Genetic Identification of Individuals with Increased Risk of Developing Occupational Skin Diseases

  • Sanja KezicEmail author
Reference work entry


Our understanding of the complex genetic susceptibility to occupational contact dermatitis (OCD) is still in the early stage. The search for candidate susceptibility genes focused mainly on proteins involved in skin barrier and immune response which have a key role in both irritant and allergic contact dermatitis (respectively, ICD and ACD). Furthermore, for ACD genetic variations in enzymes involved in metabolism of contact allergens have been investigated. Among skin barrier genes, loss-of-function mutations in the filaggrin gene (FLG) have been identified as a risk factor for irritant contact dermatitis (ICD); the risk-modifying effect of FLG mutations was stronger in the presence of atopic dermatitis. In ACD, the impact of FLG mutations was allergen specific and dependent on the outcome measure and the exposure pattern. Several studies reported association of genetic polymorphisms in the metabolizing enzymes N-acetyltransferase and glutathione S-transferase with ACD; however the results are so far inconclusive. Among inflammatory genes, there appears to be an effect of TNF gene polymorphisms on susceptibility to both irritant and allergic CD, suggesting that they share some common pathways.

At present, the predictive value of genetic markers for the appearance of OCD is too low for reasonable identification of susceptible individuals in occupational health practice.

Further well-designed studies in larger cohorts with a well-defined disease phenotype and external exposure in the control as well as in the case group are needed to confirm and extend our knowledge of the impact of genetic variations on the susceptibility to OCD.


Allergic contact dermatitis Irritant contact dermatitis Genetic susceptibilty Occupational 


