Allergy Asthma Respir Dis.  2013 Jun;1(2):129-137. 10.4168/aard.2013.1.2.129.

Gene-environment interaction between Toll-like receptor 4 and mold exposure in the development of atopic dermatitis in preschool children

• Kim HY
• Jung YH
• Hong K
• Jang GC
• Seo JH
• Kwon JW
• Kim BJ
• Kim HB
• Lee SY
• Song DJ
• Kim WK
• Shim JY
• Kang MJ
• Kim YJ
• Yu HS
• Hong SJ

• KMID: 2261860
• DOI: http://doi.org/10.4168/aard.2013.1.2.129

Abstract

PURPOSE
Genetic factors and environmental exposures are recognized as important risk factors for atopic dermatitis (AD) in children. Inflammatory responses by molds can be mediated via Toll-like receptor 4 (TLR4). The aims of this study were to investigate mold as risk factor of AD and gene-environment interaction on AD in preschool children.
METHODS
We undertook a cross-sectional survey with 986 preschool children. We investigated five mold exposure measures (dampness stain, dampness damage, visible mold, mold odor, and house repair). The TLR4 polymorphism (rs1927911) was genotyped by TaqMan assay.
RESULTS
The prevalence of AD was as follows: AD diagnosis by questionnaire, 35.1%; current AD (lifetime diagnosis together with symptoms in the last 12 months), 21.5%. When children with parental history of AD were exposed to mold odor during infancy and house repair during the last 12 months, the risk for current AD (adjusted odds ratio [aOR], 6.826; 95% confidence interval [CI], 2.511 to 18.554 vs. aOR, 6.143; 95% CI, 2.348 to 16.074) was further increased than only with parental history of AD. In children with the CC genotype of TLR4 polymorphism, the risk of AD was increased by mold exposure.
CONCLUSION
This investigation identified that mold exposure is potential risk factor for AD in preschool children. Parental history of AD and mold exposure during infancy and the last 12 months had synergistic effect on high prevalence of AD. We identified that mold exposure and TLR4 polymorphism have an effect on the development of atopic dermatitis.

Keyword

Atopic dermatitis; Mold; Risk factor; Toll-like receptor 4; Polymorphism

MeSH Terms

Child
Child, Preschool
Cross-Sectional Studies
Dermatitis, Atopic
Environmental Exposure
Fungi
Gene-Environment Interaction
Genotype
Humans
Odds Ratio
Odors
Parents
Prevalence
Risk Factors
Toll-Like Receptor 4
Toll-Like Receptors
Surveys and Questionnaires
Toll-Like Receptor 4
Toll-Like Receptors

Reference

1. Leung DY. Atopic dermatitis: new insights and opportunities for therapeutic intervention. J Allergy Clin Immunol. 2000; 105:860–876.

2. Asher MI, Montefort S, Bjorksten B, Lai CK, Strachan DP, Weiland SK, et al. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet. 2006; 368:733–743.

3. Suh M, Kim HH, Sohn MH, Kim KE, Kim C, Shin DC. Prevalence of allergic diseases among Korean school-age children: a nationwide cross-sectional questionnaire study. J Korean Med Sci. 2011; 26:332–338.

4. Lee JY, Seo JH, Kwon JW, Yu J, Kim BJ, Lee SY, et al. Exposure to gene-environment interactions before 1 year of age may favor the development of atopic dermatitis. Int Arch Allergy Immunol. 2012; 157:363–371.

5. Lee SY, Kwon JW, Seo JH, Song YH, Kim BJ, Yu J, et al. Prevalence of atopy and allergic diseases in Korean children: associations with a farming environment and rural lifestyle. Int Arch Allergy Immunol. 2012; 158:168–174.

6. Purvis DJ, Thompson JM, Clark PM, Robinson E, Black PN, Wild CJ, et al. Risk factors for atopic dermatitis in New Zealand children at 3.5 years of age. Br J Dermatol. 2005; 152:742–749.

7. Morar N, Willis-Owen SA, Moffatt MF, Cookson WO. The genetics of atopic dermatitis. J Allergy Clin Immunol. 2006; 118:24–34.

8. Kim WK, Kwon JW, Seo JH, Kim HY, Yu J, Kim BJ, et al. Interaction between IL13 genotype and environmental factors in the risk for allergic rhinitis in Korean children. J Allergy Clin Immunol. 2012; 130:421–426.e6.

9. Reijmerink NE, Kerkhof M, Bottema RW, Gerritsen J, Stelma FF, Thijs C, et al. Toll-like receptors and microbial exposure: gene-gene and gene-environment interaction in the development of atopy. Eur Respir J. 2011; 38:833–840.

10. Simpson A, John SL, Jury F, Niven R, Woodcock A, Ollier WE, et al. Endotoxin exposure, CD14, and allergic disease: an interaction between genes and the environment. Am J Respir Crit Care Med. 2006; 174:386–392.

11. Cork MJ, Robinson DA, Vasilopoulos Y, Ferguson A, Moustafa M, MacGowan A, et al. New perspectives on epidermal barrier dysfunction in atopic dermatitis: gene-environment interactions. J Allergy Clin Immunol. 2006; 118:3–21.

12. Marenholz I, Nickel R, Ruschendorf F, Schulz F, Esparza-Gordillo J, Kerscher T, et al. Filaggrin loss-of-function mutations predispose to phenotypes involved in the atopic march. J Allergy Clin Immunol. 2006; 118:866–871.

13. Weidinger S, Illig T, Baurecht H, Irvine AD, Rodriguez E, Diaz-Lacava A, et al. Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations. J Allergy Clin Immunol. 2006; 118:214–219.

