Archives of Dermatological Research

, Volume 307, Issue 8, pp 659–670 | Cite as

Unravelling the complex genetic background of atopic dermatitis: from genetic association results towards novel therapeutic strategies

Review

Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin disease arising from complex interaction between genetic and environmental factors. As the starting point of the so-called “atopic march”, e.g. the progression towards allergic asthma in some but not all affected children, AD has come into focus for potential disease-modifying strategies. To elucidate the genetic factors influencing AD development, linkage, association as well as genome-wide association studies have been performed over the last two decades. The results suggest that besides variation in immune-mediated pathways, an intact skin barrier function plays a key role in AD development. Mutations in the gene encoding filaggrin, a major structural protein in the epidermis, have been consistently associated with AD, especially the early-onset persistent form of disease, and are regarded as the most significant known risk factor for AD development to date. Additionally, variation in some other genes involved in skin integrity and barrier function have shown association with AD. However, the known genetic risk factors can only explain a small part of the heritability at the moment. Whole-exome or whole-genome sequencing studies have not been reported yet, but will probably soon evaluate the influence of rare variations for AD development. Additionally, large multi-centre studies comprehensively incorporating gene–gene and gene–environment interactions as well as epigenetic mechanisms might further elucidate the genetic factors underlying AD pathogenesis and, thus, open the way for a more individualized treatment in the future.

Keywords

Atopic dermatitis Eczema Association GWAS Filaggrin Personalized therapy 

Abbreviations

AD

Atopic dermatitis

EDC

Epidermal differentiation complex

FLG

Filaggrin

GWAS

Genome-wide association study

IgE

Immunoglobulin E

IV

Ichthyosis vulgaris

MHC

Major histocompatibility complex

NLR

NOD-like receptor

PRR

Pattern recognition receptor

RLR

RIG-I-like receptor

SNP

Single nucleotide polymorphism

Th

T helper lymphocyte

TLR

Toll-like receptor

Notes

Acknowledgments

We thank Katharina Batzke and Kathrin Bruch for technical assistance.

Conflict of interest

The authors declare that they have no competing interests.

