Novel Human FCGR1A Variants Affect CD64 Functions and Are Risk Factors for Sarcoidosis.
Novel Human FCGR1A Variants Affect CD64 Functions and Are Risk Factors for Sarcoidosis.
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DOI：
10.3389/fimmu.2022.841099
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发表时间：
2022
影响因子：
7.3
通讯作者：
Bhargava M
中科院分区：
文献类型：
--
作者：
Wu J;Li Y;Rendahl A;Bhargava M
CD 64（又称FcγRIA）是由FCGR 1A基因编码的唯一功能性高亲和力IgG Fc受体。FCGR 1A遗传学尚未得到全面研究，人FCGR 1A变体对免疫功能的影响仍然未知。在当前的研究中，我们鉴定了三种新的FCGR 1A变体，包括单核苷酸变体（SNV）rs 1848781（c.- 131)在FCGR 1A基因启动子近端区域，在FCGR 1A内含子5内的rs 587598788 indel变体，以及在FCGR 1A编码区的非同义SNV rs 1050204（c.970G>A或FcγRIA-p. D324 N）。基因型-表型分析显示SNV rs 1848781基因型与CD 64表达水平显著相关。启动子报告基因分析表明rs 1848781 G等位基因的启动子活性显著高于rs 1848781 C，证实rs 1848781是一个影响启动子活性和基因表达的功能性FCGR 1A SNV。rs 587598788 indel基因型也与CD 64表达水平显著相关。此外，非同义SNV rs 1050204（FcγRIA-p. D324 N）等位基因显著影响CD 64介导的吞噬作用、脱粒作用和促炎细胞因子产生。遗传分析显示FCGR 1A基因型与结节病的易感性和严重程度显著相关。我们的数据表明，FCGR 1A基因变异可能影响免疫反应，并在结节病中发挥作用。
CD64 (or FcγRIA) is the sole functional high affinity IgG Fc receptor coded by FCGR1A gene in humans. The FCGR1A genetics has not been comprehensively investigated and effects of human FCGR1A variants on immune functions remain unknown. In the current study, we identified three novel FCGR1A variants including the single nucleotide variant (SNV) rs1848781 (c.-131) in the proximal FCGR1A gene promoter region, the rs587598788 indel variant within the FCGR1A intron 5, and the non-synonymous SNV rs1050204 (c.970G>A or FcγRIA-p.D324N) in the FCGR1A coding 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 functional FCGR1A SNV 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 that FCGR1A genotypes were significantly associated with sarcoidosis susceptibility and severity. Our data suggest that FCGR1A genetic variants may affect immune responses and play a role in sarcoidosis.