H131R Polymorphism Research Articles

Association of IgG1 Antibody Clearance with FcγRIIA Polymorphism and Platelet Count in Infliximab-Treated Patients.

The FcγRIIA/CD32A is mainly expressed on platelets, myeloid and several endothelial cells. Its affinity is considered insufficient for allowing significant binding of monomeric IgG, while its H131R polymorphism (histidine > arginine at position 131) influences affinity for multimeric IgG2. Platelet FcγRIIA has been reported to contribute to IgG-containing immune-complexe clearance. Given our finding that platelet FcγRIIA actually binds monomeric IgG, we investigated the role of platelets and FcγRIIA in IgG antibody elimination. We used pharmacokinetics analysis of infliximab (IgG1) in individuals with controlled Crohn’s disease. The influence of platelet count and FcγRIIA polymorphism was quantified by multivariate linear modelling. The infliximab half-life increased with R allele number (13.2, 14.4 and 15.6 days for HH, HR and RR patients, respectively). It decreased with increasing platelet count in R carriers: from ≈20 days (RR) and ≈17 days (HR) at 150 × 109/L, respectively, to ≈13 days (both HR and RR) at 350 × 109/L. Moreover, a flow cytometry assay showed that infliximab and monomeric IgG1 bound efficiently to platelet FcγRIIA H and R allotypes, whereas panitumumab and IgG2 bound poorly to the latter. We propose that infliximab (and presumably any IgG1 antibody) elimination is partly due to an unappreciated mechanism dependent on binding to platelet FcγRIIA, which is probably tuned by its affinity for IgG2.

Associations between FCGR polymorphisms and immune thrombocytopenia: A meta-analysis.

Several studies already explored associations between Fc gamma receptor (FCGR) polymorphisms and immune thrombocytopenia (ITP), but the results of these studies were not consistent. Consequently, we conducted a meta-analysis of relevant studies to better analyse the effects of FCGR polymorphisms on individual susceptibility to ITP. PubMed, Web of Science, Embase and CNKI were searched for eligible studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Totally 17 studies were eligible for analyses (1200 cases and 1723 controls). Significant associations with ITP were observed for FCGR3A F158V polymorphism in dominant (P<0.0001, OR=0.47, 95% CI 0.39-0.57), recessive (P<0.0001, OR=2.03, 95% CI 1.58-2.61), overdominant (P<0.0001, OR=1.42, 95% CI 1.19-1.69) and allele (P<0.0001, OR=0.58, 95% CI 0.51-0.65) models in overall analyses. But we did not observe any significant associations with ITP for FCGR2A H131R and FCGR2B I232T polymorphisms in overall analyses. Subgroup analyses by ethnicity yielded similar positive results for FCGR3A F158V polymorphism in both Asians and Caucasians. Furthermore, subgroup analyses by type of disease revealed that FCGR2A H131R polymorphism was significantly associated with childhood-onset ITP, and FCGR3A F158V polymorphism was significantly associated with both childhood-onset and adult-onset ITP. In summary, our findings suggested that FCGR2A H131R polymorphism may serve as a potential genetic biomarker of childhood-onset ITP, while FCGR3A F158V polymorphism may serve as a potential genetic biomarker of both childhood-onset and adult-onset ITP.

Pharmacogenetics to prevent heparin-induced thrombocytopenia: what do we know?

Heparin-induced thrombocytopenia (HIT) is a life-threatening, immune-mediated adverse reaction to heparin anticoagulants. The inability to predict HIT represents a considerable liability associated with heparin administration. Genetic studies of HIT are challenging due to the scarcity of true HIT cases, potential for misclassification, and many environmental risk factors. Genetic studies have not consistently identified risk alleles for HIT, the production of platelet factor 4/heparin antibodies or the thromboembolic complications of HIT. Genes implicated in HIT and platelet factor 4/heparin antibody levels include FCGR2A, TDAG8, HLA-DR and others. Compelling evidence also suggests that the FCGR2A H131R polymorphism is associated with HIT-related thrombosis. There is a need for well-powered, multiethnic studies with laboratory confirmation of HIT, detailed patient- and drug-specific data, and inclusion of both serologic and thromboembolic outcomes. Genomic biomarkers identified from such studies offer the possibility of shifting current clinical practice paradigms from early detection and treatment to prevention.

