Novel Human FCGR1A Variants Affect CD64 Functions and Are Risk Factors for Sarcoidosis

Abstract

CD64 (or FcγRIA) is the sole functional high affinity IgG Fc receptor coded byFCGR1Agene in humans. TheFCGR1Agenetics has not been comprehensively investigated and effects of humanFCGR1Avariants on immune functions remain unknown. In the current study, we identified three novelFCGR1Avariants including the single nucleotide variant (SNV) rs1848781 (c.-131) in the proximalFCGR1Agene promoter region, the rs587598788 indel variant within theFCGR1Aintron 5, and the non-synonymous SNV rs1050204 (c.970G>A or FcγRIA-p.D324N) in theFCGR1Acoding region. Genotype-phenotype analyses revealed that SNV rs1848781 genotypes were significantly associated with CD64 expression levels. Promoter reporter assays show that rs1848781G allele had significantly higher promoter activity than the rs1848781C, confirming that the rs1848781 is a functionalFCGR1ASNV affecting promoter activity and gene expression. The rs587598788 indel genotypes were also significantly associated with levels of CD64 expression. Moreover, the non-synonymous SNV rs1050204 (FcγRIA-p.D324N) alleles significantly affected CD64-mediated phagocytosis, degranulation, and pro-inflammatory cytokine productions. Genetic analyses revealed thatFCGR1Agenotypes were significantly associated with sarcoidosis susceptibility and severity. Our data suggest thatFCGR1Agenetic variants may affect immune responses and play a role in sarcoidosis.