The Genetics and Epigenetics of Atopic Dermatitis—Filaggrin and Other Polymorphisms

Clinical Reviews in Allergy and Immunology

Volumn 51, Issue 3, 2016, Pages 315-328

  Liang, Yunsheng ^a   Chang, Christopher ^b   Lu, Qianjin ^a  

^a CENTRAL SOUTH UNIVERSITY   (China)

^b UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

Atopic dermatitis; Epidermal barrier; Epigenetics; Filaggrin; Genetics; Polymorphism

Indexed keywords

FILAGGRIN; INTERLEUKIN 1; INTERLEUKIN 13; INTERLEUKIN 31; INTERLEUKIN 4; INTERLEUKIN 5; MICRORNA; NERVE GROWTH FACTOR; PATTERN RECOGNITION RECEPTOR; POLYPEPTIDE ANTIBIOTIC AGENT; THYMIC STROMAL LYMPHOPOIETIN; VITAMIN D; CYTOKINE; CYTOKINE RECEPTOR; INTERMEDIATE FILAMENT PROTEIN;

ADAPTIVE IMMUNITY; ATOPIC DERMATITIS; DNA METHYLATION; ENVIRONMENTAL FACTOR; EPIGENETICS; FCERIA GENE; FLG GENE; GENE; GENE LOCUS; GENE MUTATION; GENETIC POLYMORPHISM; GENETIC SUSCEPTIBILITY; GENETIC VARIABILITY; GENETICS; GENOME-WIDE ASSOCIATION STUDY; HUMAN; HYGIENE; INDUSTRIALIZATION; INFLAMMATION; INNATE IMMUNITY; LIFESTYLE; NONHUMAN; PATHOGENESIS; REGULATORY T LYMPHOCYTE; REVIEW; SIGNAL TRANSDUCTION; SPINK5 GENE; WESTERN DIET; ANIMAL; CYTOLOGY; ENVIRONMENT; EPIDERMIS; GENETIC ASSOCIATION STUDY; GENETIC EPIGENESIS; GENETIC PREDISPOSITION; GENOTYPE ENVIRONMENT INTERACTION; IMMUNE SYSTEM; IMMUNOLOGY; METABOLISM; MUTATION; PATHOLOGY;

ANIMALS; CYTOKINES; DERMATITIS, ATOPIC; ENVIRONMENT; EPIDERMIS; EPIGENESIS, GENETIC; GENE-ENVIRONMENT INTERACTION; GENETIC ASSOCIATION STUDIES; GENETIC PREDISPOSITION TO DISEASE; GENOME-WIDE ASSOCIATION STUDY; HUMANS; IMMUNE SYSTEM; INTERMEDIATE FILAMENT PROTEINS; MUTATION; POLYMORPHISM, GENETIC; RECEPTORS, CYTOKINE;

EID: 84942036132     PISSN: 10800549     EISSN: 15590267     Source Type: Journal    
DOI: 10.1007/s12016-015-8508-5     Document Type: Review

References (174)

1. Bieber T (2008) Atopic dermatitis. N Engl J Med 358:1483–1494
2. Esparza-Gordillo J, Weidinger S, Folster-Holst R et al (2009) A common variant on chromosome 11q13 is associated with atopic dermatitis. Nat Genet 41:596–601
3. Sun LD, Xiao FL, Li Y et al (2011) Genome-wide association study identifies two new susceptibility loci for atopic dermatitis in the Chinese Han population. Nat Genet 43:690–694
4. Paternoster L, Standl M, Chen CM et al (2011) Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis. Nat Genet 44:187–192
5. Hirota T, Takahashi A, Kubo M et al (2012) Genome-wide association study identifies eight new susceptibility loci for atopic dermatitis in the Japanese population. Nat Genet 44:1222–1226
6. Ellinghaus D, Baurecht H, Esparza-Gordillo J et al (2013) High-density genotyping study identifies four new susceptibility loci for atopic dermatitis. Nat Genet 45:808–812
7. Mu Z, Zhao Y, Liu X, Chang C, Zhang J (2014) Molecular biology of atopic dermatitis. Clin Rev Allergy Immunol 47:193–218
8. Morales Suarez-Varela M, Garcia-Marcos L, Kogan MD et al (2008) Parents’ smoking habit and prevalence of atopic eczema in 6-7 and 13-14 year-old schoolchildren in Spain. ISAAC phase III. Allergol Immunopathol (Madr) 36:336–342
9. Leung DY, Bieber T (2003) Atopic dermatitis. Lancet 361:151–160
10. Schafer T, Heinrich J, Wjst M et al (1999) Indoor risk factors for atopic eczema in school children from East Germany. Environ Res 81:151–158
11. Wang IJ, Chen SL, Lu TP, Chuang EY, Chen PC (2013) Prenatal smoke exposure, DNA methylation, and childhood atopic dermatitis. Clin Exp Allergy 43:535–543
12. Jirtle RL, Skinner MK (2007) Environmental epigenomics and disease susceptibility. Nat Rev Genet 8:253–262
13. Feil R, Fraga MF (2012) Epigenetics and the environment: emerging patterns and implications. Nat Rev Genet 13:97–109
14. Herberth G, Bauer M, Gasch M et al (2014) Maternal and cord blood miR-223 expression associates with prenatal tobacco smoke exposure and low regulatory T-cell numbers. J Allergy Clin Immunol 133:543–550
15. Hinz D, Bauer M, Roder S et al (2012) Cord blood Tregs with stable FOXP3 expression are influenced by prenatal environment and associated with atopic dermatitis at the age of one year. Allergy 67:380–389
