Atopic dermatitis is a common inflammatory skin disease caused by interaction of genetic and environmental factors. On the basis of data from a genome-wide association study (GWAS) and a validation study comprising a total of 3,328 subjects with atopic dermatitis and 14,992 controls in the Japanese population, we report here 8 new susceptibility loci: IL1RL1-IL18R1-IL18RAP (Pcombined = 8.36 × 10−18), the major histocompatibility complex (MHC) region (P = 8.38 × 10−20), OR10A3-NLRP10 (P = 1.54 × 10−22), GLB1 (P = 2.77 × 10−16), CCDC80 (P = 1.56 × 10−19), CARD11 (P = 7.83 × 10−9), ZNF365 (P = 5.85 × 10−20) and CYP24A1-PFDN4 (P = 1.65 × 10−8). We also replicated the associations of the FLG, C11orf30, TMEM232-SLC25A46, TNFRSF6B-ZGPAT, OVOL1, ACTL9 and KIF3A-IL13 loci that were previously reported in GWAS of European and Chinese individuals and a meta-analysis of GWAS for atopic dermatitis. These findings advance the understanding of the genetic basis of atopic dermatitis.
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Bieber, T. Mechanisms of disease: atopic dermatitis. N. Engl. J. Med. 358, 1483–1494 (2008).
Boguniewicz, M. & Leung, D.Y. Recent insights into atopic dermatitis and implications for management of infectious complications. J. Allergy Clin. Immunol. 125, 4–13 (2010).
Palmer, C.N. et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat. Genet. 38, 441–446 (2006).
Irvine, A.D., McLean, W.H. & Leung, D.Y. Filaggrin mutations associated with skin and allergic diseases. N. Engl. J. Med. 365, 1315–1327 (2011).
Esparza-Gordillo, J. et al. A common variant on chromosome 11q13 is associated with atopic dermatitis. Nat. Genet. 41, 596–601 (2009).
Sun, L.D. et al. Genome-wide association study identifies two new susceptibility loci for atopic dermatitis in the Chinese Han population. Nat. Genet. 43, 690–694 (2011).
Paternoster, L. et al. Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis. Nat. Genet. 44, 187–192 (2012).
Johnston, A. et al. IL-1F5, -F6, -F8, and -F9: a novel IL-1 family signaling system that is active in psoriasis and promotes keratinocyte antimicrobial peptide expression. J. Immunol. 186, 2613–2622 (2011).
Liew, F.Y., Pitman, N.I. & McInnes, I.B. Disease-associated functions of IL-33: the new kid in the IL-1 family. Nat. Rev. Immunol. 10, 103–110 (2010).
Moffatt, M.F. et al. A large-scale, consortium-based genomewide association study of asthma. N. Engl. J. Med. 363, 1211–1221 (2010).
Torgerson, D.G. et al. Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations. Nat. Genet. 43, 887–892 (2011).
Horton, R. et al. Gene map of the extended human MHC. Nat. Rev. Genet. 5, 889–899 (2004).
Altrichter, S. et al. Serum IgE autoantibodies target keratinocytes in patients with atopic dermatitis. J. Invest. Dermatol. 128, 2232–2239 (2008).
Magalhaes, J.G. et al. What is new with Nods? Curr. Opin. Immunol. 23, 29–34 (2011).
Imamura, R. et al. Anti-inflammatory activity of PYNOD and its mechanism in humans and mice. J. Immunol. 184, 5874–5884 (2010).
Vestergaard, C. et al. A Th2 chemokine, TARC, produced by keratinocytes may recruit CLA+CCR4+ lymphocytes into lesional atopic dermatitis skin. J. Invest. Dermatol. 115, 640–646 (2000).
Tremblay, F. et al. Bidirectional modulation of adipogenesis by the secreted protein Ccdc80/DRO1/URB. J. Biol. Chem. 284, 8136–8147 (2009).
Lopez, R.G. et al. C/EBPα and β couple interfollicular keratinocyte proliferation arrest to commitment and terminal differentiation. Nat. Cell Biol. 11, 1181–1190 (2009).