References

  1. 1.
    Ahmad-Nejad P, Mrabet-Dahbi S, Breuer K, Klotz M, Werfel T, Herz U, Heeg K, Neumaier M, Renz H (2004) The toll-like receptor 2 R753Q polymorphism defines a subgroup of patients with atopic dermatitis having severe phenotype. J Allergy Clin Immunol 113(3):565–567CrossRefPubMedGoogle Scholar
  2. 2.
    An Y, Ohnishi H, Matsui E, Funato M, Kato Z, Teramoto T, Kaneko H, Kimura T, Kubota K, Kasahara K, Kondo N (2011) Genetic variations in MyD88 adaptor-like are associated with atopic dermatitis. Int J Mol Med 27(6):795–801PubMedGoogle Scholar
  3. 3.
    Barnes KC (2010) An update on the genetics of atopic dermatitis: scratching the surface in 2009. J Allergy Clin Immunol 125(1):16–29PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Bergboer JG, Zeeuwen PL, Irvine AD, Weidinger S, Giardina E, Novelli G, Den Heijer M, Rodriguez E, Illig T, Riveira-Munoz E, Campbell LE, Tyson J, Dannhauser EN, O’Regan GM, Galli E, Klopp N, Koppelman GH, Novak N, Estivill X, McLean WH, Postma DS, Armour JA, Schalkwijk J (2010) Deletion of late cornified envelope 3B and 3C genes is not associated with atopic dermatitis. J Invest Dermatol 130(8):2057–2061CrossRefPubMedGoogle Scholar
  5. 5.
    Beyene J, Pare G (2014) Statistical genetics with application to population-based study design: a primer for clinicians. Eur Heart J 35(8):495–500CrossRefPubMedGoogle Scholar
  6. 6.
    Bieber T, Cork M, Reitamo S (2012) Atopic dermatitis: a candidate for disease-modifying strategy. Allergy 67(8):969–975CrossRefPubMedGoogle Scholar
  7. 7.
    Bisgaard H, Simpson A, Palmer CN, Bonnelykke K, McLean I, Mukhopadhyay S, Pipper CB, Halkjaer LB, Lipworth B, Hankinson J, Woodcock A, Custovic A (2008) Gene–environment interaction in the onset of eczema in infancy: filaggrin loss-of-function mutations enhanced by neonatal cat exposure. PLoS Med 5(6):e131PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Boguniewicz M, Leung DY (2011) Atopic dermatitis: a disease of altered skin barrier and immune dysregulation. Immunol Rev 242(1):233–246PubMedCentralCrossRefPubMedGoogle Scholar
  9. 9.
    Brown SJ, Kroboth K, Sandilands A, Campbell LE, Pohler E, Kezic S, Cordell HJ, McLean WH, Irvine AD (2012) Intragenic copy number variation within filaggrin contributes to the risk of atopic dermatitis with a dose-dependent effect. J Invest Dermatol 132(1):98–104PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Bussmann C, Weidinger S, Novak N (2011) Genetics of atopic dermatitis. J Dtsch Dermatol Ges 9(9):670–676PubMedGoogle Scholar
  11. 11.
    Candi E, Schmidt R, Melino G (2005) The cornified envelope: a model of cell death in the skin. Nat Rev Mol Cell Biol 6(4):328–340CrossRefPubMedGoogle Scholar
  12. 12.
    Casaca VI, Illi S, Klucker E, Ballenberger N, Schedel M, von Mutius E, Kabesch M, Schaub B (2013) STAT6 polymorphisms are associated with neonatal regulatory T cells and cytokines and atopic diseases at 3 years. Allergy 68(10):1249–1258CrossRefPubMedGoogle Scholar
  13. 13.
    Chavanas S, Bodemer C, Rochat A, Hamel-Teillac D, Ali M, Irvine AD, Bonafe JL, Wilkinson J, Taieb A, Barrandon Y, Harper JI, de Prost Y, Hovnanian A (2000) Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome. Nat Genet 25(2):141–142CrossRefPubMedGoogle Scholar
  14. 14.
    Cookson WO, Ubhi B, Lawrence R, Abecasis GR, Walley AJ, Cox HE, Coleman R, Leaves NI, Trembath RC, Moffatt MF, Harper JI (2001) Genetic linkage of childhood atopic dermatitis to psoriasis susceptibility loci. Nat Genet 27(4):372–373CrossRefPubMedGoogle Scholar
  15. 15.
    Cortes A, Brown MA (2011) Promise and pitfalls of the immunochip. Arthritis Res Ther 13(1):101PubMedCentralCrossRefPubMedGoogle Scholar
  16. 16.
    DaVeiga SP (2012) Epidemiology of atopic dermatitis: a review. Allergy Asthma Proc 33(3):227–234CrossRefPubMedGoogle Scholar
  17. 17.
    De Benedetto A, Rafaels NM, McGirt LY, Ivanov AI, Georas SN, Cheadle C, Berger AE, Zhang K, Vidyasagar S, Yoshida T, Boguniewicz M, Hata T, Schneider LC, Hanifin JM, Gallo RL, Novak N, Weidinger S, Beaty TH, Leung DY, Barnes KC, Beck LA (2011) Tight junction defects in patients with atopic dermatitis. J Allergy Clin Immunol 127(3):773–786PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    de Guia RM, Ramos JD (2010) The −590C/TIL4 single-nucleotide polymorphism as a genetic factor of atopic allergy. Int J Mol Epidemiol Genet 1(1):67–73PubMedCentralPubMedGoogle Scholar
  19. 19.
