Is EPHX2 rs751141 GG associated with higher soluble epoxide hydrolase activity?

The EPHX2 gene encodes soluble epoxide hydrolase (sEH), an enzyme critical to cardiovascular, vasoactive, and inflammatory regulation. The rs751141 single nucleotide polymorphism (G→A) significantly dictates this enzyme's functional capacity.

Enzymatic activity differences

• Loss-of-function variant: The rs751141 A-allele (Arg287Gln) is a robust loss-of-function variant. Recombinant human enzyme kinetics demonstrate that the Gln287 variant retains only 25% to 60% of wild-type sEH catalytic activity.
• Higher activity in GG genotypes: Consequently, individuals with the wild-type GG genotype exhibit significantly higher sEH activity compared to A-allele carriers (AG and AA genotypes), who experience a 40% to 75% reduction in both epoxide hydrolase and N-terminal lipid phosphatase activities.

Biochemical and mechanistic pathways

• EET degradation: Soluble epoxide hydrolase is the primary enzyme responsible for metabolizing epoxyeicosatrienoic acids (EETs)—bioactive signaling lipids with key anti-inflammatory, vasodilatory, and cardioprotective properties.
• Hydrolysis to DHETs: Higher sEH activity associated with the GG genotype leads to the rapid hydrolysis of protective EETs (such as 14,15-EET) into their less active diols, dihydroxyeicosatrienoic acids (DHETs). Conversely, A-carriers experience impaired EET hydrolysis, preserving higher levels of these protective mediators.
• Structural disruption: Mechanistically, the G-to-A substitution in A-carriers disrupts a critical salt bridge in the exon 8-encoded region of the enzyme, compromising the spatial configuration and reducing the formation of the active sEH homodimer.

Bottom line

• The EPHX2 rs751141 GG genotype is associated with significantly higher soluble epoxide hydrolase activity compared to A-carrier genotypes, resulting in the accelerated enzymatic degradation of anti-inflammatory and vasodilatory epoxyeicosatrienoic acids (EETs) into DHETs.