16. Rodriguez E, Baurecht H, Wahn AF et al (2014) An integrated epigenetic and transcriptomic analysis reveals distinct tissue-specific patterns of DNA methylation associated with atopic dermatitis. J Investig Dermatol 134:1873–1883
17. Tezza G, Mazzei F, Boner A (2013) Epigenetics of allergy. Early Hum Dev 89(Suppl 1):S20–S21
18. Sharma S, Litonjua A (2014) Asthma, allergy, and responses to methyl donor supplements and nutrients. J Allergy Clin Immunol 133:1246–1254
19. Sandilands A, Sutherland C, Irvine AD, McLean WH (2009) Filaggrin in the frontline: role in skin barrier function and disease. J Cell Sci 122:1285–1294
20. Brown SJ, McLean WH (2012) One remarkable molecule: filaggrin. J Investig Dermatol 132:751–762
21. McAleer MA, Irvine AD (2013) The multifunctional role of filaggrin in allergic skin disease. J Allergy Clin Immunol 131:280–291
22. Irvine AD, McLean WH, Leung DY (2011) Filaggrin mutations associated with skin and allergic diseases. N Engl J Med 365:1315–1327
23. Elias PM, Wakefield JS (2014) Mechanisms of abnormal lamellar body secretion and the dysfunctional skin barrier in patients with atopic dermatitis. J Allergy Clin Immunol 134:781–791
24. Palmer CN, Irvine AD, Terron-Kwiatkowski A et al (2006) Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet 38:441–446
25. Rodriguez E, Baurecht H, Herberich E et al (2009) Meta-analysis of filaggrin polymorphisms in eczema and asthma: robust risk factors in atopic disease. J Allergy Clin Immunol 123:1361–1370
26. van den Oord RA, Sheikh A (2009) Filaggrin gene defects and risk of developing allergic sensitisation and allergic disorders: systematic review and meta-analysis. BMJ 339:b2433
27. Brown SJ, McLean WH (2009) Eczema genetics: current state of knowledge and future goals. J Investig Dermatol 129:543–552
28. Brown SJ, Sandilands A, Zhao Y et al (2008) Prevalent and low-frequency null mutations in the filaggrin gene are associated with early-onset and persistent atopic eczema. J Investig Dermatol 128:1591–1594
29. Margolis DJ, Apter AJ, Gupta J et al (2012) The persistence of atopic dermatitis and filaggrin (FLG) mutations in a US longitudinal cohort. J Allergy Clin Immunol 130:912–917
30. Weidinger S, Rodriguez E, Stahl C et al (2007) Filaggrin mutations strongly predispose to early-onset and extrinsic atopic dermatitis. J Investig Dermatol 127:724–726
31. Gao PS, Rafaels NM, Hand T et al (2009) Filaggrin mutations that confer risk of atopic dermatitis confer greater risk for eczema herpeticum. J Allergy Clin Immunol 124:507–513, 513 e501-507
32. Weidinger S, O’Sullivan M, Illig T et al (2008) Filaggrin mutations, atopic eczema, hay fever, and asthma in children. J Allergy Clin Immunol 121:1203–1209
33. Palmer CN, Ismail T, Lee SP et al (2007) Filaggrin null mutations are associated with increased asthma severity in children and young adults. J Allergy Clin Immunol 120:64–68
34. Brown SJ, Asai Y, Cordell HJ et al (2011) Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy. J Allergy Clin Immunol 127:661–667
35. Henderson J, Northstone K, Lee SP et al (2008) The burden of disease associated with filaggrin mutations: a population-based, longitudinal birth cohort study. J Allergy Clin Immunol 121:872–877
36. O’Regan GM, Kemperman PM, Sandilands A et al (2008) Raman profiles of the stratum corneum define 3 filaggrin genotype-determined atopic dermatitis endophenotypes. J Allergy Clin Immunol 126:574–580
37. Kezic S, O’Regan GM, Lutter R et al (2012) Filaggrin loss-of-function mutations are associated with enhanced expression of IL-1 cytokines in the stratum corneum of patients with atopic dermatitis and in a murine model of filaggrin deficiency. J Allergy Clin Immunol 129:1031–1039
38. Murphy JE, Robert C, Kupper TS (2000) Interleukin-1 and cutaneous inflammation: a crucial link between innate and acquired immunity. J Investig Dermatol 114:602–608
39. Brown SJ, Kroboth K, Sandilands A et al (2012) Intragenic copy number variation within filaggrin contributes to the risk of atopic dermatitis with a dose-dependent effect. J Investig Dermatol 132:98–104