Risk factors for heparin-induced thrombocytopenia: Focus on Fcγ receptors.

Fcγ receptors have critical roles in the pathophysiology of heparin-induced thrombocytopenia (HIT), a severe immune-mediated complication of heparin treatment. Activation of platelets, monocytes and neutrophils by platelet-activating anti-PF4/heparin IgG antibodies results in thrombocytopenia, hypercoagulability and thrombosis in susceptible patients, effects that depend on FcγRIIA. In addition, FcγRIIIA receptors probably contribute to clearance of platelets sensitised by HIT immune complexes. FcγRI has also been reported to be involved in monocyte activation by HIT IgG antibodies and synthesis of tissue factor. This review focuses on the role of these FcγRs in HIT pathophysiology, including the potential influence of several gene variations associated with variable risk of HIT and related thrombosis. In particular, the 276P and 326Q alleles of CD148, a protein tyrosine phosphatase that regulates FcγRIIA signalling, are associated with a lower risk of HIT, and platelets from healthy donors expressing these alleles are hyporesponsive to anti-PF4/H antibodies. It was also recently demonstrated that the risk of thrombosis is higher in HIT patients expressing the R isoform of the FcγRIIA H131R polymorphism, with HIT antibodies shown to activate RR platelets more efficiently, mainly explained by an inhibitory effect of normal IgG2, which bound to the FcγRIIA 131H isoform more efficiently. Environmental risk factors probably interact with these gene polymorphisms affecting FcγRs, thereby increasing thrombosis risk in HIT.

Association between the FCGR2A gene H131R polymorphism and risk of Kawasaki disease: a meta-analysis.

Several previous studies have investigated whether the FCGR2A gene H131R polymorphism confers an increased risk of Kawasaki disease (KD), but conflicting results have been reported. To further explore the association of this polymorphism with KD susceptibility, we performed an extensive search of relevant studies and conducted a meta-analysis to obtain a more precise estimate of risk. Systematic searches of the electronic databases Embase, PubMed, and Google Scholar were performed to identify relevant studies. Odds ratios (ORs) and their 95% confidence intervals (CIs) were used for statistical analysis. Six studies were included in the meta-analysis, involving 1709 patients with KD and 3207 controls. Significant association was found between the FCGR2A gene H131R polymorphism and KD risk in analysis of the total population (HH vs RR: OR = 1.97, 95%CI = 1.55-2.50; HH vs HR: OR = 1.38, 95%CI = 1.21-1.57; the dominant model: OR = 0.69, 95%CI = 0.60-0.78; and the recessive model: OR = 1.65, 95%CI = 1.32-2.07). In subgroup analysis by ethnicity, significant association was found between the H131R polymorphism and KD risk in Asians, but not in Caucasians. In addition, we found no significant association between the FCGR2A gene H131R polymorphism and risk of KD-associated coronary artery lesions. In conclusion, this meta-analysis suggested that the H131R polymorphism in the FCGR2A gene might be associated with susceptibility to KD in Asians.

Novel association of FCGR2A polymorphism with age-related macular degeneration (AMD) and development of a novel CFH real-time genotyping method.

