Analysis of the high affinity IgE receptor genes reveals epistatic effects of FCER1A variants on eczema risk

[en] To cite this article: Mahachie John JM, Baurecht H, Rodriguez E, Naumann A, Wagenpfeil S, Klopp N, Mempel M, Novak N, Bieber T, Wichmann H-E, Ring J, Illig T, Cattaert T, Van Steen K, Weidinger S. Analysis of the high-affinity IgE receptor genes reveals epistatic effects of FCER1A variants on total IgE levels and eczema risk. Allergy 2009; DOI: 10.1111/j.1398-9995.2009.02297.x. Abstract Background: High levels of total and allergen-specific IgE levels are a key feature in allergic diseases. The high-affinity receptor for IgE, which is composed of one alpha (FCER1A), one beta (FCER1B), and two gamma (FCER1G) subunits, represents the central receptor of IgE-induced reactions. In a genome-wide association scan, we recently identified associations between functional FCER1A variants and total serum IgE levels. Previous studies had reported linkage and association of FCER1B variants with IgE and atopic traits. The FCER1G gene has not yet been investigated with regard to atopy. Filaggrin (FLG) is the strongest known risk gene for eczema, in particular the allergic subtype of eczema. Methods: We investigated the association of FCER1A, FCER1B, and FCER1G variants with IgE in a large population-based cohort (n = 4261) and tested for epistatic effects using the model-based multifactor dimensionality reduction (MB-MDR) method. In addition, we investigated a potential interaction between FLG and FCER1A variants in a large collection of eczema cases (n = 1018) and population controls. Results: Three strongly correlated FCER1A polymorphisms were significantly associated with total and specific IgE levels as well as allergic sensitization. No associations were seen for FCER1B and FCER1G. After adjustment for FLG effects, a significant epistatic effect of the FCER1A variants rs10489854 and rs2511211 on eczema risk was detected. Conclusions: These results suggest that FCER1A variants by themselves and in combination influence IgE levels and act synergistically to influence eczema risk.

Disciplines :

Cardiovascular & respiratory systems
Genetics & genetic processes

Author, co-author :

Mahachie John, Jestinah ; Université de Liège - ULiège > Dép. d'électric., électron. et informat. (Inst.Montefiore) > Bioinformatique

Baurecht, H.

Rodriguez, E.

Naumann, A.

Wagenpfeil, S.

Klopp, N.

Mempel, M.

Novak, N.

Bieber, T.

Wichmann, H. E.

More authors (5 more)

Language :

English

Title :

Analysis of the high affinity IgE receptor genes reveals epistatic effects of FCER1A variants on eczema risk

Publication date :

2010

Journal title :

Allergy

ISSN :

0105-4538

eISSN :

1398-9995

Publisher :

Blackwell Publishing, Oxford, United Kingdom

Volume :

Issue :

Pages :

875-882

Peer reviewed :

Peer Reviewed verified by ORBi

Commentary :

2009/12/24

Available on ORBi :

since 18 May 2010

Statistics

Number of views

96 (12 by ULiège)

Number of downloads

1 (0 by ULiège)

