Human low‐affinity IgG receptor FcγRIIA polymorphism H131R associates with subclinical atherosclerosis and increased platelet activity in systemic lupus erythematosus

Abstract

Essentials Systemic lupus erythematosus (SLE) patients are at increased risk for premature CVD. Platelet activity, vascular dysfunction and carotid artery plaque are associated with FcγRIIA genotype in SLE. FcγRIIA genotype was not associated with platelet activity or carotid plaque in healthy controls. FcγRIIA represents a link that connects platelet activity, vascular health and CVD in SLE. SUMMARY: Background Systemic lupus erythematosus (SLE) is a complex autoimmune disease associated with an elevated risk of premature cardiovascular disease. Platelets express receptors contributing to inflammation and immunity, including FcγRIIA, the low affinity receptor of the Fc portion of IgG antibodies. The variation at a single amino acid substitution, H131R, in the extracellular binding domain alters the affinity for IgG, which may account for individual variation in platelet activity and platelet-mediated disease. Objectives This study was performed to investigate the association between FcγRIIA genotype, preclinical atherosclerosis, platelet reactivity and vascular health. Methods FcγRIIA was genotyped in 80 SLE patients and 30 healthy controls. Carotid ultrasound plaque, soluble E-selectin and platelet aggregability were evaluated in SLE and matched controls. Results Carotid plaque was significantly more prevalent in SLE patients carrying a variant allele compared to those with a homozygous ancestral allele (58% vs. 25%, P=0.04). In contrast, prevalent carotid plaque was not associated with genotype in controls. Consistently, SLE variant FcγRIIA carriers vs. ancestral allele carriers had a significant increase in the levels of soluble E-selectin, which was not observed in controls. Monocyte and leukocyte-platelet aggregation and platelet aggregation in response to submaximal agonist stimulation were significantly elevated in SLE patients with the variant vs. ancestral genotype. Conclusions Carotid ultrasound plaque, soluble E-selectin levels and platelet activity were more frequently prevalent in SLE patients carrying variant FcγRIIA. The interplay between FcγRIIA-mediated platelet activation and endothelial cells might represent a mechanism underlying the pathogenesis of cardiovascular disease in SLE patients.