A comprehensive literature search was performed to examine the association between FCGR2A rs1801274 and FCGR3A rs396991 polymorphisms and autoimmune diseases. The following terms were searched: ″Fcγ receptor″, ″Fc gamma receptor″, ″FCGR″, ″CD32″, ″CD16″, ″polymorphism″, ″variant″, ″mutation″, ″autoimmune disease″ in four source databases: PubMed ( https://pubmed.ncbi.nlm.nih.gov/ ), Google Scholar ( https://scholar.google.com/ ), Cochrane Library ( https://www.cochranelibrary.com/ ) and Science.gov ( https://www.science.gov/ ) between January 1^st, 2004 and October 14^th, 2024, and relevant articles were identified for further filtering.

In line with the research objective and the planned meta-analysis, the following criteria had to be met by the included studies: (a) case-control studies investigating FCGR polymorphism (FCGR2A H131R or FCGR3A F158V) in relation to ITP, SLE, RA, GBS or CD; (b) providing data for the calculation of odds ratios (ORs) and 95% confidence intervals (CIs); (c) the full text had to be available in English. Studies were excluded if they met any of the following criteria: (a) not related to FCGR2A/3A polymorphisms and autoimmune disease; (b) animal or cancer studies; (c) no control group included; (d) case reports or case series.

The following information was extracted from the eligible studies: (a) the first author’s name; (b) the year of publication; (c) the country and ethnicity of the participants; (d) the sample size; and (e) the genotypic distributions of FCGR2A/3A polymorphisms in cases and controls.

Hardy-Weinberg equilibrium (HWE) was assessed for each study using Chi-squared tests to determine whether observed genotype frequencies deviated significantly from expected frequencies. HWE P values were calculated using Meta Genyo (21), with P values ≤ 0.05 indicating statistically significant departure from equilibrium assumptions.

The Newcastle-Ottawa scale (NOS) was used to evaluate the quality of the eligible studies (22). The NOS has a score range of zero to nine, and studies achieving a score of more than seven were regarded as high-quality data. A flowchart illustrating the study selection process is given in Figure 2 .

Statistical meta-analyses were performed using RStudio 4.4.3 with the ‘metafor’ package (version 4.8-0), supplemented by Meta Genyo (21) (https://metagenyo.genyo.es), and MetaAnalysisOnline (23) (https://metaanalysisonline.com) platforms. The association between FCGR2A rs1801274 and FCGR3A rs396991 polymorphisms and the onset of autoimmune diseases was evaluated using odds ratios (ORs) — a measure of association strength — and 95% confidence intervals (CIs), which reflect the precision of the estimates. Four genetic models were evaluated, including dominant (variant carrier vs. wild-type homozygote), recessive (variant homozygote vs. others), overdominant (heterozygote vs. combined homozygotes), and allelic (variant allele vs. wild-type allele) models.

The statistical significance of pooled ORs was determined using Z tests, with P values ≤ 0.05 considered statistically significant. Heterogeneity between studies was quantified using the I² statistic, where I² values of 25%, 50%, and 75% indicated low, moderate, and high heterogeneity, respectively (24). Given the expected clinical and methodological diversity across studies, random-effects models (DerSimonian and Laird method (25)) were employed for all analyses.

To explore potential sources of heterogeneity, subgroup analyses were conducted. The primary analyses were based on ethnicity (European, East Asian and North African populations) for each polymorphism in a specific disease. In the second analysis, several other populations were included in the studies’ pooled meta-analysis, which grouped each polymorphism with all diseases, as shown in Figures 3 and 4 . For immune thrombocytopenia (ITP) studies, additional stratification by age (pediatric vs. adult) was performed in the primary analysis.

Sensitivity analyses were carried out by sequentially excluding individual studies to assess their impact on the overall effect magnitude.

Results were visualized using forest plots displaying individual and pooled effect sizes with corresponding 95% CIs. These forest plots illustrate the strength and direction of associations across individual studies, as well as the overall pooled population estimates. Publication bias was evaluated using Egger’s regression test (26). All statistical analyses were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (27).

