Table 1.
Overview of single nucleotide polymorphisms (SNPs) and copy number variation (CNV) at the FCGR2/3 locus.
| Rs # | Nucleotide** | Amino acid position*** | Amino acid | Functional change | Associations with disease |
|---|---|---|---|---|---|
| FCGR2A | |||||
| rs201218628 | c.184C c.185A | 62 (27) | Gln | Possibly reduced signaling (42), no influence on expression (43) | |
| c.184T c.185G | Trp | ||||
| rs1801274 | c.497A | 166 (131) | His | higher affinity for human IgG (44) | KD (45), childhood ITP (46, 47), possibly Guillain Barre Syndrome (48, 49) |
| c.497G | Arg | SLE (50, 51), meningococcal sepsis (52), sepsis (53, 54) | |||
| rs150311303 | c.612_613 insCTT | 205 (170) | Leu | higher affinity for human IgG (55) | |
| rs72717038 | c.739 +871 A>G | – | – | G retains exon 6, increased signaling (39) | Anaphylaxis in patients with hypogammaglobulinemia (39) |
| rs382627 | c.818C | 273 | Leu | ||
| c.818T | Pro | Introduced by deletion of CNR2, decreased expression (56) | |||
| FCGR2B | |||||
| rs143796418 | −386 C>G*** | – | – | Promoter haplotypes 2B.1, 2B.2 and 2B.4 influences expression (57, 58) | 2B.4 haplotype associated with susceptibility to SLE (57, 58) |
| rs780467580 | −120 T>A*** | – | – | ||
| rs755222686 | 106 | Asn | |||
| c.316_318del | Del | Deletion abolishes IgG-binding | Increased serum levels of IgG1 and IgG3 (59) | ||
| rs1050501 | c.695T | 232 | Ile | ||
| c.695C | Thr | Excludes receptor from lipid rafts (60, 61) | Susceptibility to SLE (50, 60), protection against malaria (62) | ||
| FCGR2C | |||||
| CNV | – | – | – | Expression levels (only in FCGR2C-ORF) (63) | KD (unexplained mechanism) (64) |
| rs149754834 | −386 C>G*** | – | – | Promoter haplotypes 2B.1, 2B.2 (possibly 2B.4) functional change unknown | |
| rs34701572 | −120 T>A*** | – | – | ||
| rs759550223 | c.169T | 57 (13) | Ter | Stop codon, no expression of FcγRIIC | |
| c.169C | Gln | Results in an open reading frame (ORF) and expression of FcγRIIC (9, 19) | ITP (19, 65), Kawasaki Disease (43), IgG subclass deficiency (66) | ||
| rs114945036 | c.134-96C>T | – | unknown | Minor allele associated with HIV disease progression (67) | |
| rs138747765 | c.353C>T | 118 | Ile/Thr | unknown | Possibly linked to rs114945036 |
| rs76277413 | c.798 +1 A>G | – | – | A causes exon7 to be spliced out (9) | |
| rs430178 | c.799−1 C>G | – | – | C leads to retention of 62 intronic base pairs (9) | |
| FCGR3A | |||||
| CNV | – | – | – | Expression levels Decreased ADCC (1 copy vs. 2 copies) | SLE (both <2 and >2 copies) (68), anti-GBM disease (>2 copies) (69) |
| rs10127939 | c.197T | 66 (48) | Leu | Linked to rs396991 (70) | |
| c.197A | Arg | Increased IgG binding in presence of FCGR3A-p.176Val (71) | |||
| c.197G | His | Increased IgG binding in presence of FCGR3A-p.176Val (71)May result in functional defects in NK cells (72, 73) | Homozygosity associated with severe Herpes infections (72–74) | ||
| rs396991 | c.526G | 176 (158) | Val | higher affinity for human IgG (44, 70) | Susceptibility to ITP (19, 47, 75), RA (76) and ulcerative colitis (77) |
| c.526T | Phe | Susceptibility to SLE (50) | |||
| FCGR3B | |||||
| CNV | – | – | – | Expression levels Uptake of immune complexes |
SLE (<2 copies) (78), Sjögren syndrome (<2 copies) (79), systemic sclerosis (<2 copies) (80), RA (<2 copies) (78, 81, 82), Ulcerative Colitis (<2 copies) (83), Ankylosing Spondylitis (84), ANCA-associated vasculitis (<2 copies) (85) Bullous Pemphigoid (inverse relation with CNV) (86) |
| rs200688856 | c.108G | 36 | Arg | NA1**** | |
| c.108C | Ser | NA2 and SH**** | NA2 associated with susceptibility to SLE (50) | ||
| rs527909462 | c.114C | 38 | Leu | NA1 | |
| c.114T | Leu | NA2 and SH | |||
| rs448740 | c.194A | 65 | Asn | NA1 | |
| c.194G | Ser | NA2 and SH | |||
| rs5030738 | c.233C | 78 | Ala | NA1 and NA2 | |
| c.233A | Asp | SH | |||
| rs147574249 | c.244G | 82 | Asp | NA1 | |
| c.244A | Asn | NA2 and SH | |||
| rs2290834 | c.316G | 106 | Val | NA1 | |
| c.316A | Ile | NA2 and SH | |||
Associations found in meta-analyses or GWAS studies are indicated in bold.