Jung, K. et al. Peroxisome proliferator-activated receptor γ–mediated suppression of dendritic cell function prevents the onset of atopic dermatitis in NC/Tnd mice. J. Allergy Clin. Immunol. 127, 420–429 (2011).
Hara, H. et al. Cell type–specific regulation of ITAM-mediated NF-κB activation by the adaptors, CARMA1 and CARD9. J. Immunol. 181, 918–930 (2008).
Blonska, M. et al. CARMA1 controls Th2 cell–specific cytokine expression through regulating JunB and GATA3 transcription factors. J. Immunol. 188, 3160–3168 (2012).
Jun, J.E. et al. Identifying the MAGUK protein Carma-1 as a central regulator of humoral immune responses and atopy by genome-wide mouse mutagenesis. Immunity 18, 751–762 (2003).
Safford, M. et al. Egr-2 and Egr-3 are negative regulators of T cell activation. Nat. Immunol. 6, 472–480 (2005).
Hart, P.H., Gorman, S. & Finlay-Jones, J.J. Modulation of the immune system by UV radiation: more than just the effects of vitamin D? Nat. Rev. Immunol. 11, 584–596 (2011).
Peroni, D.G. et al. Correlation between serum 25–hydroxyvitamin D levels and severity of atopic dermatitis in children. Br. J. Dermatol. 164, 1078–1082 (2011).
Wang, R. et al. Expression of GARP selectively identifies activated human FOXP3+ regulatory T cells. Proc. Natl. Acad. Sci. USA 106, 13439–13444 (2009).
Spergel, J.M. & Paller, A.S. Atopic dermatitis and the atopic march. J. Allergy Clin. Immunol. 112, S118–S127 (2003).
Hirota, T. et al. Genome-wide association study identifies three new susceptibility loci for adult asthma in the Japanese population. Nat. Genet. 43, 893–896 (2011).
Ferreira, M.A. et al. Identification of IL6R and chromosome 11q13.5 as risk loci for asthma. Lancet 378, 1006–1014 (2011).
Ramasamy, A. et al. A genome-wide meta-analysis of genetic variants associated with allergic rhinitis and grass sensitization and their interaction with birth order. J. Allergy Clin. Immunol. 128, 996–1005 (2011).
Hanifin, J.M. & Rajka, R.G. Diagnostic features of atopic dermatitis. Acta Derm. (Stockholm) 92 (suppl. 92), 44–47 (1980).
Nakamura, Y. The BioBank Japan Project. Clin. Adv. Hematol. Oncol. 5, 696–697 (2007).
Takata, R. et al. Genome-wide association study identifies five new susceptibility loci for prostate cancer in the Japanese population. Nat. Genet. 42, 751–754 (2010).
Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).
Breslow, N.E. & Day, N.E. Statistical methods in cancer research. Volume II—the design and analysis of cohort studies. IARC Sci. Publ. 1–406 (1987).
Pruim, R.J. et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26, 2336–2337 (2010).
Li, Y. et al. MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet. Epidemiol. 34, 816–834 (2010).
Li, Y. et al. Genotype imputation. Annu. Rev. Genomics Hum. Genet. 10, 387–406 (2009).
1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010).
We thank all the individuals who participated in the study and also thank the collaborating physicians for helping with sample collection. We are grateful to the members of BioBank Japan and the Rotary Club of Osaka-Midosuji District 2660 Rotary International in Japan for supporting our study. We thank M.T. Shimizu, H. Sekiguchi, A.I. Jodo, N. Kawaraichi and the technical staff of the Center for Genomic Medicine for providing technical assistance and K. Barrymore for proofreading this manuscript. This work was conducted as part of the BioBank Japan Project, which is supported by the Ministry of Education, Culture, Sports, Science and Technology, Japan. This work was also partly supported by grants from the Ministry of Health, Labour and Welfare, Japan.
The authors declare no competing financial interests.
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Hirota, T., Takahashi, A., Kubo, M. et al. Genome-wide association study identifies eight new susceptibility loci for atopic dermatitis in the Japanese population. Nat Genet 44, 1222–1226 (2012). https://doi.org/10.1038/ng.2438
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