Age-related macular degeneration (AMD) is a degenerative ocular disease, which may lead to loss of central vision. In Caucasian populations, a strong correlation has been established with polymorphism Y402H (rs1061170) in the complement factor H gene (CFH). The H131R polymorphism (rs1801274) in the FCGR2A gene has been associated with many inflammatory diseases, but has not been investigated in relation to AMD. The goal of our study was the development of a novel method for Y402H (g.43097C>T) genotyping, the confirmation of its association with AMD in the Greek population and the investigation of the H131R polymorphism in AMD. DNAs were extracted from blood samples of 120 patients with the severe wet form of AMD and 103 age- and sex-matched controls, all of whom were clinically evaluated. A real-time PCR and melting curve analysis method for Y402H genotyping was developed in the LightCycler platform, after in silico design of appropriate primers and probes. Genotyping for H131R was performed using a real-time PCR method previously described by our group. The novel genotyping method for Y402H in the CFH gene is fast, reproducible (Efficiency=1.79, reproducibility CVCq=3.33%, Tm C allele 53.36 °C and T allele 61.91 °C, ΔTm=8.55) and accurate as results were confirmed with the gold standard DNA Sequencing method. The present study confirmed the association between CFH Y402H SNP and wet AMD in the Greek population (OR=1.77, p=0.002). FCGR2A H131R polymorphism was investigated for the first time in this present study for possible correlation with wet AMD and a statistically significant association was detected (OR=1.74, p=0.006), that awaits further confirmation in a larger set of samples.

Influence of FcγRIIA H131R Polymorphism on the Risk of Thrombosis in HIT and Variable Effect of Normal IgG on Platelet Activation

Introduction. Heparin-induced thrombocytopenia (HIT) results from an atypical immune response to platelet factor 4/heparin complexes (PF4/H), with rapid synthesis of IgG antibodies that activate platelets via FcγRIIA receptors. HIT is associated with thrombotic complications occurring in about 50% of affected patients.Moreover, the response of platelets to anti-PF4/H IgG varies from one subject to another. This variability, partly explained by gene polymorphisms affecting FcγRIIA signaling (Rollin et al, Blood 2012), might also depend on variations in the binding of HIT antibodies to FcγRIIA receptors.Objective. The influence of FcγRIIA H131R polymorphism on the risk of HIT and thrombosis was investigated in parallel with the effect of normal IgG on the platelet response to HIT antibodies.Patients and Methods. A cohort of 89 patients with definite HIT (PF4-specific ELISA and serotonin release assay both positive) and two control groups with (Abpos ; n=160) or without (Abneg ; n=179) significant levels of PF4-specific antibodies after cardiac surgery were studied. Platelet aggregation tests (PAT) were performed in 59 healthy donors using HIT plasma samples or 5B9, a humanized chimeric monoclonal antibody specific to PF4/H complexes that we have recently developed which fully mimics the effects of human HIT antibodies. The influence of normal IgG and IgG subclasses on platelet aggregation was also evaluated according to the FcγRIIA H131R polymorphism. Finally, tissue factor mRNA levels and plasma phospholipid-dependent procoagulant activity were measured after addition of HIT antibodies and heparin in the whole blood collected from healthy donors with different FCGR2A genotypes.Results. Genotypes and allele frequencies were similar in the HIT patients and both Abneg and Abpos controls. However, interestingly, homozygous FcγRIIA 131RR subjects were more frequent among the HIT patients who had developed thrombotic complications compared to those without thrombosis (34.5% vs. 8.5%, respectively, p=0.008). The FcγRIIA 131RR genotype therefore appeared to increase the risk of thrombosis in HIT significantly (OR = 5.9; 95% CI 1.7-20). This association was not found in two other cohorts of patients who had developed ischemic stroke or venous thromboembolism in a medical context other than HIT, thus indicating that the impact of FcγRIIA H131R polymorphism on the risk of thrombosis was specific to HIT. PAT performed with platelet-rich plasma (PRP) showed that the lag time measured in response to 5B9 with heparin (5B9/H) was significantly longer with FcγRIIA 131HH platelets compared to RR platelets (p=0.03). Importantly, this variable platelet response to 5B9/H related to the FcγRIIA polymorphism was no longer detectable when PAT were performed with washed platelets, when the IgG fraction had been removed from the plasma, and when collagen was used as inducer. On the other hand, the addition of human polyvalent IgG to IgG-depleted PRP inhibited the aggregation induced by 5B9/H, but lower concentrations of IgG were required to achieve this effect in FcγRIIA 131HH subjects compared to RR donors. Importantly, this variable effect of normal IgG on platelet aggregation induced by HIT antibodies was shown to depend mainly on the IgG2 subclass, which binds to the H131 isoform more effectively, whereas IgG1 exerted a similar inhibitory effect in RR and HH homozygous donors. Finally, a stronger increase in TF mRNA levels was also evidenced in homozygous FcγRIIARR donors compared to homozygous FcγRIIAHH donors after incubation of 5B9 and heparin in whole blood. Moreover, this effect was associated with a greater relative shortening of plasma clotting time indicating that the release of procoagulant phospholipid microparticles was more pronounced in RR subjects in response to HIT antibodies (p=0.04).Conclusion. These results demonstrate that HIT patients homozygous for the FcγRIIA 131R allele have a higher risk of thrombosis, probably due to an increased cell activation induced by antibodies to PF4/H with a lower inhibitory effect of endogenous IgG, especially of the IgG2subclass. DisclosuresNo relevant conflicts of interest to declare.

