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From SNPedia

Geno Mag Summary
(G;G) 0 normal
(G;T) complex; generally greater risk for cancer progression
(T;T) 0 complex; generally greater risk for cancer progression
ReferenceGRCh38 38.1/141
is asnp
is mentioned by
dbSNP (classic)rs396991
1000 genomesrs396991
GWAS Ctlgrs396991
Max Magnitude0
? (G;G) (G;T) (T;T) 28

rs396991 is a SNP in the Fc fragment of IgG, low affinity IIIa, receptor (CD16a) FCGR3A gene. rs396991(T) encodes the phenylalanine (F) allele, with the (G) allele encoding the variant valine (V). The (V) isoform is considered high-binding to IgG1 and IgG3, while the (F) isoform is considered low-binding. This SNP is known in the literature by many names, including A559C, T559G, 158F/V, and 176F/V.[PMID 9276722OA-icon.png]

What's the importance of this? FcgRIIIa stimulatory receptors are expressed by most cells in the immune system, including monocytes, dendritic cells, macrophages, natural killer cells, platelets and endothelial cells, as well as a subpopulation of T-cells. FcgR isoforms have been linked to the pathogenic consequences triggered by autoantibodies or immune complexes in autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), as well as to the efficacy of some immunotherapeutic treatments such as rituximab.

Many studies have been published about this FCGR3A SNP, roughly divided by either disorder or treatment as follows:

  • HIV to AIDs, including susceptibility and progression:
    • In a study of 2 cohorts of men infected with HIV, the rs396991(T;T) (ie F/F) genotype was underrepresented in patients with Kaposi's sarcoma, whereas the heterozygous genotype was associated with its development. A similar association was observed between rs396991 genotypes and human herpesvirus-8 (HHV-8) seropositivity.[PMID 10733511]
  • Crohn's disease
    • A study of 300+ patients with Crohn's disease determined that the rs396991(T) allele had an odds ratio of 1.58 (CI: 1.06-2.35) and the (G;T) genotype an odds ratio of 1.64 (CI: 1.08-2.5) for the disease.[PMID 17600378]
  • Rheumatoid arthritis
    • Meta-analysis of 10 different studies concluded that amongst European subjects (and not Asians), the VV (rs396991(G;G)) genotype was associated with increased risk for rheumatoid arthritis, with an odds ratio of 1.374 (CI: 1.101-1.714, p = 0.005) as compared to the FF genotype.[PMID 18843786]
    • Although rs396991 is unlikely to play a major role by itself in susceptibility to rheumatoid arthritis, the presence of the rs396991(G) high-binding allele may predispose shared epitope positive individuals to the disease.[PMID 12734884]

Classifying the reports by immunotherapeutic treatment studied yields the following:

  • Studies involving rituximab:
    • In a study of ~200 Korean patients, the FCGR3A valine (V) allele was significantly correlated with a higher complete response rate to rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone (R-CHOP) therapy compared with the phenylalanine (F) allele (88% in V/V vs 79% in V/F vs 50% in F/F; p = .002), although it did not correlate with survival in patients with diffuse large B-cell lymphoma (DLBCL).[PMID 16609067]
    • In a study of 58 Croatian patients with diffuse large B-cell lymphoma, rs396991 did not influence response, event-free or overall survival.[PMID 17606457]
    • A study of 49 patients receiving rituximab for previously untreated follicular non-Hodgkin's lymphoma concluded that rs396991(G;G) patients have a 75% to 90% chance of experiencing a clinical response to rituximab monotherapy, whereas patients with at least one rs396991(T) allele have a 25% to 51% chance of responding.[PMID 11806974]
    • Another study of 89 patients with follicular lymphoma found that rs396991 genotype was associated with the response rate and freedom from progression after treatment with rituximab. [PMID 12975461]
  • Studies involving trastuzumab:
    • A retrospective analysis of 1,251 patients included in a phase III trial of women with ERBB2/HER2-positive breast cancer concluded that rs396991(G) carriers (i.e. FCGR3A-158 V carriers) benefit the most, as measured by disease-free survival, from trastuzumab use compared to rs396991(T:T) (i.e. FCGR3A-158 F/F) genotypes.[PMID 27812689OA-icon.png]