    de Koning HD, Simon A, Zeeuwen PL, Schalkwijk J (2012) Pattern recognition receptors in immune disorders affecting the skin. J Innate Immun 4(3):225–240CrossRefPubMedGoogle Scholar
  20. 20.
    DeWan AT, Egan KB, Hellenbrand K, Sorrentino K, Pizzoferrato N, Walsh KM, Bracken MB (2012) Whole-exome sequencing of a pedigree segregating asthma. BMC Med Genet 13:95PubMedCentralCrossRefPubMedGoogle Scholar
  21. 21.
    Ellinghaus D, Baurecht H, Esparza-Gordillo J, Rodriguez E, Matanovic A, Marenholz I, Hubner N, Schaarschmidt H, Novak N, Michel S, Maintz L, Werfel T, Meyer-Hoffert U, Hotze M, Prokisch H, Heim K, Herder C, Hirota T, Tamari M, Kubo M, Takahashi A, Nakamura Y, Tsoi LC, Stuart P, Elder JT, Sun L, Zuo X, Yang S, Zhang X, Hoffmann P, Nothen MM, Folster-Holst R, Winkelmann J, Illig T, Boehm BO, Duerr RH, Buning C, Brand S, Glas J, McAleer MA, Fahy CM, Kabesch M, Brown S, McLean WH, Irvine AD, Schreiber S, Lee YA, Franke A, Weidinger S (2013) High-density genotyping study identifies four new susceptibility loci for atopic dermatitis. Nat Genet 45(7):808–812PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    Esparza-Gordillo J, Weidinger S, Folster-Holst R, Bauerfeind A, Ruschendorf F, Patone G, Rohde K, Marenholz I, Schulz F, Kerscher T, Hubner N, Wahn U, Schreiber S, Franke A, Vogler R, Heath S, Baurecht H, Novak N, Rodriguez E, Illig T, Lee-Kirsch MA, Ciechanowicz A, Kurek M, Piskackova T, Macek M, Lee YA, Ruether A (2009) A common variant on chromosome 11q13 is associated with atopic dermatitis. Nat Genet 41(5):596–601CrossRefPubMedGoogle Scholar
  23. 23.
    Eyerich K, Novak N (2013) Immunology of atopic eczema: overcoming the Th1/Th2 paradigm. Allergy 68(8):974–982CrossRefPubMedGoogle Scholar
  24. 24.
    Ezell SA, Tsichlis PN (2012) Akt1, EMSY, BRCA2 and type I IFN signaling: a novel arm of the IFN response. Transcription 3(6):305–309PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    Flohr C, Yeo L (2011) Atopic dermatitis and the hygiene hypothesis revisited. Curr Probl Dermatol 41:1–34CrossRefPubMedGoogle Scholar
  26. 26.
    Gunzel D, Fromm M (2012) Claudins and other tight junction proteins. Compr Physiol 2(3):1819–1852PubMedGoogle Scholar
  27. 27.
    Harazin M, Parwez Q, Petrasch-Parwez E, Epplen JT, Arinir U, Hoffjan S, Stemmler S (2010) Variation in the COL29A1 gene in German patients with atopic dermatitis, asthma and chronic obstructive pulmonary disease. J Dermatol 37(8):740–742CrossRefPubMedGoogle Scholar
  28. 28.
    He JQ, Chan-Yeung M, Becker AB, Dimich-Ward H, Ferguson AC, Manfreda J, Watson WT, Sandford AJ (2003) Genetic variants of the IL13 and IL4 genes and atopic diseases in at-risk children. Genes Immun 4(5):385–389CrossRefPubMedGoogle Scholar
  29. 29.
    Hirota T, Takahashi A, Kubo M, Tsunoda T, Tomita K, Sakashita M, Yamada T, Fujieda S, Tanaka S, Doi S, Miyatake A, Enomoto T, Nishiyama C, Nakano N, Maeda K, Okumura K, Ogawa H, Ikeda S, Noguchi E, Sakamoto T, Hizawa N, Ebe K, Saeki H, Sasaki T, Ebihara T, Amagai M, Takeuchi S, Furue M, Nakamura Y, Tamari M (2012) Genome-wide association study identifies eight new susceptibility loci for atopic dermatitis in the Japanese population. Nat Genet 44(11):1222–1226Google Scholar
  30. 30.
    Hoffjan S, Stemmler S (2007) On the role of the epidermal differentiation complex in ichthyosis vulgaris, atopic dermatitis and psoriasis. Br J Dermatol 157(3):441–449CrossRefPubMedGoogle Scholar
  31. 31.
    Hon KL, Leung AK, Barankin B (2013) Barrier repair therapy in atopic dermatitis: an overview. Am J Clin Dermatol 14(5):389–399CrossRefPubMedGoogle Scholar
  32. 32.
    Hosomi N, Fukai K, Oiso N, Kato A, Ishii M, Kunimoto H, Nakajima K (2004) Polymorphisms in the promoter of the interleukin-4 receptor alpha chain gene are associated with atopic dermatitis in Japan. J Invest Dermatol 122(3):843–845CrossRefPubMedGoogle Scholar
  33. 33.
    Hummelshoj T, Bodtger U, Datta P, Malling HJ, Oturai A, Poulsen LK, Ryder LP, Sorensen PS, Svejgaard E, Svejgaard A (2003) Association between an interleukin-13 promoter polymorphism and atopy. Eur J Immunogenet 30(5):355–359CrossRefPubMedGoogle Scholar
  34. 34.
    Irvine AD (2014) Crossing barriers; restoring barriers? Filaggrin protein replacement takes a bow. J Invest Dermatol 134(2):313–314CrossRefPubMedGoogle Scholar
  35. 35.
    Irvine AD (2007) Fleshing out filaggrin phenotypes. J Invest Dermatol 127(3):504–507CrossRefPubMedGoogle Scholar
  36. 36.
    Irvine AD, McLean WH, Leung DY (2011) Filaggrin mutations associated with skin and allergic diseases. N Engl J Med 365(14):1315–1327CrossRefPubMedGoogle Scholar