14. Tham KW, Zuraimi MS, Koh D, Chew FT, Ooi PL. Associations between home dampness and presence of molds with asthma and allergic symptoms among young children in the tropics. Pediatr Allergy Immunol. 2007; 18:418–424.

15. Ege MJ, Mayer M, Normand AC, Genuneit J, Cookson WO, Braun-Fahrländer C, et al. Exposure to environmental microorganisms and childhood asthma. N Engl J Med. 2011; 364:701–709.

16. Ahluwalia SK, Matsui EC. The indoor environment and its effects on childhood asthma. Curr Opin Allergy Clin Immunol. 2011; 11:137–143.

17. Zutavern A, Hirsch T, Leupold W, Weiland S, Keil U, von Mutius E. Atopic dermatitis, extrinsic atopic dermatitis and the hygiene hypothesis: results from a cross-sectional study. Clin Exp Allergy. 2005; 35:1301–1308.

18. Kilpelainen M, Terho EO, Helenius H, Koskenvuo M. Home dampness, current allergic diseases, and respiratory infections among young adults. Thorax. 2001; 56:462–467.

19. Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol. 2003; 21:335–376.

20. Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science. 1998; 282:2085–2088.

21. Pamer EG. TLR polymorphisms and the risk of invasive fungal infections. N Engl J Med. 2008; 359:1836–1838.

22. Loures FV, Pina A, Felonato M, Araujo EF, Leite KR, Calich VL. Toll-like receptor 4 signaling leads to severe fungal infection associated with enhanced proinflammatory immunity and impaired expansion of regulatory T cells. Infect Immun. 2010; 78:1078–1088.

23. Li M, Chen Q, Sun J, Shen Y, Liu W. Inflammatory response of human keratinocytes triggered by Sporothrix schenckii via Toll-like receptor 2 and 4. J Dermatol Sci. 2012; 66:80–82.

24. Shin SH, Lee YH. Airborne fungi induce nasal polyp epithelial cell activation and Toll-like receptor expression. Int Arch Allergy Immunol. 2010; 153:46–52.

25. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. Lancet. 1998; 351:1225–1232.

26. Hong SJ, Lee MS, Sohn MH, Shim JY, Han YS, Park KS, et al. Self-reported prevalence and risk factors of asthma among Korean adolescents: 5-year follow-up study, 1995-2000. Clin Exp Allergy. 2004; 34:1556–1562.

27. Zock JP, Jarvis D, Luczynska C, Sunyer J, Burney P. European Community Respiratory Health Survey. Housing characteristics, reported mold exposure, and asthma in the European Community Respiratory Health Survey. J Allergy Clin Immunol. 2002; 110:285–292.

28. Hussein YM, Awad HA, Shalaby SM, Ali AS, Alzahrani SS. Toll-like receptor 2 and Toll-like receptor 4 polymorphisms and susceptibility to asthma and allergic rhinitis: a case-control analysis. Cell Immunol. 2012; 274:34–38.

29. Li DQ, Zhang L, Pflugfelder SC, De Paiva CS, Zhang X, Zhao G, et al. Short ragweed pollen triggers allergic inflammation through Toll-like receptor 4-dependent thymic stromal lymphopoietin/OX40 ligand/OX40 signaling pathways. J Allergy Clin Immunol. 2011; 128:1318–1325.e2.

30. Harris JM, Cullinan P, Williams HC, Mills P, Moffat S, White C, et al. Environmental associations with eczema in early life. Br J Dermatol. 2001; 144:795–802.

31. Garrett MH, Rayment PR, Hooper MA, Abramson MJ, Hooper BM. Indoor airborne fungal spores, house dampness and associations with environmental factors and respiratory health in children. Clin Exp Allergy. 1998; 28:459–467.

32. Apfelbacher CJ, Diepgen TL, Schmitt J. Determinants of eczema: population-based cross-sectional study in Germany. Allergy. 2011; 66:206–213.

33. Lee YL, Li CW, Sung FC, Yu HS, Sheu HM, Guo YL. Environmental factors, parental atopy and atopic eczema in primary-school children: a cross-sectional study in Taiwan. Br J Dermatol. 2007; 157:1217–1224.

34. Miyake Y, Ohya Y, Tanaka K, Yokoyama T, Sasaki S, Fukushima W, et al. Home environment and suspected atopic eczema in Japanese infants: the Osaka Maternal and Child Health Study. Pediatr Allergy Immunol. 2007; 18:425–432.

35. Ibargoyen-Roteta N, Aguinaga-Ontoso I, Fernandez-Benitez M, Marin-Fernandez B, Guillen-Grima F, Serrano-Monzo I, et al. Role of the home environment in rhinoconjunctivitis and eczema in schoolchildren in Pamplona, Spain. J Investig Allergol Clin Immunol. 2007; 17:137–144.

36. Schäfer T, Stieger B, Polzius R, Krauspe A. Atopic eczema and indoor climate: results from the children from Lübeck allergy and environment study (KLAUS). Allergy. 2008; 63:244–246.

37. Strid J, Strobel S. Skin barrier dysfunction and systemic sensitization to allergens through the skin. Curr Drug Targets Inflamm Allergy. 2005; 4:531–541.

38. Takai T, Ikeda S. Barrier dysfunction caused by environmental proteases in the pathogenesis of allergic diseases. Allergol Int. 2011; 60:25–35.

39. Straus DC. Molds, mycotoxins, and sick building syndrome. Toxicol Ind Health. 2009; 25:617–635.

40. Gent JF, Ren P, Belanger K, Triche E, Bracken MB, Holford TR, et al. Levels of household mold associated with respiratory symptoms in the first year of life in a cohort at risk for asthma. Environ Health Perspect. 2002; 110:A781–A786.