More statistics

Scopus citations^®

Scopus citations^®
without self-citations

OpenCitations

Bibliography

Brown SJ, McLean WH. Eczema genetics: current state of knowledge and future goals. J Invest Dermatol 2009 129 : 543 552.
Vercelli D. Discovering susceptibility genes for asthma and allergy. Nat Rev Immunol 2008 8 : 169 182.
Gould HJ, Sutton BJ. IgE in allergy and asthma today. Nat Rev Immunol 2008 8 : 205 217.
Geha RS, Jabara HH, Brodeur SR. The regulation of immunoglobulin E class-switch recombination. Nat Rev Immunol 2003 3 : 721 732.
Jacobsen HP, Herskind AM, Nielsen BW, Husby S. IgE in unselected like-sexed monozygotic and dizygotic twins at birth and at 6 to 9 years of age: high but dissimilar genetic influence on IgE levels. J Allergy Clin Immunol 2001 107 : 659 663.
Strachan DP, Wong HJ, Spector TD. Concordance and interrelationship of atopic diseases and markers of allergic sensitization among adult female twins. J Allergy Clin Immunol 2001 108 : 901 907.
Gibson G. Decanalization and the origin of complex disease. Nat Rev Genet 2009 10 : 134 140.
Gieger C, Geistlinger L, Altmaier E, Hrabe de Angelis M, Kronenberg F, Meitinger T et al. Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum. PLoS Genet 2008 4 : e1000282.
Frankel WN, Schork NJ. Who's afraid of epistasis? Nat Genet 1996 14 : 371 373.
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.
Rodriguez E, Baurecht H, Herberich E, Wagenpfeil S, Brown SJ, Cordell HJ et al. Meta-analysis of filaggrin polymorphisms in eczema and asthma: robust risk factors in atopic disease. J Allergy Clin Immunol 2009 123 : 1361 1370 e7.
Bieber T. Atopic dermatitis. N Engl J Med 2008 358 : 1483 1494.
Esparza-Gordillo J, Weidinger S, Folster-Holst R, Bauerfeind A, Ruschendorf F, Patone G et al. A common variant on chromosome 11q13 is associated with atopic dermatitis. Nat Genet 2009 41 : 596 601.
Wichmann HE, Gieger C, Illig T. KORA-gen - resource for population genetics, controls and a broad spectrum of disease phenotypes. Gesundheitswesen 2005 67 (Suppl. 1 S26 S30.
Holle R, Happich M, Lowel H, Wichmann HE. KORA - a research platform for population based health research. Gesundheitswesen 2005 67 (Suppl. 1 S19 S25.
Burney PG, Luczynska C, Chinn S, Jarvis D. The European Community Respiratory Health Survey. Eur Respir J 1994 7 : 954 960.
Williams HC, Burney PG, Hay RJ, Archer CB, Shipley MJ, Hunter JJ et al. The U.K. Working Party's Diagnostic Criteria for Atopic Dermatitis. I. Derivation of a minimum set of discriminators for atopic dermatitis. Br J Dermatol 1994 131 : 383 396.
Bae JS, Kim SH, Ye YM, Yoon HJ, Suh CH, Nahm DH et al. Significant association of FcepsilonRIalpha promoter polymorphisms with aspirin-intolerant chronic urticaria. J Allergy Clin Immunol 2007 119 : 449 456.
Traherne JA, Hill MR, Hysi P, D'Amato M, Broxholme J, Mott R et al. LD mapping of maternally and non-maternally derived alleles and atopy in FcepsilonRI-beta. Hum Mol Genet 2003 12 : 2577 2585.
Calle ML, Urrea V, Vellalta G, Malats N, Steen KV. Improving strategies for detecting genetic patterns of disease susceptibility in association studies. Stat Med 2008 27 : 6532 6546.
Calle ML, Urrea V, Mallats N, van Steen K. MB-MDR: model-based multifactor dimensionality reduction for detecting interactions in high-dimensional genomic data.
Westfall PH, Young SS. Resampling-based Multiple Testing.
Strobl C, Boulesteix AL, Zeileis A, Hothorn T. Bias in random forest variable importance measures: illustrations, sources and a solution. BMC Bioinformatics 2007 8 : 25.
Team RDC. R: a language and environment for statistical computing.
Burrows B, Martinez FD, Halonen M, Barbee RA, Cline MG. Association of asthma with serum IgE levels and skin-test reactivity to allergens. N Engl J Med 1989 320 : 271 277.
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 64 : 1327 1332.
Kraft S, Kinet JP. New developments in FcepsilonRI regulation, function and inhibition. Nat Rev Immunol 2007 7 : 365 378.
Cookson WO, Young RP, Sandford AJ, Moffatt MF, Shirakawa T, Sharp PA et al. Maternal inheritance of atopic IgE responsiveness on chromosome 11q. Lancet 1992 340 : 381 384.
Maier LM, Howson JM, Walker N, Spickett GP, Jones RW, Ring SM et al. Association of IL13 with total IgE: evidence against an inverse association of atopy and diabetes. J Allergy Clin Immunol 2006 117 : 1306 1313.
Moore JH. A global view of epistasis. Nat Genet 2005 37 : 13 14.
Phillips PC. Epistasis - the essential role of gene interactions in the structure and evolution of genetic systems. Nat Rev Genet 2008 9 : 855 867.
Carlborg O, Haley CS. Epistasis: too often neglected in complex trait studies? Nat Rev Genet 2004 5 : 618 625.
Moore JH. The ubiquitous nature of epistasis in determining susceptibility to common human diseases. Hum Hered 2003 56 : 73 82.
Ritchie MD, Hahn LW, Roodi N, Bailey LR, Dupont WD, Parl FF et al. Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer. Am J Hum Genet 2001 69 : 138 147.