Our research strategy identified 781 potentially relevant articles from the four different databases PubMed, Google Scholar, Cochrane Library and Science.gov. A total of 648 records were retrieved after removing duplicates. After excluding irrelevant articles, 161 articles were retrieved for further evaluation. Upon reading the full text, 127 articles were subsequently excluded and a further 34 eligible studies (ITP - 9 studies (28–36), SLE - 16 studies (37–52), RA - 6 studies (53–58) Guillain-Barré syndrome (GBS) - 2 studies (56, 60) or celiac disease (CD) - 1 study (61)) were included for further quantitative analysis ( Figure 2 ). All selected studies are given in Table 1 .

Using the Newcastle-Ottawa scale (NOS), the quality of included studies ranged in between 7 and 8 and is shown in Table 1 .

The pooled results remained unaltered in all comparisons, which suggests that our findings are statistically stable. The results were confirmed with three independent software applications.

The potential for publication bias was evaluated by Egger’s linear regression test, and a P value ≤ 0.05 was considered indicative of statistical publication bias (26). We cannot exclude the possibility of publication bias affecting our pooled estimates (see also Discussion and Limitations sections).

The FCGR2A rs1801274 polymorphism is due to an A-to-G nucleotide exchange at coding nucleotide c.500 (NM_001136219.3), that encodes either histidine (H) or arginine (R) at amino acid position p.131 in the FcγRIIa receptor protein (62). This single amino acid substitution significantly influences the receptor’s binding affinity for IC handling: the H131 variant binds IgG2 and IgG3 with much higher affinity than R131 due to optimized electrostatic interactions with the Fc region (48). The reduced IgG2 affinity in R131 carriers specifically impairs neutrophil phagocytosis of IgG2-opsonized targets, while responses to IgG1/IgG3/IgG4 remain intact (63). This diminished IgG2 binding compromises the clearance of IgG2 immune complexes, allowing their deposition in tissues such as renal glomeruli and dermal vasculature (64, 65), which in turn promotes inflammation through FcγRIIa-mediated platelet activation and upregulation of endothelial adhesion molecules. These mechanisms contribute to thrombotic complications and accelerate atherosclerosis, particularly in SLE (66).

In addition, the R131 variant’s reduced IgG2 binding capacity appears to suppress neutrophil activation and matrix metalloproteinase (MMPs) release (67) which may help explain its association with reduced progression in RA despite its pro-inflammatory implications. This protective linkage was confirmed in our meta-analysis between the R131 polymorphism and RA in the overall population, suggesting a disease-specific influence on autoimmune pathogenesis.

The H131 variant demonstrates heightened binding affinity for IgG2 immune complexes (ICs) (68), facilitating efficient phagocytic clearance by neutrophils and macrophages. This increased efficiency not only enhances phagocytosis, neutrophil activation (69, 70), and IL-1β secretion (71), but also supports a more robust inflammatory response to IgG2 ICs. This enhanced clearance can trigger complement cascades and the production of pro-inflammatory cytokines, such as TNF-α and IL-6 (72). It can also promote sustained immune activation, driving chronic inflammation and the generation of autoantibodies — key pathogenic features of SLE, RA and multiple sclerosis (MS) (73). When this immune activation persists, the incomplete clearance of immune complexes (ICs) can lead to complications: these complexes may then accumulate in tissues such as the renal glomeruli and synovium (74), where complement-mediated lysis and cytokine-driven pathways can further exacerbate tissue injury and inflammation (75).

The higher prevalence of the H131 allele in Asian populations (76) as observed in our East Asian subgroup analysis by ethnicity, correlates with increased susceptibility to SLE (43) ( Supplementary Table S2 ).

Therefore, the functional impact of the H131R polymorphism is context-dependent, modulating both immune defense and the risk of autoimmune tissue injury ( Table 5 ).

The F158V polymorphism arises from a T-to-G substitution at coding nucleotide c.526 (NM_000569.8), substituting phenylalanine (F158) with valine (V158) in the receptor’s extracellular domain (77). The V158 variant increases binding affinity for IgG1/IgG3 by ~5-fold compared to F158 (78), likely due to valine’s smaller side chain reducing steric hindrance and optimizing hydrophobic interactions with the Fc region. The high-affinity V158 variant enhances antibody-dependent cellular cytotoxicity (ADCC) by strengthening interactions between FcγRIIIa and the Fc region of IgG1/IgG3 (79, 80) which affects neutrophil activation and effector functions, including phagocytosis and reactive oxygen species production. Functionally, natural killer (NK) cells from individuals homozygous for FcγRIIIa 158V display increased calcium influx, elevated CD25 expression, and accelerated apoptosis relative to those from FcγRIIIa 158F homozygotes, reflecting a more robust activation profile. Concurrently, FcγRIIIa 158V enhances antibody-dependent cellular cytotoxicity (ADCC) in NK cells by stabilizing FcγRIIIa engagement with IgG1/IgG3-opsonized targets (81), driving perforin/granzyme polarization inducing apoptosis.

