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Gene Review

MS4A2  -  membrane-spanning 4-domains, subfamily A,...

Homo sapiens

Synonyms: APY, ATOPY, FCER1B, FCERI, Fc epsilon receptor I beta-chain, ...
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Disease relevance of MS4A2

  • Atopy patch test skin was used as a model for acute inflammation in atopic dermatitis, while chronic lesional skin was used to investigate FcgammaR expression in chronically inflamed skin [1].
  • The beta-subunit of the high-affinity IgE receptor (Fc epsilon RI-beta) on chromosome 11 is maternally linked to atopy, the state of enhanced IgE responsiveness underlying allergic asthma and rhinitis [2].
  • An important locus for Atopy (familial asthma, hay fever and eczema) has been localized to the 11q12-q13 region with the minimum recombination fraction around the CD20 gene [3].
  • Atopy and airways responsiveness in chronic obstructive pulmonary disease [4].
  • Atopy is characterized by immediate immunoglobulin E (IgE)-mediated hypersensitivity to agents such as dust mites and pollen, and it underlies the increasingly prevalent disorder asthma [5].

Psychiatry related information on MS4A2

  • Evidence linking psychological stress to the expression of asthma and atopy continues to grow [6].
  • METHODS: In the children of the cross-sectional Prevention of Allergy Risk Factors for Sensitization in Children Related to Farming and Anthroposophic Life Style study, asthma and atopy were assessed by means of standardized questionnaires (n = 8263) and serum IgE measurements (n = 2086) [7].
  • For example, we have characterised patients with type 1 brittle asthma, as defined in this review, on the basis of peak flow variability and treatment and these patients remain a separate group when assessed by other means such as psychosocial factors, immunoglobulin levels, and atopy [8].
  • OBJECTIVE: The aim was to investigate the association between alcohol consumption and atopy (aeroallergen sensitization) [9].
  • The risk reduction was stronger for allergies related to atopy (RR, 0.71; 95% CI, 0.64-0.80), but not for asthma (RR, 1.01; 95% CI, 0.77-1.31) [10].

High impact information on MS4A2

  • Both of these approaches have implicated multiple regions in the human and mouse genomes, which are currently being evaluated as harboring putative atopy genes [11].
  • Chromosome 13q14 shows consistent linkage to atopy and the total serum IgE concentration [12].
  • We have identified six coding polymorphisms in SPINK5 (Table 1) and found that a Glu420-->Lys variant shows significant association with atopy and AD in two independent panels of families [13].
  • We obtained evidence for linkage in a 20-cM region of chromosome 7p14-p15 for three phenotypes: asthma, a high level of immunoglobulin E (IgE; atopy) and the combination of the phenotypes [14].
  • The genetics of asthma and atopy have been difficult to determine because these diseases are genetically heterogeneous and modified by environment [14].

Chemical compound and disease context of MS4A2


Biological context of MS4A2

  • Our data indicate that Fc epsilon RI-beta, subject to maternal modification, may be the atopy-causing locus on chromosome 11q [2].
  • We found that the beta subunit of the high-affinity receptor for IgE (Fc epsilon RI-beta) also lies on chromosome 11q13, and that it is in close genetic linkage with the gene for atopy [20].
  • These results suggest that the SNPs in the FcepsilonRIbeta promoter are causally linked with atopy via regulation of FcepsilonRI expression [21].
  • Polymorphisms in the Fc epsilon RI beta promoter region affecting transcription activity: a possible promoter-dependent mechanism for association between Fc epsilon RI beta and atopy [21].
  • BACKGROUND: Atopic diseases are very common, and atopy has a strong genetic predisposition [22].

