Rs1801274

rs1801274 is a SNP in the Fc fragment of IgG, low affinity IIa, receptor (CD32) FCGR2A gene. rs1801274(C) encodes the arginine (R) allele, with the (T) allele encoding the variant histidine (H). The (H) isoform is considered high-binding to IgG2 and IgG3, while the (R) isoform is considered low-binding. This SNP is known in the literature by many names, including A519C and H131R.

What's the importance of this? FcgR isoforms expressed on immune system cells 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 FCGR2A SNP, roughly divided by either disorder or treatment as follows:


 * HIV to AIDS, including susceptibility and progression
 * In a study of HIV-infected men, those with a FCGR2a CC genotype progressed to a CD4+ cell count of <200/mm3 at a faster rate than individuals with either of the other genotypes (relative hazard = 1.6; p = 0.0001). However, the authors noted that the progression to AIDS was less impacted by this SNP, largely because TT homozygotes had an increased risk of pneumonia as an AIDS-defining illness.


 * Lymphoma
 * A US study of 1,172 lymphoma patients and 982 controls looked at 57 SNPs in 36 immune function genes. The AG and AA genotypes of rs1801274 were associated with higher risk of follicular and small lymphocytic lymphomas: 1.26x (95% CI, 1.01-1.56) and 1.41x (95% CI, 1.10-1.81), respectively (P(trend) = 0.006).


 * Hemophilia A
 * In a case-control study of 85 individuals a more than 3-fold increased risk of inhibitor development was found compared to patients with the RR genotype


 * Malaria
 * Based on a study of more than 1,800 individuals in India, rs1801274(T;T) homozgyotes were significantly associated with protection from disease manifestation, with stronger association observed in the malaria non-endemic region.


 * Systemic lupus erythematosus (SLE)
 * A study of 90 Japanese patients with SLE concluded that individuals with rs1801274(C) alleles were at higher risk for the disease.

Classifying the reports by immunotherapeutic treatment studied yields the following:


 * Studies involving cetuximab:
 * In a study of 39 patients with metastatic colorectal cancer treated with cetuximab, the rs1801274(T) (ie H) allele was associated with longer progression-free survival (PFS; p = 0.055), by perhaps 1-2 months.


 * Studies involving infliximab:
 * A study of 91 patients with rheumatoid arthritis found that at week 30 of treatment with infliximab, rs1801274(C;C) homozygotes had a better ACR20 response (RR: 60% and HH-RH: 33.3%; p= 0.035).


 * Studies involving rituximab:
 * In a study of 58 Croatian patients with diffuse large B-cell lymphoma, rs1801274 did not influence response, event-free or overall survival.


 * Studies involving 3F8, an anti-GD2 antibody:
 * In a study of 136 patients with high risk neuroblastoma treated with the anti-GD2 antibody 3F8 plus GM-CSF immunotherapy, the rs1801274(C;C)(ie R/R) genotype was correlated with progression-free survival for the entire cohort (p = .049) and for the subset of patients with no history of prior relapse (p = .023).

Malaria Complications