Genetic variation in soluble epoxide hydrolase (EPHX2) is associated with forearm vasodilator responses in humans

Abstract

Cytochrome P450-derived epoxyeicosatrienoic acids are potent vasodilators in preclinical models and are hydrolyzed by soluble epoxide hydrolase (EPHX2). Associations between the EPHX2 Lys55Arg and Arg287Gln polymorphisms and cardiovascular disease risk have been reported; however, their impact on vascular function in humans has not been investigated. In 265 volunteers (198 white, 67 black American), forearm blood flow was measured by strain-gauge venous occlusion plethysmography at baseline and in response to bradykinin, methacholine, and sodium nitroprusside. Forearm vascular resistance was calculated as mean arterial pressure/forearm blood flow. In white Americans, Lys55Arg genotype was associated with vasodilator response to bradykinin, such that forearm blood flow was significantly lower (P = 0.043) and forearm vascular resistance was significantly higher (P = 0.013) in Arg55 variant allele carriers compared to wild-type individuals. Significant associations were also observed with methacholine and sodium nitroprusside. In contrast, no relationship was observed in black Americans. In black Americans, Arg287Gln genotype was associated with vasodilator response to bradykinin. Although the difference in forearm blood flow did not reach statistical significance (P = 0.058), forearm vascular resistance was significantly lower (P = 0.037) in Gln287 variant allele carriers compared to wild-type individuals. Significant associations were also observed with methacholine and sodium nitroprusside. In white Americans, Gln287 variant allele carriers did not exhibit significantly higher forearm blood flow (P = 0.128) or lower forearm vascular resistance (P = 0.080). Genetic variation in EPHX2 is associated with forearm vasodilator responses in a bradykinin receptor- and endothelium-independent manner, suggesting an important role for soluble epoxide hydrolase in the regulation of vascular function in humans.

Figure 1. EPHX2 Lys55Arg polymorphism and vasodilator responses to bradykinin

Least-squares mean ± SE FBF (A, B) and FVR (C, D) at baseline and in response to incremental doses of bradykinin (BK, 100 and 200 ng/min) among EPHX2 Lys55Arg genotype groups in white (A, C) and black (B, D) Americans. The repeated-measures ANOVA P-value for the genotype group comparison is provided. *Post-hoc P<0.05 versus wild-type (Lys/Lys).

Figure 2. EPHX2 Arg287Gln polymorphism and vasodilator responses to bradykinin

Least-squares mean ± SE FBF (A, B) and FVR (C, D) at baseline and in response to incremental doses of bradykinin (BK, 100 and 200 ng/min) among EPHX2 Arg287Gln genotype groups in white (A, C) and black (B, D) Americans. The repeated-measures ANOVA P-value for the genotype group comparison is provided. *Post-hoc P<0.05 versus wild-type (Arg/Arg).

Figure 3. EPHX2 haplotypes and vasodilator responses to bradykinin in white Americans

Least-squares mean ± SE FBF (A, C) and FVR (B, D) at baseline and in response to incremental doses of bradykinin (BK, 100, 200 and 400 ng/min) among those carrying the Arg55-tagged (C, D) and Gln287-tagged (E, F) haplotypes compared to all other EPHX2 haplotypes (Hap-WT). The repeated-measures ANOVA P-value for the haplotype group comparison is provided. *Post-hoc P<0.05 versus all other haplotype groups (Hap-WT).