For each SNP, Rs numbers (Reference SNP cluster ID, the common identification method of SNPs as included in the dbSNP database), nucleotide and amino acid positions, functional changes, and associations with disease are shown.
Nucleotide numbering excludes exon6 in FCGR2A and FCGR2C transcripts, because this exon is spliced out from these transcripts, but includes exon 6 in FCGR2B, in which it is retained in many transcripts (splice variant known as FCGR2B1).
In FCGR2A transcripts, inconsistencies exist as a result of alternative splicing at the beginning of exon3 because of two adjacent splice acceptor sites that can both be used. The most commonly used amino-acid numbering is derived from the shorter transcript in which the 3′ splice acceptor site is used, so we chose to use this transcript for nucleotide numbering throughout this manuscript.
Inconsistencies exist in the amino-acid numbering used in the literature, because some SNPs are named by the position when including the signal peptides, and others are named by their position in the mature protein, excluding the signal peptides. To comply with the official HGVS guidelines, we propose to use the amino acid in the full protein and have done this throughout the manuscript. In this table, position in the mature protein is shown between brackets for some of the SNP which are commonly known by that position.
Relative to the start of translation. Three haplotypes have been described: 2B.1 (−386, −120T); 2B.2 (−386C, −120T) and 2B.4 (−386C, −120A). −386G, −120A has never been found to date.
The set of 6 SNPs in FCGR3B determines the NA1,NA2 and SH haplotypes. These are the three major haplotypes that exist, although rare additional variants have been reported (87). The term “NA” is derived from “Neutrophil Antigen.” The term “SH” derives from the fact that an alloantibody recognizing this antigen was first found in serum “h” among several different investigated sera (Jürgen Bux, personal communication). FCGR3B-NA1 and -NA2 nucleotide sequences differ at five positions (c.108G>C, c.114C>T, c.194A>G, c.244G>A and c.316G>A), with four predicted amino acid differences (p.Arg36Ser, p.Asn65Ser, p.Asp82Asn and p.Val106Ile for NA1 and NA2, respectively). As a consequence, the NA2 variant has two additional N-linked glycosylation sites compared to NA1 (the p.65Ser of NA2 completes a consensus sequence for N-linked glycosylation with the non-polymorphic p.63Asn residue, and the p.82Asn of NA2 forms a consensus sequence with the non-polymorphic p.84Ser) (88). The SH variant is identical to NA2 at the five positions that distinguish NA1 from NA2, but differs from both variants at one additional position (c.233C>A), resulting in an p.Ala78Asp amino acid change that predicts a change in the tertiary structure of the protein (89). Additional complexity is added by the discovery of rare individuals carrying other mutations within this gene or different combinations of these nucleotide polymorphisms (87, 90), indicating that the NA1/NA2/SH typing is incomplete. Sometimes, the NA1/NA2/SH haplotypes are indicated, respectively, as FCGR3B*01, FCGR3B*02 and FCGR3B*03, to prevent confusion with the nomenclature for antigenic epitopes determined by these haplotypes. These haplotypes determine the allotypic variants of the Human Neutrophil Antigen1 (HNA1), which is involved in allo-immunization against neutrophilic granulocytes. The HNA classification system recognizes HNA1a (encoded by FCGR3B-NA1), HNA1b (encoded by FCGR3B-NA2 and FCGR3B-SH) and HNA1c (encoded by FCGR3B-SH) (41, 89, 91–93). Recently, a fourth antigenic epitope was described (HNA1d, also encoded by FCGR3B-NA2) (93).
Note that the nucleotide positions as indicated here are indicating the position in the coding sequence, which differs from nucleotide positions often used in the literature for these haplotypes, as derived from Ravetch and Perussia (94) who used a nucleotide numbering not related to the coding sequence of FCGR3B, which includes 33 additional nucleotides of the 5′UTR.