its preserved structural salt bridge. This heightened activity accelerates the degradation of active EETs into DHETs, directly compromising downstream $BK_{Ca}$-mediated vasodilation and NF-κB-dependent anti-inflammatory pathways.