  37. 37.
    Jensen JM, Proksch E (2009) The skin’s barrier. G Ital Dermatol Venereol 144(6):689–700PubMedGoogle Scholar
  38. 38.
    Kabashima K (2013) New concept of the pathogenesis of atopic dermatitis: interplay among the barrier, allergy, and pruritus as a trinity. J Dermatol Sci 70(1):3–11CrossRefPubMedGoogle Scholar
  39. 39.
    Kawashima T, Noguchi E, Arinami T, Yamakawa-Kobayashi K, Nakagawa H, Otsuka F, Hamaguchi H (1998) Linkage and association of an interleukin 4 gene polymorphism with atopic dermatitis in Japanese families. J Med Genet 35(6):502–504PubMedCentralCrossRefPubMedGoogle Scholar
  40. 40.
    Kezic S, Novak N, Jakasa I, Jungersted JM, Simon M, Brandner JM, Middelkamp-Hup MA, Weidinger S (2014) Skin barrier in atopic dermatitis. Front Biosci (Landmark Ed) 19:542–556CrossRefGoogle Scholar
  41. 41.
    Kuo IH, Yoshida T, De Benedetto A, Beck LA (2013) The cutaneous innate immune response in patients with atopic dermatitis. J Allergy Clin Immunol 131(2):266–278CrossRefPubMedGoogle Scholar
  42. 42.
    Kypriotou M, Huber M, Hohl D (2012) The human epidermal differentiation complex: cornified envelope precursors, S100 proteins and the ‘fused genes’ family. Exp Dermatol 21(9):643–649CrossRefPubMedGoogle Scholar
  43. 43.
    Li X, Ampleford EJ, Howard TD, Moore WC, Li H, Busse WW, Castro M, Erzurum SC, Fitzpatrick AM, Gaston B, Israel E, Jarjour NN, Teague WG, Wenzel SE, Hawkins GA, Bleecker ER, Meyers DA (2012) The C11orf30-LRRC32 region is associated with total serum IgE levels in asthmatic patients. J Allergy Clin Immunol 129(2):575–578PubMedCentralCrossRefPubMedGoogle Scholar
  44. 44.
    Liu X, Nickel R, Beyer K, Wahn U, Ehrlich E, Freidhoff LR, Bjorksten B, Beaty TH, Huang SK (2000) An IL13 coding region variant is associated with a high total serum IgE level and atopic dermatitis in the German multicenter atopy study (MAS-90). J Allergy Clin Immunol 106(1 Pt 1):167–170CrossRefPubMedGoogle Scholar
  45. 45.
    Macaluso F, Nothnagel M, Parwez Q, Petrasch-Parwez E, Bechara FG, Epplen JT, Hoffjan S (2007) Polymorphisms in NACHT-LRR (NLR) genes in atopic dermatitis. Exp Dermatol 16(8):692–698CrossRefPubMedGoogle Scholar
  46. 46.
    Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, McCarthy MI, Ramos EM, Cardon LR, Chakravarti A, Cho JH, Guttmacher AE, Kong A, Kruglyak L, Mardis E, Rotimi CN, Slatkin M, Valle D, Whittemore AS, Boehnke M, Clark AG, Eichler EE, Gibson G, Haines JL, Mackay TF, McCarroll SA, Visscher PM (2009) Finding the missing heritability of complex diseases. Nature 461(7265):747–753PubMedCentralCrossRefPubMedGoogle Scholar
  47. 47.
    Marenholz I, Bauerfeind A, Esparza-Gordillo J, Kerscher T, Granell R, Nickel R, Lau S, Henderson J, Lee YA (2011) The eczema risk variant on chromosome 11q13 (rs7927894) in the population-based ALSPAC cohort: a novel susceptibility factor for asthma and hay fever. Hum Mol Genet 20(12):2443–2449CrossRefPubMedGoogle Scholar
  48. 48.
    Marenholz I, Rivera VA, Esparza-Gordillo J, Bauerfeind A, Lee-Kirsch MA, Ciechanowicz A, Kurek M, Piskackova T, Macek M, Lee YA (2011) Association screening in the epidermal differentiation complex (EDC) identifies an SPRR3 repeat number variant as a risk factor for eczema. J Invest Dermatol 131(8):1644–1649CrossRefPubMedGoogle Scholar
  49. 49.
    Margolis DJ, Gupta J, Apter AJ, Ganguly T, Hoffstad O, Papadopoulos M, Rebbeck TR, Mitra N (2014) Filaggrin-2 variation is associated with more persistent atopic dermatitis in African American subjects. J Allergy Clin Immunol 133(3):784–789PubMedCentralCrossRefPubMedGoogle Scholar
  50. 50.
    Margolis DJ, Gupta J, Apter AJ, Hoffstad O, Papadopoulos M, Rebbeck TR, Wubbenhorst B, Mitra N (2014) Exome sequencing of filaggrin and related genes in African–American children with atopic dermatitis. J Invest Dermatol 134(8):2272–2274PubMedCentralCrossRefPubMedGoogle Scholar
  51. 51.
    McAleer MA, Irvine AD (2013) The multifunctional role of filaggrin in allergic skin disease. J Allergy Clin Immunol 131(2):280–291CrossRefPubMedGoogle Scholar
  52. 52.
    Miyake Y, Tanaka K, Arakawa M (2013) Case-control study of eczema in relation to IL4Ralpha genetic polymorphisms in Japanese women: the Kyushu Okinawa Maternal and Child Health Study. Scand J Immunol 77(5):413–418CrossRefPubMedGoogle Scholar
  53. 53.
    Morar N, Cookson WO, Harper JI, Moffatt MF (2007) Filaggrin mutations in children with severe atopic dermatitis. J Invest Dermatol 127(7):1667–1672PubMedGoogle Scholar