Anatomical context of MS4A2

  • In atopy patch test sites no increase in the number of CD1a+ dendritic cells and a slight increase in macrophages compared with non-lesional skin was observed [1].
  • The known roles of Fc epsilon RI in antigen-induced mast-cell degranulation and in the release of cytokines that enhance IgE production make the gene for its beta subunit a candidate for the chromosome 11 atopy locus [20].
  • Two promising candidates for the atopy locus, the beta subunit of the high affinity immunoglobulin E receptor (Fc epsilon RI beta) and CD20, a molecule involved in B cell differentiation, have been placed within the contig [3].
  • Twelve patients, 14 to 47 years of age, undergoing allogeneic bone marrow transplantation for the treatment of hematologic cancer were selected, along with their donors, by a screening questionnaire for a history of atopy in the donor [23].
  • Asthma is a chronic inflammatory disease of the airways and lung mucosa with a strong correlation to atopy and acquired (IgE) immunity [24].

Associations of MS4A2 with chemical compounds

  • Atopy is the genetic predisposition toward responses that result in the formation of large quantities of allergen-specific IgE [25].
  • We examined the genetic linkage of the Fc epsilon RI beta gene with clinical asthma and the underlying phenotypes of BHR (to methacholine) and atopy (defined by skinprick testing) in 123 affected sibling-pairs recruited from the general population [26].
  • Dietary vitamin E, IgE concentrations, and atopy [27].
  • BACKGROUND: Distinct wheezing disorders co-exist in young (preschool) children, some of which (early transient wheeze and viral wheeze) are thought to be unrelated to atopy [28].
  • These seven patients had higher serum total IgE antibody levels (328 [113-1,000] kU/I) than atopic patients without latex sensitization (n = 35; 124 [24-857] kU/I; P < 0.05) or patients without atopy (n = 70; 33 [2-339] kU/I; P < 0.001) [29].

Regulatory relationships of MS4A2

  • CONCLUSION: Our findings indicate that the IL-4 receptor alpha gene does not exert a substantial influence on the inheritance of atopy or asthma in this Japanese population [30].
  • OBJECTIVE: To assess whether the protective effect of farm exposure on atopy is influenced by a CD14 promoter functional polymorphism [31].
  • We describe an association study designed to examine whether allelic variation at the glutathione-S-transferase GSTP1 locus influences expression of the BHR and atopy phenotypes in asthma [32].
  • OBJECTICIVE: To examine whether FCER1B promoter polymorphisms (- 109C/T and - 654C/T) influence the genetic effects of the functional polymorphism (4G/5G) at the PAI-1 promoter region on asthma susceptibility using a case-control analysis [33].
  • Furthermore, semi-quantitative RT-PCR analyses revealed marked down-modulation of a Th1 cytokine, interferon (IFN)-gamma, in IL-4-stimulated PBMC derived from atopy patients, but not that from healthy individuals [34].

Other interactions of MS4A2

  • A 2.8 Mb YAC contig in 11q12-q13 localizes candidate genes for atopy: Fc epsilon RI beta and CD20 [3].
  • Association between atopy and variants of the beta subunit of the high-affinity immunoglobulin E receptor [2].
  • By considering the probands and their spouses as an unrelated sample, we observed significant associations of atopy and asthma-related phenotypes with several IL4RA polymorphisms, including S478P and total serum IgE levels (P=.0007) [35].
  • In whites in the CAMP cohort, the A allele of the IL12B G4237A polymorphism was undertransmitted to asthmatic children (P=.0008, recessive model), the global test for haplotypes for affection status was positive (P=.009, multiallelic chi (2)), and two polymorphisms were associated with different atopy phenotypes [36].
  • Taken together, findings of the present study demonstrate that CCL18 is associated with an atopy/allergy skin phenotype, and is expressed at the interface between the environment and the host by cells constantly screening foreign Ags [37].

Analytical, diagnostic and therapeutic context of MS4A2

  • Subjects with atopy were identified on the basis of an elevated serum IgE level (> or = 95 IU per milliliter) or a positive radioimmunosorbent test in response to standard inhalant allergens [22].
  • Laboratory studies, food diaries, and skin tests were not helpful in establishing an etiology, although atopy was present in 12 of 15 patients tested [38].
  • The risk of atopy in BCG-vaccinated children was not associated with age at vaccination (P =.17) [39].
  • The positive association between measles and atopy was evident at all ages, in both urban and rural dwellers, and among subjects with many or few contacts at home or in day care [40].
  • In a prenatally randomised, controlled study 120 infants with family history of atopy and high (greater than 0.5 kU/l) cord-blood concentrations of total IgE were allocated randomly to prophylactic and control groups [41].


