rs511278 — FCGR2A

FCGR2A — When Your Immune Receptor Grips IgG2 Too Tightly or Too Loosely

The Fc gamma receptor IIa (FcγRIIa, encoded by FCGR2A) is the immune system's main sensor for IgG-coated threats. Displayed on the surface of macrophages, neutrophils, and dendritic cells, it binds the tail region (Fc) of IgG antibodies and triggers phagocytosis — the engulfing and destruction of bacteria, viral immune complexes, and cellular debris. rs511278 is an intronic variant in FCGR2A that sits within the same haplotype block¹¹ haplotype block
A segment of DNA inherited together because variants within it are in strong linkage disequilibrium — they rarely separate during recombination as the classical functional variant rs1801274 (H131R). The T allele at rs511278 co-segregates with the histidine-131 (H131) form of FcγRIIa — the receptor variant that binds IgG2 efficiently. The C allele at rs511278 co-segregates with the arginine-131 (R131) form, which barely binds IgG2 at all.

The Mechanism

The H131R substitution at position 131 of the mature FcγRIIa protein changes a histidine to an arginine in the second immunoglobulin-like domain²² immunoglobulin-like domain
A structural fold shaped like an antibody constant region domain; FcγRIIa has two of these Ig-like domains that directly contact the Fc region of IgG of the receptor. This single amino acid swap has a major functional consequence: H131 binds IgG2 and IgG3 efficiently, while R131 barely interacts with IgG2 at all — and IgG2 is the dominant antibody subclass produced against polysaccharide antigens on the surface of encapsulated bacteria like Streptococcus pneumoniae and Haemophilus influenzae.

The two alleles are co-dominantly expressed, meaning heterozygotes (CT at rs511278, corresponding to H131/R131) have intermediate receptor function between the two homozygous states. The T allele at rs511278 is the minor allele globally (~18%), but its frequency varies substantially by ancestry: ~21% in Europeans, ~12% in Africans, and only ~7% in East Asians.

Because rs511278 is intronic and not itself the functional change, the biological effects described here derive from its linkage disequilibrium³³ linkage disequilibrium
The statistical tendency for two nearby alleles to be inherited together; when LD is high, an intronic tag SNP reliably predicts which functional allele is present with rs1801274 (H131R). The T allele tags H131; the C allele tags R131.

The Evidence

The highest-confidence association is Kawasaki disease (KD), a vasculitis predominantly affecting children under 5 that causes coronary artery aneurysms. The 2011 landmark GWAS by Khor et al.⁴⁴ landmark GWAS by Khor et al.
Genome-wide association study identifies FCGR2A as a susceptibility locus for Kawasaki disease. Nature Genetics, 2011 — 2,173 KD cases and 9,383 controls across five international cohorts — identified rs1801274 as the lead SNP at this locus (P = 7.35×10⁻¹¹, OR = 1.32 per A allele). The A allele at rs1801274 corresponds to H131 — the same haplotype tagged by the T allele at rs511278. Higher IgG-mediated immune activation from H131 may contribute to the disproportionate vasculitis response in KD-susceptible children.

A meta-analysis of 6 KD studies⁵⁵ meta-analysis of 6 KD studies
Association between FCGR2A rs1801274 H131R polymorphism and risk of Kawasaki disease. PLoS ONE, 2015 with 1,709 cases and 3,207 controls found H/H homozygotes had OR = 1.97 (95% CI 1.55–2.50) versus R/R homozygotes. The association was significant in Asians but not Caucasians — consistent with the lower H131 (T allele) frequency in East Asians, where the variant is rarer and cases carrying it have a proportionally larger genetic signal.

The SLE picture is the mirror image⁶⁶ SLE picture is the mirror image
Comprehensive Assessment of FCGRs polymorphisms and SLE risk. Arthritis Research and Therapy, 2016: the A allele (H131, tagged by T at rs511278) is protective against overall SLE susceptibility (OR = 0.879 per A allele, P = 3.31×10⁻⁴), but the R131 allele (C at rs511278) is specifically associated with lupus nephritis severity in some populations. This apparent paradox reflects that H131's efficient IgG immune complex clearance protects against SLE development (preventing accumulation of inflammatory complexes) while paradoxically contributing to immune hyperactivation in conditions like KD.

For infectious disease, the consequence reverses again⁷⁷ consequence reverses again
Protective Effects of FCGR2A Polymorphism in Invasive Pneumococcal Diseases. Chest, 2012: R/R homozygotes (CC at rs511278) showed 75% lower hospital mortality in severe invasive pneumococcal disease (OR 0.251, P = .004). The proposed mechanism is that the H131 allele, while enabling better phagocytic clearance, may also drive a more intense and potentially damaging inflammatory response in severe systemic infections. Meanwhile, for pneumococcal vaccination⁸⁸ pneumococcal vaccination
Pneumococcal vaccine efficacy for mucosal infections depends on FcγRIIa polymorphism. Vaccine, 2005, the H131 allele is critical: R/R homozygotes show significantly higher recurrence of acute otitis media after pneumococcal vaccination, as IgG2 antibodies induced by the vaccine cannot efficiently engage R131 receptors on phagocytic cells.

In COVID-19, a 2022 ICU cohort study⁹⁹ 2022 ICU cohort study
FCGR2A rs1801274 polymorphism associated with risk of death among COVID-19 patients. Scientific Reports, 2022 found the G allele (R131) was associated with increased mortality (OR = 1.47), with the dominant model (GG + AG vs AA) yielding OR = 2.22. This aligns with the IgG2-clearing hypothesis: H131 carriers clear viral immune complexes more efficiently.

Practical Actions

The clinical picture is inherently bidirectional: the T allele (H131 haplotype) confers both immune advantages (better vaccination response, better viral and bacterial immune complex clearance) and immune risks (higher KD susceptibility, possible contribution to inflammatory overactivation). For TT homozygotes, awareness of KD family history and monitoring for autoimmune triggers is appropriate. For CC homozygotes (R131 haplotype), vaccine responses to IgG2-dependent immunizations (pneumococcal polysaccharide vaccines) may be attenuated, and infection surveillance is warranted.

Interactions

rs511278 is in the same haplotype block as rs1801274 (H131R missense), meaning these two SNPs typically co-occur and should be interpreted together. The functional variant rs396991 in FCGR3A (V158F, CD16a) operates through a complementary but distinct receptor pathway — FcγRIIIa is expressed on NK cells and mediates ADCC, while FcγRIIa on phagocytes mediates opsonophagocytosis. Combined low-affinity genotypes at both FCGR2A and FCGR3A may compound impaired IgG-mediated immune responses.