  54. 54.
    Namkung JH, Lee JE, Kim E, Kim HJ, Seo EY, Jang HY, Shin ES, Cho EY, Yang JM (2011) Association of polymorphisms in genes encoding IL-4, IL-13 and their receptors with atopic dermatitis in a Korean population. Exp Dermatol 20(11):915–919CrossRefPubMedGoogle Scholar
  55. 55.
    Naumann A, Soderhall C, Folster-Holst R, Baurecht H, Harde V, Muller-Wehling K, Rodriguez E, Ruether A, Franke A, Wagenpfeil S, Novak N, Mempel M, Kalali BN, Allgaeuer M, Koch J, Gerhard M, Melen E, Wahlgren CF, Kull I, Stahl C, Pershagen G, Lauener R, Riedler J, Doekes G, Scheynius A, Illig T, von Mutius E, Schreiber S, Kere J, Kabesch M, Weidinger S (2011) A comprehensive analysis of the COL29A1 gene does not support a role in eczema. J Allergy Clin Immunol 127(5):1187–1194CrossRefPubMedGoogle Scholar
  56. 56.
    Nishio Y, Noguchi E, Shibasaki M, Kamioka M, Ichikawa E, Ichikawa K, Umebayashi Y, Otsuka F, Arinami T (2003) Association between polymorphisms in the SPINK5 gene and atopic dermatitis in the Japanese. Genes Immun 4(7):515–517CrossRefPubMedGoogle Scholar
  57. 57.
    Niwa Y, Potaczek DP, Kanada S, Takagi A, Shimokawa N, Ito T, Mitsuishi K, Okubo Y, Tajima M, Hobo A, Ng W, Tsuboi R, Ikeda S, Ogawa H, Okumura K, Nishiyama C (2010) FcepsilonRIalpha gene (FCER1A) promoter polymorphisms and total serum IgE levels in Japanese atopic dermatitis patients. Int J Immunogenet 37(2):139–141CrossRefPubMedGoogle Scholar
  58. 58.
    Nomura T, Akiyama M, Sandilands A, Nemoto-Hasebe I, Sakai K, Nagasaki A, Ota M, Hata H, Evans AT, Palmer CN, Shimizu H, McLean WH (2008) Specific filaggrin mutations cause ichthyosis vulgaris and are significantly associated with atopic dermatitis in Japan. J Invest Dermatol 128(6):1436–1441CrossRefPubMedGoogle Scholar
  59. 59.
    Nomura T, Sandilands A, Akiyama M, Liao H, Evans AT, Sakai K, Ota M, Sugiura H, Yamamoto K, Sato H, Palmer CN, Smith FJ, McLean WH, Shimizu H (2007) Unique mutations in the filaggrin gene in Japanese patients with ichthyosis vulgaris and atopic dermatitis. J Allergy Clin Immunol 119(2):434–440CrossRefPubMedGoogle Scholar
  60. 60.
    Novak N, Simon D (2011) Atopic dermatitis—from new pathophysiologic insights to individualized therapy. Allergy 66(7):830–839CrossRefPubMedGoogle Scholar
  61. 61.
    Novak N, Yu CF, Bussmann C, Maintz L, Peng WM, Hart J, Hagemann T, Diaz-Lacava A, Baurecht HJ, Klopp N, Wagenpfeil S, Behrendt H, Bieber T, Ring J, Illig T, Weidinger S (2007) Putative association of a TLR9 promoter polymorphism with atopic eczema. Allergy 62(7):766–772CrossRefPubMedGoogle Scholar
  62. 62.
    O’Regan GM, Campbell LE, Cordell HJ, Irvine AD, McLean WH, Brown SJ (2010) Chromosome 11q13.5 variant associated with childhood eczema: an effect supplementary to filaggrin mutations. J Allergy Clin Immunol 125(1):170–174PubMedCentralCrossRefPubMedGoogle Scholar
  63. 63.
    Oh DY, Schumann RR, Hamann L, Neumann K, Worm M, Heine G (2009) Association of the toll-like receptor 2 A-16934T promoter polymorphism with severe atopic dermatitis. Allergy 64(11):1608–1615CrossRefPubMedGoogle Scholar
  64. 64.
    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(5):1003–1006CrossRefPubMedGoogle Scholar
  65. 65.
    Otsuka A, Doi H, Egawa G, Maekawa A, Fujita T, Nakamizo S, Nakashima C, Nakajima S, Watanabe T, Miyachi Y, Narumiya S, Kabashima K (2014) Possible new therapeutic strategy to regulate atopic dermatitis through upregulating filaggrin expression. J Allergy Clin Immunol 133(1):139–146Google Scholar
  66. 66.
    Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, Goudie DR, Sandilands A, Campbell LE, Smith FJ, O’Regan GM, Watson RM, Cecil JE, Bale SJ, Compton JG, DiGiovanna JJ, Fleckman P, Lewis-Jones S, Arseculeratne G, Sergeant A, Munro CS, El Houate B, McElreavey K, Halkjaer LB, Bisgaard H, Mukhopadhyay S, McLean WH (2006) Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet 38(4):441–446CrossRefPubMedGoogle Scholar
  67. 67.
