Letter to the editor FCER1A genetic variability and serum IgE levels We read with keen interest a very recent study by Chen et al. (1), which further expands on the recent findings by Weidinger et al. (2) who reported on the results of large genome-wide scan that demonstrated IgE receptor (FceRI) a-chain (FcRIa) gene (FCER1A) variability to be a major marker of serum IgE levels in population. Chen et al. (1) successfully showed an association between FCER1A variants and serum IgE levels present in cord blood/small children to be independent of environmental stimuli, which seems to be an important genetic input on our under- standing of multi-factorial etiology of allergic disorders.We would like to con- gratulate the authors of both the above very analytically powerful studies (1, 2) for scientific and statistical power as well as for elegance and excellence of their work. The large and powerful trials by Wei- dinger et al. (2) and Chen et al. (1) dem- onstrated two common variants FCER1A rs2427837 and rs2251746 to be strongly associated with serum IgE levels in general and paediatric populations. While direct evidence for strong functional activity of rs2251746 FCER1A proximal promoter polymorphism was previously demon- strated (3, 4), showing it to be a potent regulator of FCER1A/FceRIa expression in mast cells and/or basophils, no such data were yet provided for rs2427837 variant. Therefore, an association between rs2427837 polymorphism and IgE levels (1, 2) might possibly result from its almost complete linkage disequilibrium (1, 2) with functional (3, 4) rs2251746 variant. One might also cautiously speculate that some more functional FCER1A variants could by their haplotypic relationships/interplay with rs2251746 polymorphism, at least in small part, functionally contribute to the association with serum IgE levels observed for rs2251746 variant in population (1, 2). For example, rs2427827 polymorphism, close neighbour of rs2251746 variant in FCER1A proximal promoter, was also demonstrated to affect FCER1A transcrip- tional activity/FceRIa expression in mast cells and/or basophils (4, 5) in an addi- tive manner with rs2251746 polymorphism (4). While the regulatory mechanism by which (serum) IgE upregulates cell surface FcRI expression is well known (6), no direct evidence for the causal role of FceRI(a), FCER1A or FCER1A genetic variants in regulation of IgE synthesis and/ or levels was yet provided. Therefore, it might be only speculated that any altera- tions in FceRI expression, including also those genotype-related, might affect IgE synthesis and/or levels. Thus, previous results showing how FCER1A proximal promoter polymorphisms regulate FceR- I(a) expression in mast cells and/or ba- sophils (3–5) might provide only a partial mechanistic background for previously observed FCER1A genetic variants-serum IgE levels genotype-phenotype associations (1, 2, 5). Further functional studies focused on the analysis evaluating the putative effects of (genotype-related) alterations in FceRI expression level on IgE production/ levels seem to be required to reveal the underlying mechanism(s). Acknowledgments D. P. P. is the Japan Society for the Promotion of Science (JSPS) Fellow. D. P. Potaczek 1 , K. Okumura 1,2 , C. Nishiyama 1 1 Atopy (Allergy) Research Center; 2 Department of Immunology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan References 1. Chen CM, Weidinger S, Klopp N, Sausenthaler S, Bischof W, Herbarth O et al. Common variants in FCER1A influence total serum IgE levels from cord blood up to six years of life. Allergy 2009; DOI: 10.1111/j.1398-9995.2009.02005.x. 2. Weidinger S, Gieger C, Rodriguez E, Baurecht H, Mempel M, Klopp N et al. Genome-wide scan on total serum IgE levels identifies FCER1A as novel susceptibility locus. PLoS Genet 2008;4:e1000166. 3. Hasegawa M, Nishiyama C, Nishiyama M, Akizawa Y, Mitsuishi K, Ito T et al. A novel )66T/C polymorphism in FceRI a-chain promoter affecting the transcription activity: possible relationship to allergic diseases. J Immunol 2003;171:1927–1933. 4. Kanada S, Nakano N, Potaczek DP, Maeda K, Shimokawa N, Niwa Y et al. Two different transcription factors discriminate the )315C>T-polymorphism of the FceRI a-chain gene: binding of Sp1 to )315C and of a high mobility group- related molecule to )315T. J Immunol 2008;180:8204–8210. 5. Bae JS, Kim SH, Ye YM, Yoon HJ, Suh CH, Nahm DH et al. Significant association of FceRIa promoter polymorphisms with aspirin-intolerant chronic urticaria. J Allergy Clin Immunol 2007;119:449–456. 6. Macglashan D Jr. IgE and FceRI regulation. Ann NY Acad Sci 2005;1050:73–88. Allergy 2009: 64: 1383 Ó 2009 John Wiley & Sons A/S DOI: 10.1111/j.1398-9995.2009.02090.x 1383