FCGR2A-HH Gene Variants Encoding the Fc Gamma Receptor for the C-Reactive Protein Are Associated with Enhanced Monocyte CD32 Expression and Cardiovascular Events' Recurrence after Primary Acute Coronary Syndrome.

Pascale Paul,Christophe Picard,Françoise Dignat-George,Marc Laine,Laurent Bonello,Corinne Frère,Laurent Arnaud,Regis Guieu,Franck Paganelli,Luc Lyonnet,Julie Di Cristofaro,Lucas Hubert,Noémie Resseguier,Florence Sabatier

doi:10.3390/biomedicines10020495

Abstract

Fcγ receptors (FcγRs) interact with the C-reactive protein (CRP) and mediate activation of inflammation-related pathogenic mechanisms affecting cardiovascular health. Our study evaluated whether FcγRIIA and FcγRIIIA profiles are associated with the recurrence of adverse cardiovascular events during the first year after a primary acute coronary syndrome (ACS). The primary endpoint was the recurrence of cardiovascular events (RCE), identified as a composite outcome comprising acute heart failure (AHF) and major adverse cardiovascular events (MACE). We obtained blood samples of 145 ACS patients to measure hsCRP circulating levels, to identify FcγRIIA-131RH rs1801274 and FcγRIIIA-158FV rs396991 polymorphisms, to analyze circulating monocytes and NK cell subsets expressing CD16 and CD32, and to detect serum-mediated FCGR2A-HH activation by luciferase reporter assays. The hsCRP, CD32-expression, and Fc-R mediated activation levels were similar in all patients regardless of their MACE risk. In contrast, the hsCRP levels and the proportion of CD14+ circulating monocytes expressing the CD32 receptor for CRP were significantly higher in the patients who developed AHF. The FCGR2A rs1801274 HH genotype was significantly more common in patients who developed RCE and MACE than in RCE-free patients and associated with an enhanced percentage of circulating CD32+CD14+ monocytes. The FCGR2A-HH genotype was identified as an independent predictor of subsequent RCE (OR, 2.7; p = 0.048; CI, 1.01–7.44) by multivariate analysis. These findings bring preliminary evidence that host FCGR2A genetic variants can influence monocyte CD32 receptor expression and may contribute to the fine-tuning of CD32-driven chronic activating signals that affect the risk of developing RCEs following primary ACS events.

Highlights

Patients undergoing percutaneous intervention (PCI) for acute coronary syndrome (ACS) are at high risk for recurrent adverse cardiovascular events
From the 27 patients with at least one major recurrent cardiovascular event occurring during the first-year post enrolment, 18 patients experienced a major adverse cardiovascular events (MACE) episode, associated with acute heart failure (AHF) in 4 patients (AHF+MACE+), while 9 additional patients experienced an episode of AHF without MACE
The recurrence of cardiovascular events (RCE)-positive group was further stratified as MACE+AHF− patients serum-induced ADCP were compared in the group of RCE+ (n = 15) and REC- patients (n = 19) that (n = 7) and AHF+MACE− patients (n = 8)

Summary

Introduction

Patients undergoing percutaneous intervention (PCI) for acute coronary syndrome (ACS) are at high risk for recurrent adverse cardiovascular events. Various biomarkers that reflect physio-pathological inflammatory mechanisms underlying cardiac injury have been previously associated with the occurrence of ACS or the subsequent risk of major adverse cardiovascular events (MACE) [1,2,3]. Elevated highly sensitive (hs) CRP has been suggested as a relevant biomarker to classify the inflammatory risk of patients [7], but mechanisms by which CRP expression is induced and activates signaling pathways that sustain CRP-driven inflammation and contribute to cardiovascular outcomes after PCI remain poorly understood. Various studies have characterized alteration of the FcγRIIA/CD32 and FcγRIIIA/CD16 activating FcγRs profiles in patients with cardiovascular diseases (reviewed in [8]).

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