[PMID 19140833] Linkage and association study of FcgammaR polymorphisms in celiac disease

[PMID 19640933] FCGR2B gene polymorphism rather than FCGR2A, FCGR3A and FCGR3B is associated with anti-GBM disease in Chinese

[PMID 20149216] Fcgamma receptor polymorphisms and their association with periodontal disease: a meta-analysis

[PMID 20439102] Analysis of MIF, FCGR2A and FCGR3A gene polymorphisms with susceptibility to pulmonary tuberculosis in Moroccan population

[PMID 21208440OA-icon.png] Polymorphisms of CD16A and CD32 Fcgamma Receptors and Circulating Immunocomplexes in Meniere Disease: a case-control study

[PMID 21723269] Genetic profiling of GSTP1, DPYD, FCGR2A, FCGR3A and CCND1 genes in an Argentinian population [PMID 18759263OA-icon.png] Features associated with, and the impact of, hemolytic anemia in patients with systemic lupus erythematosus: LX, results from a multiethnic cohort.

[PMID 19421223OA-icon.png] Fcgamma receptors: structure, function and role as genetic risk factors in SLE.

[PMID 20018222] Association of polymorphism in FcGR3A gene and progression of low-grade precursor lesions of cervical carcinoma.

[PMID 20400988] A single-nucleotide polymorphism of the Fcgamma receptor type IIIA gene in the recipient predicts transplant outcomes after HLA fully matched unrelated BMT for myeloid malignancies.

[PMID 20508037OA-icon.png] Copy number, linkage disequilibrium and disease association in the FCGR locus.

[PMID 22417159] DNA sequence variation and regulation of genes involved in pathogenesis of pulmonary tuberculosis.

[PMID 23075294] Association of the FCGR3A-158F/V Gene Polymorphism with the Response to Rituximab Treatment in Spanish Systemic Autoimmune Disease Patients

[PMID 23680410] Detection of the FCGR3a polymorphism using a real-time polymerase chain reaction assay

[PMID 24375423] FcγRIIIa SNPs and haplotypes affect human IgG binding and association with lupus nephritis in African Americans

[PMID 24586589OA-icon.png] Functional fcgamma receptor polymorphisms are associated with human allergy [PMID 22922574] Fcgamma receptor polymorphisms do not predict response to intravenous immunoglobulin in myasthenia gravis.

[PMID 23649770] Associations between FCGR2A rs1801274, FCGR3A rs396991, FCGR3B NA1/NA2 polymorphisms and periodontitis: a meta-analysis.

[PMID 24782186OA-icon.png] Fcγ Receptor IIIa Single-Nucleotide Polymorphisms and Haplotypes Affect Human IgG Binding and Are Associated With Lupus Nephritis in African Americans

Risk rs396991(C;C) Rs396991(G;G)
Alt rs396991(C;C) Rs396991(G;G)
Reference Rs396991(T;T)
Significance Drug-response
Disease rituximab response - Efficacy cetuximab response - Efficacy trastuzumab response - Efficacy not specified
Variation info
CLNDBN rituximab response - Efficacy cetuximab response - Efficacy trastuzumab response - Efficacy not specified
Reversed 1
HGVS NC_000001.10:g.161514542A>C
CLNSRC PharmGKB Clinical Annotation
CLNACC RCV000211135.1, RCV000211261.1, RCV000211344.1, RCV000455498.1,

[PMID 32235430OA-icon.png] A Comparative Analysis of CD32A and CD16A Polymorphisms in Relation to Autoimmune Responses in Pemphigus Diseases and Subepithelial Autoimmune Blistering Disorders.