MS4A2

Abstract: Summary Background and objective The MS4A2 gene, the b chain of the high-affinity receptor for immunoglobulin (Ig)E, has previously been linked to atopy and asthma. The b-chain of FceR1 enhances receptor maturation and signal transduction capacity, leading to the release of proinflammatory mediators and cytokines that can exacerbate the symptom of asthma. This study was performed to evaluate whether two genetic polymorphisms of the FceR1b gene (FceR1b � 109T4C and FceR1b E237G) are associated with aspirin-intolerant asthma (AIA). Methods The MS4A2 gene polymorphisms (FceR1b � 109T4C and FceR1b E237G) were determined by SNP-IT TM assays in patients with AIA (N=164), aspirin-tolerant asthma (ATA, N=144) and normal controls (NC, N=264) recruited from a Korean population. Results The genotype frequencies of FceR1b � 109T4C and E237G polymorphisms were not significantly associated with the pathogenesis of AIA. However, FceR1b � 109T4C polymorphism was significantly associated with the presence of specific IgE to Staphylococcal enterotoxin B (SEB); the number of subjects carrying both homozygous TT genotype of FceR1b � 109T4C and specific IgE to SEB was significantly higher in the AIA group when compared with the other control groups (P=0.01, odds ratio (OR)=7.723, 95% confidence interval (CI)=1.327‐39.860 for AIAvs. ATA; P=0.02, OR=6.364, 95% CI=1.149� 35.229 for AIA vs. NC). In addition, luciferase reporter assays also showed that the FceR1b � 109T allele was associated with higher promoter activity of MS4A2 in both RBL-2H3 and A549 cell lines. Conclusion FceR1b � 109T4C polymorphism may increase expression of MS4A2 by mast cells, leading to enhanced release of proinflammatory mediators in the asthmatic airway, contributing to increased susceptibility to AIA.

Abstract: Polymorphisms in the beta chain of the high affinity receptor for IgE (Fc epsilon RI-beta, MS4A2) are consistently associated with traits underlying asthma and atopy (immunoglobulin E-mediated allergy). However, the causal variants and haplotypes underlying disease have not yet been identified. Maternal effects, with association confined to maternally derived alleles, have been shown in some studies but not in others. We have therefore extended the known sequence and systematically detected polymorphisms across an 18.1 Kb genomic region that includes Fc epsilon RI-beta. Association testing in two panels of subjects showed the presence of single-nucleotide polymorphisms (SNPs) affecting prick skin tests and specific IgE responses in several clusters. Stepwise analyses indicated that the clusters represent independent effects. Interferon regulatory factor 2 (IRF-2) sites were altered by significantly associated SNPs in two regions. Strong association to maternally derived alleles was seen in one panel of subjects and not in the other. Maternal and non-maternally derived associations tended to share the same SNP clusters, but associations were stronger in the presence of maternal effects. Two regions of increased CpG concentration were identified in Fc epsilon RI-beta. One of these approximated a SNP cluster that showed strong association and maternal effects, providing a potential substrate for epigenetic effects.

Abstract: Mast cells contribute to allergy through IgE-dependent activation via the high-affinity IgE receptor FceRI. The role of the FceRIβ chain (MS4A2) in mast cell function is not understood fully, although it serves to amplify FceRI-dependent signaling. We demonstrate the expression of a novel MS4A2 truncation lacking exon 3 in human mast cells termed MS4A2(trunc). MS4A2(trunc) gene expression was regulated negatively by the mast cell growth factor stem cell factor (SCF), and its expression was not detected in the SCF receptor gain-of-function human mast cell line HMC-1. Unlike MS4A2, MS4A2(trunc) did not traffic to the cytoplasmic membrane but instead was associated with the nuclear membrane. Overexpression of MS4A2(trunc) induced human lung mast cell death and profoundly inhibited HMC-1 cell proliferation by inducing G(2)-phase cell cycle arrest and apoptosis. Thus, we have identified a novel splice variant of MS4A2 that might be important in the regulation of human mast cell proliferation and survival. This finding demonstrates that the MS4A2 gene has multiple roles, extending beyond the regulation of acute allergic responses. By understanding the mechanisms regulating its function, it might be possible to induce its expression in mast cells in vivo, which could lead to better treatments for diseases such as mastocytosis and asthma.

Abstract: Background The hormonal form of vitamin D affects both adaptive and innate immune functions involved in the development of allergies. Certain genotypes have been seen to alter the association between vitamin D deficiency (VDD) and the risk of food sensitization in children. Methods We examined 27 functional single nucleotide polymorphisms (SNPs) in/near selected candidate genes for association with total immunoglobulin E (IgE) and effect modification by 25-hydroxyvitamin D in the 1958 British birth cohort (aged 45 years, n = 4921). A cut-off value of 50 nmol/L was used to define VDD. Results Four SNPs (in FCER1A, IL13, and CYP24A1) and three SNPs (in IL4 and CYP24A1) were associated with total IgE and specific IgE, respectively, after correction for multiple testing. As in a previous study, MS4A2 (rs512555, Pinteraction = 0.04) and IL4 (rs2243250, Pinteraction = 0.02), and their composite score (Pinteraction = 0.009) modified the association between VDD and allergy-related outcome. Vitamin D deficiency was associated with higher total IgE only in the carriers of the ‘C’ allele (IL4), which is present in 86% of white Europeans, while only 26% of Chinese and <20% of some African populations are carriers. Conclusions Our study on white European adults was consistent with a previous study on children from largely non-white ethnic groups, suggesting that IL4 and MS4A2 genotypes modify the association between VDD and allergy risk. The risk allele in IL4 is present in nearly 90% of white Europeans, while less than a quarter are carriers in some other populations, highlighting the need to consider possible ethnic differences in allergy-related responsiveness to VDD.