FCG RECEPTOR IIA GENOTYPE, AFFECTING BINDING OF C-REACTIVE PROTEIN TO PHAGOZYTES IN VITRO, IS ASSOCIATED WITH ENDOTHELIAL FUNCTION IN VIVO: 1D.05

Abstract

Objective: Experimental studies suggest C-reactive protein (CRP) directly promotes atherosclerosis, but supporting evidence in humans is scarce. Recently, a gene polymorphism substituting arginine (R) for histidine (H) at position 131 has been described within the Fcγ receptor IIa (FcγRIIa), increasing CRP-binding and subsequent calcium signaling of phagocytes. We hypothesized this would affect endothelial function in vivo. Design and Methods: Genomic DNA was extracted and allele-specific PCR reactions were used to determine the presence or absence of the H and/or R alleles in 36 hypercholesterolemic subjects, previously included in a trial on endothelial effects of antihyperlipidemic treatment. Forearm blood flow (FBF) responses to intraarterial infusion of acetylcholine (ACH, 12 and 48 μg/min), for endothelium-dependent vasodilation (EDV), and to nitroprusside (NP, 3.2 and 12.8 μg/min), for endothelium-independent vasodilation (EIV), were assessed by plethysmography. Results: Compared to homozygous carriers of the H allele (n = 12), EDV was significantly attenuated in carriers of the R allele (H/R and R/R genotypes combined, n = 24) (% increase of FBF to 12 and 48 μg/min ACH: 419 ± 316 and 614 ± 387 versus 219 ± 161 and 508 ± 378, p = 0.05 by 2-way ANOVA). In contrast, EIV was not affected by genotype (% increase to 3.2 and 12.8 μg/min NP: 241 ± 135 and 404 ± 228 versus 242 ± 131 and 568 ± 349, n.s.). Conclusions: The arginine for histidine substitution at position 131 of the FcγRIIa receptor is associated with impaired EDV in hypercholesterolemic human subjects. These data suggest that the increased CRP-binding of phagocytes previously observed in carriers of the R allele in vitro translates into a clinically relevant impairment of endothelial function in vivo.