rs396991

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. 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. * 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. * 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. ** 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. 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). ** In a study of 58 Croatian patients with diffuse large B-cell lymphoma, rs396991 did not influence response, event-free or overall survival. ** 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. ** 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. * Studies involving cetuximab: ** In a study of 39 patients with metastatic colorectal cancer treated with cetuximab, the rs396991(G) (ie F) allele was associated with longer progression-free survival (PFS; p = 0.055), by perhaps 1-2 months. * 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.