FCGR2A rs1801274 polymorphism is associated with risk of childhood-onset idiopathic (immune) thrombocytopenic purpura: Evidence from a meta-analysis

IntroductionPrevious studies have evaluated the association between FCGR2A H131R (rs1801274) polymorphism and idiopathic (immune) thrombocytopenic purpura (ITP), but results remain inconsistent. This meta-analysis was conducted to clarify these controversies. MethodsLiteratures on PubMed/ Medline, Embase and CENTRAL databases up to September 2013 were searched by two investigators. The distributions of alleles and genotypes between cases and controls were compared by using odds ratios (ORs) and 95% confidence intervals (95% CIs). Fixed or Random-effects models were used when appropriate. Results10 studies involving 553 patients and 1088 controls were available for this study, including 7 studies of Caucasian descendents, 2 studies of Asian descendents, and 1 study contained diverse ethnicity. In this studied overall population, we didn’t found any significant association between the FCGR H131R polymorphism and the risk of ITP for all genetic models. But in the subgroup analysis, a significant association between FCGR H131R polymorphism and ITP susceptibility was observed in Caucasian population of childhood-onset group for H vs. R (OR=1.246, 95% CI 1.021-1.522, p=0.031), HH vs. HR+RR (OR=1.562, 95% CI 1.145-2.129, p=0.005), HH vs. HR (OR=1.598, 95% CI 1.146-2.228, p=0.006), HH vs. RR (OR=1.484, 95% CI 1.005-2.191, p=0.047). No significantly between-study heterogeneity was observed for all genotype models in Caucasian childhood-onset ITP subtype analysis. However, this association was not stable after sensitivity analysis. ConclusionOur present meta-analysis indicated that FCGR H131R polymorphism might not be associated with risk of ITP in overall population. However, in Caucasian childhood-onset subgroup, there might be an association between FCGR2A H131R polymorphism and ITP risk, which is not robust and should be explained with caution.

Association of FCGR2A with the response to infliximab treatment of patients with rheumatoid arthritis

We aimed to assess a functional polymorphism in FCGR2A H131R, for association with the treatment response to Fc-containing inhibitors of tumor necrosis factor (TNF). A total of 429 biologic-naive patients with rheumatoid arthritis collected in two sets (299 and 130) were treated during standard care with infliximab (INX), etanercept, or adalimumab. Response to the treatment was evaluated at 3, 6, and 12 months of follow-up as the change in the Disease Activity Score (DAS) 28 from baseline and as the response by the European League Against Rheumatism (EULAR) criteria. These variables were analyzed for association with linear and logistic regression models that included sex, inhibitors of TNF, and baseline DAS28 as covariates. Significant association was found between the FCGR2A H131R polymorphism and the response to treatment with INX, but not with the other two TNF inhibitors. The 131R allele was associated with a lower change in DAS28 (P=0.04-0.008 at different times) in the first set of patients and confirmed in the second group of patients (P=0.026 at 3 months of follow-up). Association was also found in the comparison between nonresponders and responders to INX by the EULAR criteria. We found an association of the FCGR2A 131R allele with poor response to INX. This finding could be of utility to understand the mechanisms behind treatment failure and contribute to biomarker panels for INX response prediction.

