Fc gamma Receptor (FcgR) Gene Polymorphism (SNP) in Assay Development
Knowledge of Fc gamma receptor (FcγR) gene polymorphisms (SNP) may be a useful tool for bioassay development in antibody-based studies. Ignyte Bio offers FcγRIIa-131 and FcγRIIIa-158 genotype data from our donors without additional charge. Below is a short primer on FcγR SNP and its role in cellular immune functions.
Fc-gamma receptors (FcγR) are the cellular receptors for Immunoglobulin G (IgG) variably expressed on different immune cell types (Figure 1). Upon binding of complexed IgG, FcγRs can trigger various cellular functions. In humans, six classic FcγRs are known, which can be distinguished into one high-affinity receptor (FcγRI) and five low-to-medium-affinity FcγRs (FcγRIIA, -B and -C, FcγRIIIA and -B).
Figure 1. Expression of Various FcγR on Different Immune Cell Types (Gilis et. al., 2014).
| Name | FcgRI | FcγRIIa | FcγRIIB | FcγRIIC | FcγRIIIA | FcγRIIIB |
| CD64 | CD32A | CD32B | CD32C | CD16A | CD16B | |
| Cell Type | ||||||
| B cell | – | – | + | – | – | – |
| T cell | – | – | – | – | – | – |
| NK cell | – | – | – | + | + | – |
| Mono/Macrophage | + | + | +/- | + | + | – |
| Neutrophil | (+) | + | +/- | + | – | + |
| Dendritic Cell | + | + | + | – | – | – |
A number of single nucleotide polymorphisms (SNPs) have been found in the genes that code for the low-to medium affinity FcγRs. Two SNPs in particular have been well-characterized for their effects in cellular immune effector functions and association with autoimmune, inflammatory, infectious diseases as well as with efficacy of immunotherapy in cancer patients (Bruns et. al. 2009, Figure 2).
Figure 2. Two Fc gamma Receptor SNPs
| FcγR Type | SNP | Other Name | Polymorphism | Effect on IgG Binding |
| FcγRIIa | rs1801724 | H131R1 | Arginine (R) | Low affinity |
| Histidine (H) | High affinity | |||
| FcγRIIIa | rs396716 | V158F2 | Phenylalanine (F) | Low affinity |
| Valine (V) | High affinity |
1 Also known as H166R based on a different nomenclature of the full protein which includes cleaved signal peptide.
1 Also known as V176F based on a different nomenclature of the full protein which includes cleaved signal peptide.
FcγRIIA is the most widely expressed isoform of FcγRII and is found on monocytes, macrophages, dendritic cells, and neutrophils. In FCGR2A gene, encoding for FcγRIIA, a well-known SNP rs1801724 is present which results in either a histidine or an arginine at position 131 (H131R). This SNP is also known as H166R based on amino acid position 166 of the full protein that includes cleaved signal peptide. FcγRIIA-131H has a higher binding affinity for IgG1 and especially IgG2, as compared to FcγRIIA-131R (Bruns et. al. 2009). Functionally, mononuclear cells from homozygous FcγRIIA-131H (known as H/H) individuals produce more IL-1b when stimulated with IgG2, and enhanced ADCC and phagocytosis compared to heterozygous or homozygous FcγRIIA-131R individuals (i.e., H/R or R/R).
FcγRIIIA expressed on NK cells can induce ADCC by these cells, and on monocytes/macrophages can induce phagocytosis. The FcγRIIIA-encoding FCGR3A gene contains the SNP rs396716 that results in either a valine or a phenylalanine at position 158 (V158F). This SNP is also known as V176F, based on a different protein nomenclature that includes cleaved signal peptide. FcγRIIIA-158V has a higher binding affinity for all human IgG classes compared to FcγRIIIA-176F (Bruns et. al. 2009).
Clinically, studies on rituximab’s (IgG1anti-CD20 mAb) efficacy in non-Hodgkin’s lymphoma patients have shown links between FcγR polymorphisms and response rates, with patients with the homozygous V/V genotype often exhibiting higher response rates compared to those with the heterozygous V/F and homozygous F/F genotypes. Additionally, responses to the anti-EGFR IgG1 mAb cetuximab have shown associations between progression-free and overall survival and Fcγ RIIa-131H/H and FcγRIIIa-158V/V homozygous genotypes.