    Paternoster L, Standl M, Chen CM, Ramasamy A, Bonnelykke K, Duijts L, Ferreira MA, Alves AC, Thyssen JP, Albrecht E, Baurecht H, Feenstra B, Sleiman PM, Hysi P, Warrington NM, Curjuric I, Myhre R, Curtin JA, Groen-Blokhuis MM, Kerkhof M, Saaf A, Franke A, Ellinghaus D, Folster-Holst R, Dermitzakis E, Montgomery SB, Prokisch H, Heim K, Hartikainen AL, Pouta A, Pekkanen J, Blakemore AI, Buxton JL, Kaakinen M, Duffy DL, Madden PA, Heath AC, Montgomery GW, Thompson PJ, Matheson MC, Le Souef P, St Pourcain B, Smith GD, Henderson J, Kemp JP, Timpson NJ, Deloukas P, Ring SM, Wichmann HE, Muller-Nurasyid M, Novak N, Klopp N, Rodriguez E, McArdle W, Linneberg A, Menne T, Nohr EA, Hofman A, Uitterlinden AG, van Duijn CM, Rivadeneira F, de Jongste JC, van der Valk RJ, Wjst M, Jogi R, Geller F, Boyd HA, Murray JC, Kim C, Mentch F, March M, Mangino M, Spector TD, Bataille V, Pennell CE, Holt PG, Sly P, Tiesler CM, Thiering E, Illig T, Imboden M, Nystad W, Simpson A, Hottenga JJ, Postma D, Koppelman GH, Smit HA, Soderhall C, Chawes B, Kreiner-Moller E, Bisgaard H, Melen E, Boomsma DI, Custovic A, Jacobsson B, Probst-Hensch NM, Palmer LJ, Glass D, Hakonarson H, Melbye M, Jarvis DL, Jaddoe VW, Gieger C, Strachan DP, Martin NG, Jarvelin MR, Heinrich J, Evans DM, Weidinger S (2011) Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis. Nat Genet 44(2):187–192PubMedCentralCrossRefPubMedGoogle Scholar
  68. 68.
    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(6):715–721CrossRefPubMedGoogle Scholar
  69. 69.
    Pothlichet J, Quintana-Murci L (2013) The genetics of innate immunity sensors and human disease. Int Rev Immunol 32(2):157–208CrossRefPubMedGoogle Scholar
  70. 70.
    Ramagopalan SV, Dyment DA, Cader MZ, Morrison KM, Disanto G, Morahan JM, Berlanga-Taylor AJ, Handel A, De Luca GC, Sadovnick AD, Lepage P, Montpetit A, Ebers GC (2011) Rare variants in the CYP27B1 gene are associated with multiple sclerosis. Ann Neurol 70(6):881–886CrossRefPubMedGoogle Scholar
  71. 71.
    Rodriguez E, Baurecht H, Wahn AF, Kretschmer A, Hotze M, Zeilinger S, Klopp N, Illig T, Schramm K, Prokisch H, Kuhnel B, Gieger C, Harder J, Cifuentes L, Novak N, Weidinger S (2014) An integrated epigenetic and transcriptomic analysis reveals distinct tissue-specific patterns of DNA methylation associated with atopic dermatitis. J Invest Dermatol 134(7):1873–1883CrossRefPubMedGoogle Scholar
  72. 72.
    Sabin BR, Peters N, Peters AT (2012) Chapter 20: Atopic dermatitis. Allergy Asthma Proc 33(Suppl 1):S67–S69Google Scholar
  73. 73.
    Schimming TT, Parwez Q, Petrasch-Parwez E, Nothnagel M, Epplen JT, Hoffjan S (2007) Association of toll-interacting protein gene polymorphisms with atopic dermatitis. BMC Dermatol 7:3PubMedCentralCrossRefPubMedGoogle Scholar
  74. 74.
    Schultz Larsen F (1993) Atopic dermatitis: a genetic-epidemiologic study in a population-based twin sample. J Am Acad Dermatol 28(5 Pt 1):719–723CrossRefPubMedGoogle Scholar
  75. 75.
    Smith FJ, Irvine AD, Terron-Kwiatkowski A, Sandilands A, Campbell LE, Zhao Y, Liao H, Evans AT, Goudie DR, Lewis-Jones S, Arseculeratne G, Munro CS, Sergeant A, O’Regan G, Bale SJ, Compton JG, DiGiovanna JJ, Presland RB, Fleckman P, McLean WH (2006) Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet 38(3):337–342CrossRefPubMedGoogle Scholar
  76. 76.
    Soderhall C, Marenholz I, Kerscher T, Ruschendorf F, Esparza-Gordillo J, Worm M, Gruber C, Mayr G, Albrecht M, Rohde K, Schulz H, Wahn U, Hubner N, Lee YA (2007) Variants in a novel epidermal collagen gene (COL29A1) are associated with atopic dermatitis. PLoS Biol 5(9):e242PubMedCentralCrossRefPubMedGoogle Scholar
  77. 77.
    Stemmler S, Nothnagel M, Parwez Q, Petrasch-Parwez E, Epplen JT, Hoffjan S (2009) Variation in genes of the epidermal differentiation complex in German atopic dermatitis patients. Int J Immunogenet 36(4):217–222CrossRefPubMedGoogle Scholar
  78. 78.
    Stemmler S, Parwez Q, Petrasch-Parwez E, Epplen JT, Hoffjan S (2014) Association of variation in the LAMA3 gene, encoding the alpha-chain of laminin 5, with atopic dermatitis in a German case–control cohort. BMC Dermatol 14(1):17PubMedCentralCrossRefPubMedGoogle Scholar
  79. 79.
    Stout TE, McFarland T, Mitchell JC, Appukuttan B, Stout JT (2014) Recombinant filaggrin is internalized and processed to correct filaggrin deficiency. J Invest Dermatol 134(2):423–429CrossRefPubMedGoogle Scholar
  80. 80.
    Sun LD, Xiao FL, Li Y, Zhou WM, Tang HY, Tang XF, Zhang H, Schaarschmidt H, Zuo XB, Foelster-Holst R, He SM, Shi M, Liu Q, Lv YM, Chen XL, Zhu KJ, Guo YF, Hu DY, Li M, Li M, Zhang YH, Zhang X, Tang JP, Guo BR, Wang H, Liu Y, Zou XY, Zhou FS, Liu XY, Chen G, Ma L, Zhang SM, Jiang AP, Zheng XD, Gao XH, Li P, Tu CX, Yin XY, Han XP, Ren YQ, Song SP, Lu ZY, Zhang XL, Cui Y, Chang J, Gao M, Luo XY, Wang PG, Dai X, Su W, Li H, Shen CP, Liu SX, Feng XB, Yang CJ, Lin GS, Wang ZX, Huang JQ, Fan X, Wang Y, Bao YX, Yang S, Liu JJ, Franke A, Weidinger S, Yao ZR, Zhang XJ (2011) Genome-wide association study identifies two new susceptibility loci for atopic dermatitis in the Chinese Han population. Nat Genet 43(7):690–694CrossRefPubMedGoogle Scholar