Associations between FCGR2A rs1801274, FCGR3A rs396991, FCGR3B NA1/NA2 polymorphisms and periodontitis: a meta-analysis

The aim of this study was to determine whether the Fcγ receptors (FCGRs) polymorphisms confer susceptibility to periodontitis in ethnically different populations. We did a literature search using PubMed and Embase, and conducted a meta-analysis on the associations between the FCGR2A H131R (rs1801274), FCGR3A F158V (rs396991), and FCGR3B NA1/NA2 polymorphisms and periodontitis using allele contrast, the recessive model, the dominant model, and the homozygote contrast. A total of 17 separate comparisons with 1,421 patients with periodontitis and 1,454 controls, involving six Caucasian, six East Asian, two African and one South Asian population were considered in the meta-analysis. Meta-analysis of the FCGR2A H131R polymorphism showed no association between periodontitis and the FCGR2A R allele (OR=0.987, 95% CI=0.881-1.107, p=0.827). Stratification by ethnicity revealed an association between the RR+RH genotype with periodontitis in Caucasian population (OR=0.624, 95% CI=0.479-0.813, p=4.7×10(-5)), but not in East Asian, and African populations. Meta-analysis of the FCGR3A F158V polymorphism revealed an association between the FCGR3A V allele and periodontitis is in Caucasians (OR=1.457, 95% CI=1.014-2.092, p=0.042), but not in East Asians and Africans. In addition, analysis using the dominant model and homozygote contrast showed the same pattern for the FCGR3A V allele. Meta-analysis of the FCGR3B NA1/NA2 polymorphism using the recessive model revealed a significant association between the NA2/NA2 genotype and periodontitis in aggressive periodontitis (OR=2.853, 95% CI=1.673-4.863, 1.1×10(-5)). This meta-analysis demonstrates that the FCGR2A, and FCGR3A polymorphisms may confer susceptibility to periodontitis in Caucasians, and that the FCGR3B polymorphism may be associated with susceptibility to aggressive periodontitis.

The Fcγ receptor IIA R131H gene polymorphism is associated with endothelial function in patients with hypercholesterolaemia

ObjectiveA gene polymorphism substituting arginine (R) for histidine (H) at position 131 has been described within the Fcγ receptor IIa (FcγRIIa). The R allele is associated with increased binding of CRP and enhanced activation of monocytes. FcγRIIa is also expressed on endothelial cells, and we hypothesized this polymorphism would be associated with alterations of endothelial function. MethodsGenomic DNA was extracted and allele-specific PCR reactions were used to determine the FcγRIIa H131R polymorphism in 78 hypercholesterolaemic subjects. Using strain gauge plethysmography, forearm blood flow (FBF) responses were determined to intra-arterial infusion of acetylcholine (ACH), for endothelium-dependent vasodilatation (EDV), to nitroprusside (NP), for endothelium-independent vasodilatation (EIV), to NG-monomethyl-l-arginine (l-NMMA), for basal NO activity, and to ACH in the presence of l-NMMA, to assess the contribution of NO release to EDV. ResultsHomozygous carriers of the H allele (n=30) had significantly better EDV than homozygous carriers of the R allele (n=15), while heterozygotes showed an intermediate phenotype (n=33) (e.g. % increase of FBF to ACH 48μg/min: 527±359% in H/H versus 452±262% in H/R versus 332±413% in R/R, p=0.0012 by 2-way ANOVA). EIV and basal NO activity were not affected by genotype, and co-infusion of l-NMMA abolished the differences in EDV. ConclusionsThe R allele of the FcγRIIa polymorphism is associated with impaired EDV and reduced NO activity during endothelial cell stimulation. These data suggest that the functional effects of the FcγRIIa H131R gene polymorphism previously observed in vitro translate into clinically relevant alterations of endothelial function in vivo.