40. Walley AJ, Chavanas S, Moffatt MF et al (2001) Gene polymorphism in Netherton and common atopic disease. Nat Genet 29:175–178
41. Hachem JP, Wagberg F, Schmuth M et al (2006) Serine protease activity and residual LEKTI expression determine phenotype in Netherton syndrome. J Investig Dermatol 126:1609–1621
42. Nishio Y, Noguchi E, Shibasaki M et al (2003) Association between polymorphisms in the SPINK5 gene and atopic dermatitis in the Japanese. Genes Immun 4:515–517
43. Kusunoki T, Okafuji I, Yoshioka T et al (2005) SPINK5 polymorphism is associated with disease severity and food allergy in children with atopic dermatitis. J Allergy Clin Immunol 115:636–638
44. Lan CC, Tu HP, Wu CS et al (2011) Distinct SPINK5 and IL-31 polymorphisms are associated with atopic eczema and non-atopic hand dermatitis in Taiwanese nursing population. Exp Dermatol 20:975–979
45. Kato A, Fukai K, Oiso N, Hosomi N, Murakami T, Ishii M (2003) Association of SPINK5 gene polymorphisms with atopic dermatitis in the Japanese population. Br J Dermatol 148:665–669
46. Zhao LP, Di Z, Zhang L et al (2012) Association of SPINK5 gene polymorphisms with atopic dermatitis in Northeast China. J Eur Acad Dermatol Venereol 26:572–577
47. Fortugno P, Furio L, Teson M et al (2012) The 420K LEKTI variant alters LEKTI proteolytic activation and results in protease deregulation: implications for atopic dermatitis. Hum Mol Genet 21:4187–4200
48. Briot A, Deraison C, Lacroix M et al (2009) Kallikrein 5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome. J Exp Med 206:1135–1147
49. Pellerin L, Henry J, Hsu CY et al (2012) Defects of filaggrin-like proteins in both lesional and nonlesional atopic skin. J Allergy Clin Immunol 131:1094–1102
50. Makino T, Mizawa M, Yamakoshi T, Takaishi M, Shimizu T (2014) Expression of filaggrin-2 protein in the epidermis of human skin diseases: a comparative analysis with filaggrin. Biochem Biophys Res Commun 449:100–106
51. Wu Z, Hansmann B, Meyer-Hoffert U, Glaser R, Schroder JM (2009) Molecular identification and expression analysis of filaggrin-2, a member of the S100 fused-type protein family. PLoS One 4:e5227
52. Margolis DJ, Gupta J, Apter AJ et al (2014) Filaggrin-2 variation is associated with more persistent atopic dermatitis in African American subjects. J Allergy Clin Immunol 133:784–789
53. Marenholz I, Rivera VA, Esparza-Gordillo J et al (2011) Association screening in the Epidermal Differentiation Complex (EDC) identifies an SPRR3 repeat number variant as a risk factor for eczema. J Investig Dermatol 131:1644–1649
54. Kelsell DP, Byrne C (2011) SNPing at the epidermal barrier. J Investig Dermatol 131:1593–1595
55. Saunders SP, Goh CS, Brown SJ et al (2013) Tmem79/Matt is the matted mouse gene and is a predisposing gene for atopic dermatitis in human subjects. J Allergy Clin Immunol 132:1121–1129
56. Sasaki T, Shiohama A, Kubo A et al (2013) A homozygous nonsense mutation in the gene for Tmem79, a component for the lamellar granule secretory system, produces spontaneous eczema in an experimental model of atopic dermatitis. J Allergy Clin Immunol 132:1111–1120
57. De Benedetto A, Slifka MK, Rafaels NM et al (2011) Reductions in claudin-1 may enhance susceptibility to herpes simplex virus 1 infections in atopic dermatitis. J Allergy Clin Immunol 128:242–246
58. Mu Z, Zhao Y, Liu X, Chang C, Zhang J (2012) Molecular biology of atopic dermatitis. Clin Rev Allergy Immunol 47:193–218
59. Eyerich K, Novak N (2013) Immunology of atopic eczema: overcoming the Th1/Th2 paradigm. Allergy 68:974–982
60. Wollenberg A, Rawer HC, Schauber J (2008) Innate immunity in atopic dermatitis. Clin Rev Allergy Immunol 41:272–281
61. Potaczek DP, Nastalek M, Okumura K, Wojas-Pelc A, Undas A, Nishiyama C (2011) An association of TLR2-16934A >T polymorphism and severity/phenotype of atopic dermatitis. J Eur Acad Dermatol Venereol 25:715–721
62. Ahmad-Nejad P, Mrabet-Dahbi S, Breuer K et al (2004) The toll-like receptor 2 R753Q polymorphism defines a subgroup of patients with atopic dermatitis having severe phenotype. J Allergy Clin Immunol 113:565–567