  81. 81.
    Tamura K, Arakawa H, Suzuki M, Kobayashi Y, Mochizuki H, Kato M, Tokuyama K, Morikawa A (2001) Novel dinucleotide repeat polymorphism in the first exon of the STAT-6 gene is associated with allergic diseases. Clin Exp Allergy 31(10):1509–1514CrossRefPubMedGoogle Scholar
  82. 82.
    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(1):33–38CrossRefPubMedGoogle Scholar
  83. 83.
    Tan HT, Ellis JA, Koplin JJ, Martino D, Dang TD, Suaini N, Saffery R, Allen KJ (2014) Methylation of the filaggrin gene promoter does not affect gene expression and allergy. Pediatr Allergy Immunol. doi: 10.1111/pai.12245 (in press)
  84. 84.
    Thawer-Esmail F, Jakasa I, Todd G, Wen Y, Brown SJ, Kroboth K, Campbell LE, O’Regan GM, McLean WH, Irvine AD, Kezic S, Sandilands A (2014) South African amaXhosa patients with atopic dermatitis have decreased levels of filaggrin breakdown products but no loss-of-function mutations in filaggrin. J Allergy Clin Immunol 133(1):280–282PubMedCentralCrossRefPubMedGoogle Scholar
  85. 85.
    Thomsen SF, Ulrik CS, Kyvik KO, Hjelmborg J, Skadhauge LR, Steffensen I, Backer V (2007) Importance of genetic factors in the etiology of atopic dermatitis: a twin study. Allergy Asthma Proc 28(5):535–539CrossRefPubMedGoogle Scholar
  86. 86.
    Venkataraman D, Soto-Ramirez N, Kurukulaaratchy RJ, Holloway JW, Karmaus W, Ewart SL, Arshad SH, Erlewyn-Lajeunesse M (2014) Filaggrin loss-of-function mutations are associated with food allergy in childhood and adolescence. J Allergy Clin Immunol 134(4):876–882CrossRefPubMedGoogle Scholar
  87. 87.
    Walley AJ, Chavanas S, Moffatt MF, Esnouf RM, Ubhi B, Lawrence R, Wong K, Abecasis GR, Jones EY, Harper JI, Hovnanian A, Cookson WO (2001) Gene polymorphism in Netherton and common atopic disease. Nat Genet 29(2):175–178CrossRefPubMedGoogle Scholar
  88. 88.
    Weidinger S, Klopp N, Rummler L, Wagenpfeil S, Novak N, Baurecht HJ, Groer W, Darsow U, Heinrich J, Gauger A, Schafer T, Jakob T, Behrendt H, Wichmann HE, Ring J, Illig T (2005) Association of NOD1 polymorphisms with atopic eczema and related phenotypes. J Allergy Clin Immunol 116(1):177–184CrossRefPubMedGoogle Scholar
  89. 89.
    Weidinger S, O’Sullivan M, Illig T, Baurecht H, Depner M, Rodriguez E, Ruether A, Klopp N, Vogelberg C, Weiland SK, McLean WH, von Mutius E, Irvine AD, Kabesch M (2008) Filaggrin mutations, atopic eczema, hay fever, and asthma in children. J Allergy Clin Immunol 121(5):1203–1209CrossRefPubMedGoogle Scholar
  90. 90.
    Weidinger S, Willis-Owen SA, Kamatani Y, Baurecht H, Morar N, Liang L, Edser P, Street T, Rodriguez E, O’Regan GM, Beattie P, Fölster-Holst R, Franke A, Novak N, Fahy CM, Winge MC, Kabesch M, Illig T, Heath S, Söderhäll C, Melén E, Pershagen G, Kere J, Bradley M, Lieden A, Nordenskjold M, Harper JI, McLean WH, Brown SJ, Cookson WO, Lathrop GM, Irvine AD, Moffatt MF (2013) A genome-wide association study of atopic dermatitis identifies loci with overlapping effects on asthma and psoriasis. Hum Mol Genet 22(23):4841–4856PubMedCentralCrossRefPubMedGoogle Scholar
  91. 91.
    Williams HC (2013) Epidemiology of human atopic dermatitis—seven areas of notable progress and seven areas of notable ignorance. Vet Dermatol 24(1):3–9CrossRefPubMedGoogle Scholar
  92. 92.
    Winge MC, Bilcha KD, Lieden A, Shibeshi D, Sandilands A, Wahlgren CF, McLean WH, Nordenskjold M, Bradley M (2011) Novel filaggrin mutation but no other loss-of-function variants found in Ethiopian patients with atopic dermatitis. Br J Dermatol 165(5):1074–1080CrossRefPubMedGoogle Scholar
  93. 93.
    Wolf R, Wolf D (2012) Abnormal epidermal barrier in the pathogenesis of atopic dermatitis. Clin Dermatol 30(3):329–334CrossRefPubMedGoogle Scholar
  94. 94.
    Zheng T, Yu J, Oh MH, Zhu Z (2011) The atopic march: progression from atopic dermatitis to allergic rhinitis and asthma. Allergy Asthma Immunol Res 3(2):67–73PubMedCentralCrossRefPubMedGoogle Scholar
  95. 95.
    Zhou J, Zhou Y, Lin LH, Wang J, Peng X, Li J, Li L (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(3):301–305CrossRefPubMedGoogle Scholar
  96. 96.
    Ziyab AH, Karmaus W, Holloway JW, Zhang H, Ewart S, Arshad SH (2013) DNA methylation of the filaggrin gene adds to the risk of eczema associated with loss-of-function variants. J Eur Acad Dermatol Venereol 27(3):e420–e423PubMedCentralCrossRefPubMedGoogle Scholar