Conflicting roles of FcγRIIa H131R polymorphism in pneumonia*

Conflicting roles of FcγRIIa H131R polymorphism in pneumonia*

FCGR2A H131R and FCGR3A V158F polymorphism status in mCRC patients treated with single-agent cetuximab (IMCL 0144 and CA225045) or with second-line irinotecan plus cetuximab (EPIC): A pooled statistical analysis.

e14025 Background: Beyond K-RAS mutation status, additional positive predictive markers are needed to identify patients who will benefit from cetuximab treatment. Recent studies demonstrate antibody-dependent cell-mediated cytotoxicity (ADCC) may be one of the modes of action for cetuximab. Previous data suggest two Fc gamma receptor polymorphisms (FCGR2A H131R/FCGR3A V158F) may predict efficacy of cetuximab. Here we present analyses of these 2 polymorphisms in 3 phase II trials of mCRC patients treated with either single agent cetuximab (IMCL0144 and CA225045 [045]) or with second-line irinotecan plus cetuximab (EPIC). Methods: A total of 317 patients (133 from IMCL 0144; 84 from EPIC; 100 from 045) had been tested for FCGR2A H131 R and FCGR3A V158F polymorphisms. FCGR2A/3A polymorphisms were tested by PCR-RFLP or allele-specific PCR technique. Results: In a pooled analysis of IMCL 0144 and EPIC, we found patients with FCGR2A 131 HH genotype had shorter PFS (median PFS=1.3 months (95%C.I: 1.2-2.4) compared to those with HR/RR genotypes. (median PFS= 2.5 months [95%CI: 1.5-3.0] p=0.036, log-rank test). No statistically significant associations were observed between FCGR2A/3A polymorphisms and tumor response rate in either all evaluable patients or in the wild-type KRAS subgroup. (p>0.05, Fisher’s exact test). There are no associations between FCGR3A polymorphisms and OS, PFS. In a separate analysis of 045, no statistically significant associations were observed between FCGR2A/3A genotype and the assessed endpoints (response rate or PFS). Conclusions: Our pooled analysis suggested that the FCGR2A polymorphism may be associated with PFS in patients with mCRC, however FCGR3A polymorphism was not associated with efficacy of cetuximab-based treatment. Further larger statistically powered studies to evaluate the significance of FCGR polymorphisms are needed, and international collaborations are necessary to address the need for larger studies to validate molecular markers in the future.

Fragment c gamma receptor gene polymorphisms and breast cancer risk in case–control studies in Japanese, Japanese Brazilians, and non-Japanese Brazilians

Previous studies showing the presence of antibodies against tumor-associated antigens in healthy individuals suggest that antibody-dependent cell cytotoxicity (ADCC) might play a role in the development of breast cancer. We hypothesized that functional polymorphisms in fragment c gamma receptor (FcgR) genes were associated with breast cancer risk. We conducted hospital-based case-control studies of patients aged 20-74 years with invasive breast cancer, and matched controls from medical checkup examinees in Nagano, Japan and from cancer-free patients in São Paulo, Brazil. A total of 869 pairs (403 Japanese, 80 Japanese Brazilians and 386 non-Japanese Brazilians) were genotyped for two single nucleotide polymorphisms (SNPs): a histidine (H)/arginine (R) polymorphism at position 131 of FcgRIIa (FcgRIIa H131R) and a valine (V)/phenylalanine (F) polymorphism at position 158 of FcgRIIIa (FcgRIIIa F158V). We found no statistically significant association between either of the two SNPs and breast cancer risk regardless of population. In analyses of the three populations combined, adjusted odds ratio (OR) was 0.93 [95% confidence interval (CI) 0.66-1.32] for women with the R/R versus H/H genotype of the FcgRIIa H131R polymorphism and 1.04 (95% CI 0.69-1.57) for the V/V versus F/F genotype of the FcgRIIIa F158V polymorphism. On combination of the two SNPs, compared to women with both the R/R genotype of the FcgRIIa H131R polymorphism and F/F genotype of the FcgRIIIa F158V polymorphism, the adjusted OR for women with both the H/H and V/V genotype was 0.68 (95% CI 0.37-1.27). In conclusion, our findings suggest that ADCC might not play a major role in the etiology of breast cancer.