63. Mrabet-Dahbi S, Dalpke AH, Niebuhr M et al (2008) The Toll-like receptor 2 R753Q mutation modifies cytokine production and Toll-like receptor expression in atopic dermatitis. J Allergy Clin Immunol 121:1013–1019
64. Niebuhr M, Lutat C, Sigel S, Werfel T (2009) Impaired TLR-2 expression and TLR-2-mediated cytokine secretion in macrophages from patients with atopic dermatitis. Allergy 64:1580–1587
65. Niebuhr M, Langnickel J, Draing C, Renz H, Kapp A, Werfel T (2008) Dysregulation of toll-like receptor-2 (TLR-2)-induced effects in monocytes from patients with atopic dermatitis: impact of the TLR-2 R753Q polymorphism. Allergy 63:728–734
66. Levchenko L, Izmailova OV, Shlykova OA, Kaidashev IP (2013) Polymorphism 896A/G of TLR4 gene rather than 1196C/T and 2258G/A of TLR2 gene determines severe and complicated course of atopic dermatitis in children. Tsitol Genet 47:46–53
67. Miedema KG, Tissing WJ, Te Poele EM et al (2005) Polymorphisms in the TLR6 gene associated with the inverse association between childhood acute lymphoblastic leukemia and atopic disease. Leukemia 26:1203–1210
68. Hoffjan S, Stemmler S, Parwez Q et al (2005) Evaluation of the toll-like receptor 6 Ser249Pro polymorphism in patients with asthma, atopic dermatitis and chronic obstructive pulmonary disease. BMC Med Genet 6:34
69. Novak N, Yu CF, Bussmann C et al (2007) Putative association of a TLR9 promoter polymorphism with atopic eczema. Allergy 62:766–772
70. Weidinger S, Klopp N, Rummler L et al (2005) Association of CARD15 polymorphisms with atopy-related traits in a population-based cohort of Caucasian adults. Clin Exp Allergy 35:866–872
71. Macaluso F, Nothnagel M, Parwez Q et al (2007) Polymorphisms in NACHT-LRR (NLR) genes in atopic dermatitis. Exp Dermatol 16:692–698
72. Weidinger S, Klopp N, Rummler L et al (2005) Association of NOD1 polymorphisms with atopic eczema and related phenotypes. J Allergy Clin Immunol 116:177–184
73. Prado-Montes de Oca E, Garcia-Vargas A, Lozano-Inocencio R et al (2007) Association of beta-defensin 1 single nucleotide polymorphisms with atopic dermatitis. Int Arch Allergy Immunol 142:211–218
74. Mohamed HG, Abbas A, El-Kabarity RH, Diab HM (2009) Association of beta-defensin 1 single nucleotide polymorphism with atopic dermatitis. Egypt J Immunol 16:125–138
75. Kim E, Lee JE, Namkung JH et al (2009) Single nucleotide polymorphisms and the haplotype in the DEFB1 gene are associated with atopic dermatitis in a Korean population. J Dermatol Sci 54:25–30
76. Montes P, de Oca E, Li W (2013) Human beta-defensin 1 (DEFB1) allele and genotype frequencies probably impact on ethnic susceptibility to atopic dermatitis. Int J Dermatol 52:115–117
77. Kou K, Aihara M, Matsunaga T et al (2012) Association of serum interleukin-18 and other biomarkers with disease severity in adults with atopic dermatitis. Arch Dermatol Res 304:305–312
78. Savinko T, Matikainen S, Saarialho-Kere U et al (2012) IL-33 and ST2 in atopic dermatitis: expression profiles and modulation by triggering factors. J Investig Dermatol 132:1392–1400
79. Novak N, Kruse S, Potreck J et al (2005) Single nucleotide polymorphisms of the IL18 gene are associated with atopic eczema. J Allergy Clin Immunol 115:828–833
80. Ibrahim GH, ElTabbakh MT, Gomaa AH, Mohamed EA (2012) Interleukin-18 gene polymorphisms in Egyptian patients with allergic diseases. Am J Rhinol Allergy 26:385–389
81. Jariwala SP, Abrams E, Benson A, Fodeman J, Zheng T (2011) The role of thymic stromal lymphopoietin in the immunopathogenesis of atopic dermatitis. Clin Exp Allergy 41:1515–1520
82. Liu YJ (2007) Thymic stromal lymphopoietin and OX40 ligand pathway in the initiation of dendritic cell-mediated allergic inflammation. J Allergy Clin Immunol 120:238–244, quiz 245-236
83. Hoffjan S, Beygo J, Akkad DA, Parwez Q, Petrasch-Parwez E, Epplen JT (2009) Analysis of variation in the IL7RA and IL2RA genes in atopic dermatitis. J Dermatol Sci 55:138–140
