The Fc gamma receptor IIA R131H gene polymorphism is associated with endothelial function in patients with hypercholesterolaemia

Objective: A gene polymorphism substituting arginine (R) for histidine (H) at position 131 has been described within the Fc gamma receptorIIa (Fc gamma RIIa). The R allele is associated with increased binding of CRP and enhanced activation of monocytes.Fc gamma ZRIIa is also expressed on endothelial cells, and we hypothesized this polymorphism would be associated with alterations of endothelial function. Methods: Genomic DNA was extracted and allele-specific PCR reactions were used to determine the Fc gamma RIIaH131R polymorphism in 78 hypercholesterolaemic subjects. Using strain gauge plethysmography, forearm blood flow (FBF) responses were determined to intra-arterial infusion of acetylcholine (ACH), for endothelium-dependent vasodilatation (EDV), to nitroprusside (NP), for endothelium-independent vasodilatation (EIV), to NG-monomethyl-l-arginine (l-NMMA), for basal NO activity, and to ACH in the presence of l-NMMA, to assess the contribution of NO release to EDV. Results: Homozygouscarriers of theHallele(n = 30) had significantly betterEDVthan homozygous carriers of the R allele (n = 15), while heterozygotes showed an intermediate phenotype (n = 33) (e. g. % increase of FBF to ACH 48 mu g/min: 527 +/- 359% in H/H versus 452 +/- 262% in H/ R versus 332 +/- 413% in R/R, p = 0.0012 by 2-way ANOVA). EIV and basal NO activity were not affected by genotype, and co-infusion of l-NMMA abolished the differences in EDV. Conclusions: The R allele of the Fc gamma RIIa polymorphism is associated with impaired EDV and reduced NO activity during endothelial cell stimulation. These data suggest that the functional effects of the Fc gamma RIIa H131R gene polymorphism previously observed in vitro translate into clinically relevant alterations of endothelial function in vivo. (C) 2011 Elsevier Ireland Ltd. All rights reserved