Fcγ receptor polymorphisms and their association with periodontal disease: a meta‐analysis

A systematic review and a meta-analysis were conducted in order to investigate the potential association of Fcgamma receptor (FcgammaR) polymorphisms with susceptibility to aggressive and chronic periodontal disease. A database search yielded a total of 17 studies involving 1685 cases and 1570 controls. Three polymorphisms were included in the meta-analysis: FcgammaRIIA H131R (rs1801274), FcgammaRIIIA F158V (rs396991) and FcgammaRIIIB NA1/NA2. Random-effect models were used in the analysis. Odds ratios (ORs) along with their 95% confidence intervals (CIs) were computed to compare the distribution of alleles and genotypes between cases and controls. The FcgammaRIIIB NA1/NA2 polymorphism was associated with both aggressive (per-allele OR 2.005, 95% CI: 1.044, 3.851) and chronic periodontitis (recessive contrast NA2NA2 versus NA1NA1+NA1NA2 OR 1.397, 95% CI: 1.039, 1.878). The analysis showed weak evidence for association between the FcgammaRIIA H131R polymorphism and aggressive periodontitis in Asians (R versus H allele OR 1.579, 95% CI: 1.025, 2.432). On the contrary, no relationship was identified between FcgammaRIIIA F158V and periodontal disease. Accumulating evidence from basic research makes the suggested association between FcgammaRIIIB NA1/NA2 polymorphism and periodontitis biologically plausible. Further research, however, is needed in order to assess possible gene-gene or gene-environment interactions (i.e. with smoking).

More Framingham data, more dietary confusion

Previous studies have evaluated the association between FCGR2A H131R (rs1801274) polymorphism and idiopathic (immune) thrombocytopenic purpura (ITP), but results remain inconsistent. This meta-analysis was conducted to clarify these controversies.Literatures on PubMed/ Medline, Embase and CENTRAL databases up to September 2013 were searched by two investigators. The distributions of alleles and genotypes between cases and controls were compared by using odds ratios (ORs) and 95% confidence intervals (95% CIs). Fixed or Random-effects models were used when appropriate.10 studies involving 553 patients and 1088 controls were available for this study, including 7 studies of Caucasian descendents, 2 studies of Asian descendents, and 1 study contained diverse ethnicity. In this studied overall population, we didn’t found any significant association between the FCGR H131R polymorphism and the risk of ITP for all genetic models. But in the subgroup analysis, a significant association between FCGR H131R polymorphism and ITP susceptibility was observed in Caucasian population of childhood-onset group for H vs. R (OR = 1.246, 95% CI 1.021-1.522, p = 0.031), HH vs. HR + RR (OR = 1.562, 95% CI 1.145-2.129, p = 0.005), HH vs. HR (OR = 1.598, 95% CI 1.146-2.228, p = 0.006), HH vs. RR (OR = 1.484, 95% CI 1.005-2.191, p = 0.047). No significantly between-study heterogeneity was observed for all genotype models in Caucasian childhood-onset ITP subtype analysis. However, this association was not stable after sensitivity analysis.Our present meta-analysis indicated that FCGR H131R polymorphism might not be associated with risk of ITP in overall population. However, in Caucasian childhood-onset subgroup, there might be an association between FCGR2A H131R polymorphism and ITP risk, which is not robust and should be explained with caution.