84. Gao PS, Rafaels NM, Mu D et al (2010) Genetic variants in thymic stromal lymphopoietin are associated with atopic dermatitis and eczema herpeticum. J Allergy Clin Immunol 125:1403–1407
85. Margolis DJ, Kim B, Apter AJ et al (2014) Thymic stromal lymphopoietin variation, filaggrin loss of function, and the persistence of atopic dermatitis. JAMA Dermatol 150:254–259
86. Benson AA, Toh JA, Vernon N, Jariwala SP (2012) The role of vitamin D in the immunopathogenesis of allergic skin diseases. Allergy 67:296–301
87. Wang SS, Hon KL, Kong AP et al (2013) Eczema phenotypes are associated with multiple vitamin D pathway genes in Chinese children. Allergy 69:118–124
88. He JQ, Chan-Yeung M, Becker AB et al (2003) Genetic variants of the IL13 and IL4 genes and atopic diseases in at-risk children. Genes Immun 4:385–389
89. Iizuka M, Katsuyama Y, Mabuchi T et al (2002) Genetic association analysis using microsatellite markers in atopic dermatitis. Tokai J Exp Clin Med 27:51–56
90. Kawashima T, Noguchi E, Arinami T et al (1998) Linkage and association of an interleukin 4 gene polymorphism with atopic dermatitis in Japanese families. J Med Genet 35:502–504
91. Namkung JH, Lee JE, Kim E et al (2011) Association of polymorphisms in genes encoding IL-4, IL-13 and their receptors with atopic dermatitis in a Korean population. Exp Dermatol 20:915–919
92. Hershey GK, Friedrich MF, Esswein LA, Thomas ML, Chatila TA (1997) The association of atopy with a gain-of-function mutation in the alpha subunit of the interleukin-4 receptor. N Engl J Med 337:1720–1725
93. Oiso N, Fukai K, Ishii M (2000) Interleukin 4 receptor alpha chain polymorphism Gln551Arg is associated with adult atopic dermatitis in Japan. Br J Dermatol 142:1003–1006
94. Isidoro-Garcia M, Davila I, Moreno E, Laffond E, Lorente F, Gonzalez-Sarmiento R (2005) IL4RA gene polymorphism (Q576R) is associated with higher total IgE levels in Spanish patients with family history of atopy. Med Clin (Barc) 124:211–212
95. Yamamoto N, Sugiura H, Tanaka K, Uehara M (2003) Heterogeneity of interleukin 5 genetic background in atopic dermatitis patients: significant difference between those with blood eosinophilia and normal eosinophil levels. J Dermatol Sci 33:121–126
96. Namkung JH, Lee JE, Kim E et al (2007) IL-5 and IL-5 receptor alpha polymorphisms are associated with atopic dermatitis in Koreans. Allergy 62:934–942
97. Vladich FD, Brazille SM, Stern D, Peck ML, Ghittoni R, Vercelli D (2005) IL-13 R130Q, a common variant associated with allergy and asthma, enhances effector mechanisms essential for human allergic inflammation. J Clin Invest 115:747–754
98. Tamura K, Arakawa H, Suzuki M et al (2001) Novel dinucleotide repeat polymorphism in the first exon of the STAT-6 gene is associated with allergic diseases. Clin Exp Allergy 31:1509–1514
99. Tamura K, Suzuki M, Arakawa H, Tokuyama K, Morikawa A (2003) Linkage and association studies of STAT6 gene polymorphisms and allergic diseases. Int Arch Allergy Immunol 131:33–38
100. Schulz F, Marenholz I, Folster-Holst R et al (2007) A common haplotype of the IL-31 gene influencing gene expression is associated with nonatopic eczema. J Allergy Clin Immunol 120:1097–1102
101. Nagy N, Tanaka A, Techanukul T, McGrath JA (2010) Common IL-31 gene haplotype associated with non-atopic eczema is not implicated in epidermolysis bullosa pruriginosa. Acta Derm Venereol 90:631–632
102. Tsunemi Y, Saeki H, Nakamura K et al (2002) Interleukin-12 p40 gene (IL12B) 3′-untranslated region polymorphism is associated with susceptibility to atopic dermatitis and psoriasis vulgaris. J Dermatol Sci 30:161–166
103. Takahashi N, Akahoshi M, Matsuda A et al (2005) Association of the IL12RB1 promoter polymorphisms with increased risk of atopic dermatitis and other allergic phenotypes. Hum Mol Genet 14:3149–3159
104. Leung DY, Gao PS, Grigoryev DN et al (2011) Human atopic dermatitis complicated by eczema herpeticum is associated with abnormalities in IFN-gamma response. J Allergy Clin Immunol 127:965–973
105. Gao PS, Leung DY, Rafaels NM et al (2012) Genetic variants in interferon regulatory factor 2 (IRF2) are associated with atopic dermatitis and eczema herpeticum. J Investig Dermatol 132:650–657