  1. Expression of Fc receptors for IgG during acute and chronic cutaneous inflammation in atopic dermatitis. Kiekens, R.C., Thepen, T., Bihari, I.C., Knol, E.F., Van De Winkel, J.G., Bruijnzeel-Koomen, C.A. Br. J. Dermatol. (2000) [Pubmed]
  2. Association between atopy and variants of the beta subunit of the high-affinity immunoglobulin E receptor. Shirakawa, T., Li, A., Dubowitz, M., Dekker, J.W., Shaw, A.E., Faux, J.A., Ra, C., Cookson, W.O., Hopkin, J.M. Nat. Genet. (1994) [Pubmed]
  3. A 2.8 Mb YAC contig in 11q12-q13 localizes candidate genes for atopy: Fc epsilon RI beta and CD20. Stafford, A.N., Rider, S.H., Hopkin, J.M., Cookson, W.O., Monaco, A.P. Hum. Mol. Genet. (1994) [Pubmed]
  4. Atopy and airways responsiveness in chronic obstructive pulmonary disease. Weiss, S.T. N. Engl. J. Med. (1987) [Pubmed]
  5. The inverse association between tuberculin responses and atopic disorder. Shirakawa, T., Enomoto, T., Shimazu, S., Hopkin, J.M. Science (1997) [Pubmed]
  6. Stress and atopic disorders. Wright, R.J. J. Allergy Clin. Immunol. (2005) [Pubmed]
  7. Prenatal farm exposure is related to the expression of receptors of the innate immunity and to atopic sensitization in school-age children. Ege, M.J., Bieli, C., Frei, R., van Strien, R.T., Riedler, J., Ublagger, E., Schram-Bijkerk, D., Brunekreef, B., van Hage, M., Scheynius, A., Pershagen, G., Benz, M.R., Lauener, R., von Mutius, E., Braun-Fahrländer, C., The Parsifal Study Team, n.u.l.l. J. Allergy Clin. Immunol. (2006) [Pubmed]
  8. Brittle asthma. Ayres, J.G., Miles, J.F., Barnes, P.J. Thorax (1998) [Pubmed]
  9. Association between alcohol consumption and aeroallergen sensitization in Danish adults. Linneberg, A., Hertzum, I., Husemoen, L.L., Johansen, N., Jørgensen, T. Clin. Exp. Allergy (2006) [Pubmed]
  10. Allergies and the risk of pancreatic cancer: a meta-analysis with review of epidemiology and biological mechanisms. Gandini, S., Lowenfels, A.B., Jaffee, E.M., Armstrong, T.D., Maisonneuve, P. Cancer Epidemiol. Biomarkers Prev. (2005) [Pubmed]
  11. Molecular genetics of allergic diseases. Ono, S.J. Annu. Rev. Immunol. (2000) [Pubmed]
  12. Positional cloning of a quantitative trait locus on chromosome 13q14 that influences immunoglobulin E levels and asthma. Zhang, Y., Leaves, N.I., Anderson, G.G., Ponting, C.P., Broxholme, J., Holt, R., Edser, P., Bhattacharyya, S., Dunham, A., Adcock, I.M., Pulleyn, L., Barnes, P.J., Harper, J.I., Abecasis, G., Cardon, L., White, M., Burton, J., Matthews, L., Mott, R., Ross, M., Cox, R., Moffatt, M.F., Cookson, W.O. Nat. Genet. (2003) [Pubmed]
  13. Gene polymorphism in Netherton and common atopic disease. Walley, A.J., Chavanas, S., Moffatt, M.F., Esnouf, R.M., Ubhi, B., Lawrence, R., Wong, K., Abecasis, G.R., Jones, E.Y., Harper, J.I., Hovnanian, A., Cookson, W.O. Nat. Genet. (2001) [Pubmed]
  14. A susceptibility locus for asthma-related traits on chromosome 7 revealed by genome-wide scan in a founder population. Laitinen, T., Daly, M.J., Rioux, J.D., Kauppi, P., Laprise, C., Petäys, T., Green, T., Cargill, M., Haahtela, T., Lander, E.S., Laitinen, L.A., Hudson, T.J., Kere, J. Nat. Genet. (2001) [Pubmed]