Related articles recently published in Archives of Dermatological Research (selected by the journal’s editorial staff):

  1. 97.
    Jiao Q, Wang H, Hu Z, Zhuang Y, Yang W, Li M, Yu X, Liang J, Guo Y, Zhang H, Chen X, Cheng R, Yao Z (2013) Lidocaine inhibits staphylococcal enterotoxin-stimulated activation of peripheral blood mononuclear cells from patients with atopic dermatitis. Arch Dermatol Res 305:629–636PubMedCentralCrossRefPubMedGoogle Scholar
  2. 98.
    Rasul A, Johansson B, Lonne-Rahm SB, Nordlind K, Theodorsson E, El Nour H (2013) Chronic mild stress modulates 5-HT1A and 5-HT2A receptor expression in the cerebellar cortex of NC/Nga atopic-like mice. Arch Dermatol Res 305:407–413CrossRefPubMedGoogle Scholar
  3. 99.
    Sugiura A, Nomura T, Mizuno A, Imokawa G (2014) Reevaluation of the non-lesional dry skin in atopic dermatitis by acute barrier disruption: an abnormal permeability barrier homeostasis with defective processing to generate ceramide. Arch Dermatol Res 306:427–440CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.Department of Human GeneticsRuhr-University BochumBochumGermany

Personalised recommendations