106. Esparza-Gordillo J, Schaarschmidt H, Liang L et al (2013) A functional IL-6 receptor (IL6R) variant is a risk factor for persistent atopic dermatitis. J Allergy Clin Immunol 132:371–377
107. Gharagozlou M, Farhadi E, Khaledi M et al (2013) Association between the interleukin 6 genotype at position -174 and atopic dermatitis. J Investig Allergol Clin Immunol 23:89–93
108. Kayserova J, Sismova K, Zentsova-Jaresova I et al (2012) A prospective study in children with a severe form of atopic dermatitis: clinical outcome in relation to cytokine gene polymorphisms. J Investig Allergol Clin Immunol 22:92–101
109. Shin HD, Park BL, Kim LH, Kim JS, Kim JW (2005) Interleukin-10 haplotype associated with total serum IgE in atopic dermatitis patients. Allergy 60:1146–1151
110. Namkung JH, Lee JE, Kim E et al (2011) An association between IL-9 and IL-9 receptor gene polymorphisms and atopic dermatitis in a Korean population. J Dermatol Sci 62:16–21
111. Niwa Y, Potaczek DP, Kanada S et al (2010) FcepsilonRIalpha gene (FCER1A) promoter polymorphisms and total serum IgE levels in Japanese atopic dermatitis patients. Int J Immunogenet 37:139–141
112. Zhou J, Zhou Y, Lin LH et al (2012) Association of polymorphisms in the promoter region of FCER1A gene with atopic dermatitis, chronic uticaria, asthma, and serum immunoglobulin E levels in a Han Chinese population. Hum Immunol 73:301–305
113. Potaczek DP, Nastalek M, Wojas-Pelc A, Okumura K, Undas A, Nishiyama C (2010) Naturally occurring FCER1A N222K mutation - its ethnicity-dependent distribution and a role in atopic dermatitis. Mol Immunol 48:979–980
114. Mahachie John JM, Baurecht H, Rodriguez E et al (2010) Analysis of the high affinity IgE receptor genes reveals epistatic effects of FCER1A variants on eczema risk. Allergy 65:875–882
115. Weidinger S, Gieger C, Rodriguez E et al (2008) Genome-wide scan on total serum IgE levels identifies FCER1A as novel susceptibility locus. PLoS Genet 4:e1000166
116. Manolio TA (2010) Genomewide association studies and assessment of the risk of disease. N Engl J Med 363:166–176
117. Trynka G, Hunt KA, Bockett NA et al (2011) Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease. Nat Genet 43:1193–1201
118. Tran DQ, Andersson J, Wang R, Ramsey H, Unutmaz D, Shevach EM (2009) GARP (LRRC32) is essential for the surface expression of latent TGF-beta on platelets and activated FOXP3+ regulatory T cells. Proc Natl Acad Sci U S A 106:13445–13450
119. Doherty TA, Soroosh P, Khorram N et al (2011) The tumor necrosis factor family member LIGHT is a target for asthmatic airway remodeling. Nat Med 17:596–603
120. Nair M, Teng A, Bilanchone V, Agrawal A, Li B, Dai X (2006) Ovol1 regulates the growth arrest of embryonic epidermal progenitor cells and represses c-myc transcription. J Cell Biol 173:253–264
121. Hulin A, Deroanne CF, Lambert CA et al (2012) Metallothionein-dependent up-regulation of TGF-beta2 participates in the remodelling of the myxomatous mitral valve. Cardiovasc Res 93:480–489
122. Horikawa T, Nakayama T, Hikita I et al (2002) IFN-gamma-inducible expression of thymus and activation-regulated chemokine/CCL17 and macrophage-derived chemokine/CCL22 in epidermal keratinocytes and their roles in atopic dermatitis. Int Immunol 14:767–773
123. Sugawara N, Yamashita T, Ote Y, Miura M, Terada N, Kurosawa M (2002) TARC in allergic disease. Allergy 57:180–181
124. Fujita H (2013) The role of IL-22 and Th22 cells in human skin diseases. J Dermatol Sci 72:3–8
125. Tremblay F, Revett T, Huard C et al (2009) Bidirectional modulation of adipogenesis by the secreted protein Ccdc80/DRO1/URB. J Biol Chem 284:8136–8147
126. Hsiao HW, Liu WH, Wang CJ et al (2009) Deltex1 is a target of the transcription factor NFAT that promotes T cell anergy. Immunity 31:72–83
127. Damm A, Lautz K, Kufer TA (2013) Roles of NLRP10 in innate and adaptive immunity. Microbes Infect 15:516–523
128. Jones G, Prosser DE, Kaufmann M (2014) Cytochrome P450-mediated metabolism of vitamin D. J Lipid Res 55:13–31