In SLE, the V158 variant’s enhanced IgG1/IgG3 binding is hypothesised to exacerbate neutrophil extracellular trap (NET) formation and renal IC deposition (82), accelerating lupus nephritis (LN) (83). Contradictorily, the same mechanism may improve clearance of apoptotic debris, reducing autoantigen persistence and dampening chronic inflammation. This duality underscores the context-dependent influence of FcγRIIIa polymorphisms. In clinical settings, the V158 variant’s heightened signalling capacity augments the efficacy of anti-CD20 therapies such as rituximab (84), as pronounced FcγRIIIa clustering on natural killer cells facilitates more effective B-cell depletion and enhances therapeutic outcomes (79, 80). Consequently, the V158 variant is associated with superior B-cell depletion and improved clinical responses to anti-CD20 treatment. Table 6 summarizes the functional implications of the F158V polymorphism.

Accumulating evidence from our study and others highlights both the H131R and F158V polymorphisms as key modulators of immune regulation, although their direct mechanistic roles in autoimmune pathogenesis remains incompletely resolved (81, 85). As outlined in the report, both FcγRIIa and FcγRIIIa are characterized by co-dominantly expressed allelic variants that modulate their ligand-binding affinities, thereby shaping the magnitude and quality of cellular responses to ICs (85, 86). Structural data show that both polymorphisms are located directly within the binding interface between the receptor ectodomains and the IgG Fc regions (87, 88) ( Figure 5 ).

The presence of functionally distinct polymorphisms in these receptors can synergistically alter effector cell activation, cytokine production, and the balance between IC clearance and inflammation. The combined inheritance of FCGR2A H131R and FCGR3A F158V polymorphisms may establish a “dual-hit” scenario, wherein compromised IC clearance due to FcγRIIa dysfunction is compounded by augmented FcγRIIIa-mediated inflammatory signaling. This interplay could amplify chronic immune activation, thereby accelerating tissue injury and promoting the progression of autoimmune diseases such as SLE and RA (Table 7).

Reports on the pathogenic versus protective roles of these variants are conflicting. For instance, FCGR3A F158V has been linked to increased ITP and RA severity. In contrast, the FCGR2A H131R polymorphism has been identified as a risk factor for SLE. However, the present study only replicated this finding in the East Asian subgroup, and no clear effect on susceptibility for LN (89) was observed. The results suggest that the effect may vary between populations. The discrepancies highlight the complexity of Fcγ receptor biology and the influence of genetic background, environmental factors, and disease context.

Resolving these inconsistencies requires functional studies that elucidate how these polymorphisms collectively alter immune cell signalling networks, particularly within myeloid lineages such as neutrophils and macrophages. Future research should map the effects of FCGR2A and FCGR3A variants on IC handling, neutrophil activation, and B-cell tolerance. Such strategies, aligned with advances in genetics and immunology, will be essential to clarify these genetic associations and identify potential therapeutic targets in autoimmune disease.

Several limitations of the present meta-analysis warrant consideration. The limited number of included studies for certain autoimmune diseases reduces the statistical power, increasing the risk of false-negative results. Variations in population characteristics, diagnostic criteria, reliability of the data, and genotyping methods may further limit comparability and applicability. Overall, heterogeneity was substantial, leading us to consistently apply random-effects models throughout our analyses. Random-effects models are the preferred method when heterogeneity is present between original studies, as they account for both within-study and between-study variance. Moreover, Egger’s linear regression test (P ≤ 0.05 threshold) identified publication bias across all comparisons, which may have influenced our outcome. Additionally, our analysis did not adjust for potential confounding variables such as sex, age, or environmental factors. These limitations indicate the requirement for future large-scale, well-controlled studies in diverse populations to confirm and extend our findings.