  15. Infantile agammaglobulinemia and immediate hypersensitivity to penicillin G. Ganier, M., Lieberman, P. JAMA (1977) [Pubmed]
  16. Is benzoic acid really harmful in cases of atopy and urticaria? Lahti, A., Hannuksela, M. Lancet (1981) [Pubmed]
  17. Altered prostaglandin E2 regulation of cytokine production in atopic dermatitis. Chan, S.C., Kim, J.W., Henderson, W.R., Hanifin, J.M. J. Immunol. (1993) [Pubmed]
  18. Effects of dog ownership and genotype on immune development and atopy in infancy. Gern, J.E., Reardon, C.L., Hoffjan, S., Nicolae, D., Li, Z., Roberg, K.A., Neaville, W.A., Carlson-Dakes, K., Adler, K., Hamilton, R., Anderson, E., Gilbertson-White, S., Tisler, C., Dasilva, D., Anklam, K., Mikus, L.D., Rosenthal, L.A., Ober, C., Gangnon, R., Lemanske, R.F. J. Allergy Clin. Immunol. (2004) [Pubmed]
  19. A cluster of anaphylactic reactions in children with spina bifida during general anesthesia: epidemiologic features, risk factors, and latex hypersensitivity. Kelly, K.J., Pearson, M.L., Kurup, V.P., Havens, P.L., Byrd, R.S., Setlock, M.A., Butler, J.C., Slater, J.E., Grammer, L.C., Resnick, A. J. Allergy Clin. Immunol. (1994) [Pubmed]
  20. Localisation of atopy and beta subunit of high-affinity IgE receptor (Fc epsilon RI) on chromosome 11q. Sandford, A.J., Shirakawa, T., Moffatt, M.F., Daniels, S.E., Ra, C., Faux, J.A., Young, R.P., Nakamura, Y., Lathrop, G.M., Cookson, W.O. Lancet (1993) [Pubmed]
  21. Polymorphisms in the Fc epsilon RI beta promoter region affecting transcription activity: a possible promoter-dependent mechanism for association between Fc epsilon RI beta and atopy. Nishiyama, C., Akizawa, Y., Nishiyama, M., Tokura, T., Kawada, H., Mitsuishi, K., Hasegawa, M., Ito, T., Nakano, N., Okamoto, A., Takagi, A., Yagita, H., Okumura, K., Ogawa, H. J. Immunol. (2004) [Pubmed]
  22. The association of atopy with a gain-of-function mutation in the alpha subunit of the interleukin-4 receptor. Hershey, G.K., Friedrich, M.F., Esswein, L.A., Thomas, M.L., Chatila, T.A. N. Engl. J. Med. (1997) [Pubmed]
  23. Transfer of allergen-specific IgE-mediated hypersensitivity with allogeneic bone marrow transplantation. Agosti, J.M., Sprenger, J.D., Lum, L.G., Witherspoon, R.P., Fisher, L.D., Storb, R., Henderson, W.R. N. Engl. J. Med. (1988) [Pubmed]
  24. A role for the C3a anaphylatoxin receptor in the effector phase of asthma. Humbles, A.A., Lu, B., Nilsson, C.A., Lilly, C., Israel, E., Fujiwara, Y., Gerard, N.P., Gerard, C. Nature (2000) [Pubmed]
  25. Allergy and immunology. Smith, D.L., deShazo, R.D. JAMA (1994) [Pubmed]
  26. Linkage of high-affinity IgE receptor gene with bronchial hyperreactivity, even in absence of atopy. van Herwerden, L., Harrap, S.B., Wong, Z.Y., Abramson, M.J., Kutin, J.J., Forbes, A.B., Raven, J., Lanigan, A., Walters, E.H. Lancet (1995) [Pubmed]
  27. Dietary vitamin E, IgE concentrations, and atopy. Fogarty, A., Lewis, S., Weiss, S., Britton, J. Lancet (2000) [Pubmed]