129. Karadag B, Ege MJ, Scheynius A et al (2007) Environmental determinants of atopic eczema phenotypes in relation to asthma and atopic sensitization. Allergy 62:1387–1393
130. Purvis DJ, Thompson JM, Clark PM et al (2005) Risk factors for atopic dermatitis in New Zealand children at 3.5 years of age. Br J Dermatol 152:742–749
131. Miyake Y, Okubo H, Sasaki S, Tanaka K, Hirota Y (2011) Maternal dietary patterns during pregnancy and risk of wheeze and eczema in Japanese infants aged 16-24 months: the Osaka Maternal and Child Health Study. Pediatr Allergy Immunol 22:734–741
132. Wang Y, Liang Y, Lu Q (2008) MicroRNA epigenetic alterations: predicting biomarkers and therapeutic targets in human diseases. Clin Genet 74:307–315
133. Martino D, Kesper DA, Amarasekera M, Harb H, Renz H, Prescott S (2014) Epigenetics in immune development and in allergic and autoimmune diseases. J Reprod Immunol 104–105:43–48
134. Prescott S, Saffery R (2011) The role of epigenetic dysregulation in the epidemic of allergic disease. Clin Epigenetics 2:223–232
135. Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY (2005) Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 22:329–341
136. Liu J, Lluis A, Illi S et al (2010) T regulatory cells in cord blood--FOXP3 demethylation as reliable quantitative marker. PLoS One 5:e13267
137. Polansky JK, Kretschmer K, Freyer J et al (2008) DNA methylation controls Foxp3 gene expression. Eur J Immunol 38:1654–1663
138. Leung PS, Shu SA, Chang C (2014) The changing geoepidemiology of food allergies. Clin Rev Allergy Immunol 46:169–179
139. Ho MH, Wong WH, Chang C (2014) Clinical spectrum of food allergies: a comprehensive review. Clin Rev Allergy Immunol 46:225–240
140. Shu SA, Chang C, Leung PS (2014) Common methodologies in the evaluation of food allergy: pitfalls and prospects of food allergy prevalence studies. Clin Rev Allergy Immunol 46:198–210
141. Liang Y, Wang P, Zhao M et al (2012) Demethylation of the FCER1G promoter leads to FcepsilonRI overexpression on monocytes of patients with atopic dermatitis. Allergy 67:424–430
142. White GP, Watt PM, Holt BJ, Holt PG (2002) Differential patterns of methylation of the IFN-gamma promoter at CpG and non-CpG sites underlie differences in IFN-gamma gene expression between human neonatal and adult CD45RO- T cells. J Immunol 168:2820–2827
143. Kaminuma O, Kitamura F, Miyatake S et al (2009) T-box 21 transcription factor is responsible for distorted T(H)2 differentiation in human peripheral CD4+ T cells. J Allergy Clin Immunol 123:813–823
144. Brand S, Teich R, Dicke T et al (2011) Epigenetic regulation in murine offspring as a novel mechanism for transmaternal asthma protection induced by microbes. J Allergy Clin Immunol 128:618–625
145. Ly NP, Litonjua A, Gold DR, Celedon JC (2011) Gut microbiota, probiotics, and vitamin D: interrelated exposures influencing allergy, asthma, and obesity? J Allergy Clin Immunol 127:1087–1094, quiz 1095-1086
146. Cao S, Feehley TJ, Nagler CR (2014) The role of commensal bacteria in the regulation of sensitization to food allergens. FEBS Lett
147. Amberbir A, Medhin G, Erku W et al (2011) Effects of Helicobacter pylori, geohelminth infection and selected commensal bacteria on the risk of allergic disease and sensitization in 3-year-old Ethiopian children. Clin Exp Allergy 41:1422–1430
148. Kummeling I, Stelma FF, Dagnelie PC et al (2007) Early life exposure to antibiotics and the subsequent development of eczema, wheeze, and allergic sensitization in the first 2 years of life: the KOALA Birth Cohort Study. Pediatrics 119:e225–e231
149. Ochoa-Reparaz J, Mielcarz DW, Haque-Begum S, Kasper LH (2010) Induction of a regulatory B cell population in experimental allergic encephalomyelitis by alteration of the gut commensal microflora. Gut Microbes 1:103–108
150. Hill DA, Siracusa MC, Abt MC et al (2012) Commensal bacteria-derived signals regulate basophil hematopoiesis and allergic inflammation. Nat Med 18:538–546