  28. Are all wheezing disorders in very young (preschool) children increasing in prevalence? Kuehni, C.E., Davis, A., Brooke, A.M., Silverman, M. Lancet (2001) [Pubmed]
  29. Prevalence of latex-specific IgE antibodies in atopic and nonatopic children with type I diabetes. Danne, T., Niggemann, B., Weber, B., Wahn, U. Diabetes Care (1997) [Pubmed]
  30. Lack of association of atopy/asthma and the interleukin-4 receptor alpha gene in Japanese. Noguchi, E., Shibasaki, M., Arinami, T., Takeda, K., Yokouchi, Y., Kobayashi, K., Imoto, N., Nakahara, S., Matsui, A., Hamaguchi, H. Clin. Exp. Allergy (1999) [Pubmed]
  31. Association between farm exposure and atopy, according to the CD14 C-159T polymorphism. Leynaert, B., Guilloud-Bataille, M., Soussan, D., Benessiano, J., Guénégou, A., Pin, I., Neukirch, F. J. Allergy Clin. Immunol. (2006) [Pubmed]
  32. Polymorphism at the glutathione S-transferase GSTP1 locus. A new marker for bronchial hyperresponsiveness and asthma. Fryer, A.A., Bianco, A., Hepple, M., Jones, P.W., Strange, R.C., Spiteri, M.A. Am. J. Respir. Crit. Care Med. (2000) [Pubmed]
  33. Genetic polymorphisms at FCER1B and PAI-1 and asthma susceptibility. Hizawa, N., Maeda, Y., Konno, S., Fukui, Y., Takahashi, D., Nishimura, M. Clin. Exp. Allergy (2006) [Pubmed]
  34. Overactivation of IL-4-induced activator protein-1 in atopic dermatitis. Yamazaki, F., Aragane, Y., Maeda, A., Matsushita, K., Ueno, K., Yudate, T., Kawada, A., Tezuka, T. J. Dermatol. Sci. (2002) [Pubmed]
  35. Gene-gene interaction in asthma: IL4RA and IL13 in a Dutch population with asthma. Howard, T.D., Koppelman, G.H., Xu, J., Zheng, S.L., Postma, D.S., Meyers, D.A., Bleecker, E.R. Am. J. Hum. Genet. (2002) [Pubmed]
  36. The IL12B gene is associated with asthma. Randolph, A.G., Lange, C., Silverman, E.K., Lazarus, R., Silverman, E.S., Raby, B., Brown, A., Ozonoff, A., Richter, B., Weiss, S.T. Am. J. Hum. Genet. (2004) [Pubmed]
  37. CC chemokine ligand 18, an atopic dermatitis-associated and dendritic cell-derived chemokine, is regulated by staphylococcal products and allergen exposure. Pivarcsi, A., Gombert, M., Dieu-Nosjean, M.C., Lauerma, A., Kubitza, R., Meller, S., Rieker, J., Muller, A., Da Cunha, L., Haahtela, A., Sonkoly, E., Fridman, W.H., Alenius, H., Kemeny, L., Ruzicka, T., Zlotnik, A., Homey, B. J. Immunol. (2004) [Pubmed]
  38. Idiopathic anaphylactoid reactions. A clinical summary. Sale, S.R., Greenberger, P.A., Patterson, R. JAMA (1981) [Pubmed]
  39. BCG vaccination and risk of atopy. Krause, T.G., Hviid, A., Koch, A., Friborg, J., Hjuler, T., Wohlfahrt, J., Olsen, O.R., Kristensen, B., Melbye, M. JAMA (2003) [Pubmed]
  40. Measles history and atopic diseases: a population-based cross-sectional study. Paunio, M., Heinonen, O.P., Virtanen, M., Leinikki, P., Patja, A., Peltola, H. JAMA (2000) [Pubmed]
  41. Effect of allergen avoidance on development of allergic disorders in infancy. Arshad, S.H., Matthews, S., Gant, C., Hide, D.W. Lancet (1992) [Pubmed]
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