151. Perera F, Tang WY, Herbstman J et al (2009) Relation of DNA methylation of 5′-CpG island of ACSL3 to transplacental exposure to airborne polycyclic aromatic hydrocarbons and childhood asthma. PLoS One 4:e4488
152. Tang WY, Levin L, Talaska G et al (2012) Maternal exposure to polycyclic aromatic hydrocarbons and 5′-CpG methylation of interferon-gamma in cord white blood cells. Environ Health Perspect 120:1195–1200
153. Nurmatov U, Devereux G, Sheikh A (2011) Nutrients and foods for the primary prevention of asthma and allergy: systematic review and meta-analysis. J Allergy Clin Immunol 127:724–733
154. Joseph CL, Ownby DR, Havstad SL et al (2011) Early complementary feeding and risk of food sensitization in a birth cohort. J Allergy Clin Immunol 127:1203–1210
155. Hollingsworth JW, Maruoka S, Boon K et al (2008) In utero supplementation with methyl donors enhances allergic airway disease in mice. J Clin Invest 118:3462–3469
156. Brown SB, Reeves KW, Bertone-Johnson ER (2014) Maternal folate exposure in pregnancy and childhood asthma and allergy: a systematic review. Nutr Rev 72:55–64
157. Bekkers MB, Elstgeest LE, Scholtens S et al (2012) Maternal use of folic acid supplements during pregnancy, and childhood respiratory health and atopy. Eur Respir J 39:1468–1474
158. Matsui EC, Matsui W (2009) Higher serum folate levels are associated with a lower risk of atopy and wheeze. J Allergy Clin Immunol 123:1253–1259
159. Whitrow MJ, Moore VM, Rumbold AR, Davies MJ (2009) Effect of supplemental folic acid in pregnancy on childhood asthma: a prospective birth cohort study. Am J Epidemiol 170:1486–1493
160. Husemoen LL, Toft U, Fenger M, Jorgensen T, Johansen N, Linneberg A (2006) The association between atopy and factors influencing folate metabolism: is low folate status causally related to the development of atopy? Int J Epidemiol 35:954–961
161. Kiefte-de Jong JC, Timmermans S, Jaddoe VW et al (2012) High circulating folate and vitamin B-12 concentrations in women during pregnancy are associated with increased prevalence of atopic dermatitis in their offspring. J Nutr 142:731–738
162. Thuesen BH, Husemoen LL, Ovesen L et al (2010) Atopy, asthma, and lung function in relation to folate and vitamin B(12) in adults. Allergy 65:1446–1454
163. Sugiura H, Ebise H, Tazawa T et al (2005) Large-scale DNA microarray analysis of atopic skin lesions shows overexpression of an epidermal differentiation gene cluster in the alternative pathway and lack of protective gene expression in the cornified envelope. Br J Dermatol 152:146–149
164. Jarzab J, Filipowska B, Zebracka J et al (2010) Locus 1q21 Gene expression changes in atopic dermatitis skin lesions: deregulation of small proline-rich region 1A. Int Arch Allergy Immunol 151:28–37
165. Bin L, Howell MD, Kim BE, Streib JE, Hall CF, Leung DY (2011) Specificity protein 1 is pivotal in the skin’s antiviral response. J Allergy Clin Immunol 127:430–438
166. Soumelis V, Reche PA, Kanzler H et al (2002) Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol 3:673–680
167. Luo Y, Zhou B, Zhao M, Tang J, Lu Q (2014) Promoter demethylation contributes to TSLP overexpression in skin lesions of patients with atopic dermatitis. Clin Exp Dermatol 39:48–53
168. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297
169. Makeyev EV, Maniatis T (2008) Multilevel regulation of gene expression by microRNAs. Science 319:1789–1790
170. Djuranovic S, Nahvi A, Green R (2011) A parsimonious model for gene regulation by miRNAs. Science 331:550–553
171. Janssen HL, Reesink HW, Lawitz EJ et al (2013) Treatment of HCV infection by targeting microRNA. N Engl J Med 368:1685–1694
172. Sonkoly E, Wei T, Janson PC et al (2007) MicroRNAs: novel regulators involved in the pathogenesis of psoriasis? PLoS One 2:e610
173. Sonkoly E, Janson P, Majuri ML et al (2010) MiR-155 is overexpressed in patients with atopic dermatitis and modulates T-cell proliferative responses by targeting cytotoxic T lymphocyte-associated antigen 4. J Allergy Clin Immunol 126:581–589
174. Bieber T (2012) Atopic dermatitis 2.0: from the clinical phenotype to the molecular taxonomy and stratified medicine. Allergy 67:1475–1482