  1. Allen MH, Wakelin SH, Holloway D, Lisby S, Baadsgaard O, Barker JNWN, McFadden JP (2000) Association of TNFA gene polymorphism at position-308 with susceptibility to irritant contact dermatitis. Immunogenetics 51:201–205PubMedCrossRefGoogle Scholar
  2. Belsito DV (2005) Occupational contact dermatitis: etiology, prevalence, and resultant impairment/disability. J Am Acad Dermatol 53:303–313PubMedCrossRefGoogle Scholar
  3. Blömeke B, Brans R, Dickel H, Bruckner T, Erdmann S, Heesen M, Merk HF, Coenraads PJ (2009a) Association between TNFA-308G/a polymorphism and sensitization to para-phenylenediamine: a case-control study. Allergy 64:279–283PubMedCrossRefGoogle Scholar
  4. Blömeke B, Brans R, Coenraads PJ, Dickel H, Bruckner T, Hein DW, Heesen M, Merk HF, Kawakubo Y (2009b) Para-phenylenediamine and allergic sensitization: risk modification by N-acetyltransferase 1 and 2 genotypes. Br J Dermatol 161:1130–1135PubMedCrossRefGoogle Scholar
  5. Bolt HM, Thier R (2006) Relevance of the deletion polymorphisms of the glutathione S-transferases GSTT1 and GSTM1 in pharmacology and toxicology. Curr Drug Metab 7:613–628PubMedCrossRefGoogle Scholar
  6. Brans R, Dickel H, Bruckner T, Coenraads PJ, Heesen M, Merk HF, Blomeke B (2005) MnSOD polymorphisms in sensitized patients with delayed-type hypersensitivity reactions to the chemical allergen para-phenylene diamine: a case-control study. Toxicology 212:148–154PubMedCrossRefGoogle Scholar
  7. Brown SJ, Cordell HJ (2008) Are filaggrin mutations associated with hand eczema or contact allergy?–we do not know. Br J Dermatol 158:1383–1384PubMedCrossRefGoogle Scholar
  8. de Cid R, Riveira-Munoz E, Zeeuwen PL, Robarge J, Liao W, Dannhauser EN, Giardina E, Stuart PE, Nair R, Helms C, Escaramís G, Ballana E, Martín-Ezquerra G, den Heijer M, Kamsteeg M, Joosten I, Eichler EE, Lázaro C, Pujol RM, Armengol L, Abecasis G, Elder JT, Novelli G, Armour JA, Kwok PY, Bowcock A, Schalkwijk J, Estivill X (2009) Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis. Nat Genet 41:211–215PubMedPubMedCentralCrossRefGoogle Scholar
  9. Colagiovanni A, Di Renzo L, Sarlo F, Schiavino D, De Lorenzo A (2016) Role of TNF-alpha polymorphism in patients with nickel allergy: a marker of susceptibility to contact polysensitization. Eur Rev Med Pharmacol Sci 20:2663–2666PubMedGoogle Scholar
  10. Diepgen TL, Kanerva L (2006) Occupational skin diseases. Eur J Dermatol 16:324–330PubMedGoogle Scholar
  11. Elias PM, Schmuth M (2009) Abnormal skin barrier in the etiopathogenesis of atopic dermatitis. Curr Allergy Asthma Rep 9:265–272PubMedCrossRefGoogle Scholar
  12. English JS (2004) Current concepts of irritant contact dermatitis. Occup Environ Med 61:722–726PubMedPubMedCentralCrossRefGoogle Scholar
  13. Ertam I, Itirli G, Onay H, Alper S, Ozkinay F (2009) Interleukin-1 receptor antagonist and tumour necrosis factor-alpha gene polymorphisms in Turkish patients with allergic contact dermatitis. Contact Dermatitis 61:86–90PubMedCrossRefGoogle Scholar
  14. Esser PR, Martin SF (2017) Pathomechanisms of contact sensitization. Curr Allergy Asthma Rep 17:83PubMedCrossRefGoogle Scholar
  15. Fluhr JW, Darlenski R, Angelova-Fischer I, Tsankov N, Basketter D (2008) Skin irritation and sensitization: mechanisms and new approaches for risk assessment. 1. Skin irritation. Skin Pharmacol Physiol 21:124–135PubMedCrossRefGoogle Scholar
  16. Friedmann PS, Sanchez-Elsner T, Schnuch A (2015) Genetic factors in susceptibility to contact sensitivity. Contact Dermatitis 72:263–274PubMedCrossRefGoogle Scholar
  17. de Jongh CM, Khrenova L, Verberk MM, Calkoen F, van Dijk FJ, Voss H, John SM, Kezic S (2008a) Loss-of-function polymorphisms in the filaggrin gene are associated with an increased susceptibility to chronic irritant contact dermatitis: a case-control study. Br J Dermatol 159:621–627PubMedCrossRefGoogle Scholar
  18. de Jongh CM, John SM, Bruynzeel DP, Calkoen F, van Dijk FJ, Khrenova L, Rustemeyer T, Verberk MM, Kezic S (2008b) Cytokine gene polymorphisms and susceptibility to chronic irritant contact dermatitis. Contact Dermatitis 58:269–277PubMedCrossRefGoogle Scholar
  19. de Jongh CM, Khrenova L, Kezic S, Rustemeyer T, Verberk MM, John SM (2008c) Polymorphisms in the interleukin-1 gene influence the stratum corneum interleukin-1alpha concentration in uninvolved skin of patients with chronic irritant contact dermatitis. Contact Dermatitis 58:263–268PubMedCrossRefGoogle Scholar
  20. Kezic S, Jakasa I (2016) Filaggrin and skin barrier function. Curr Probl Dermato 49:1–7CrossRefGoogle Scholar
  21. Kimber I, Basketter DA, Gerberick GF, Dearman RJ (2002) Allergic contact dermatitis. Int Immunopharmacol 2:201–211PubMedCrossRefGoogle Scholar
  22. Koppes SA, Engebretsen KA, Agner T, Angelova-Fischer I, Berents T, Brandner J, Brans R, Clausen ML, Hummler E, Jakasa I, Jurakić-Tončic R, John SM, Khnykin D, Molin S, Holm JO, Suomela S, Thierse HJ, Kezic S, Martin SF, Thyssen JP (2017) Current knowledge on biomarkers for contact sensitization and allergic contact dermatitis. Contact Dermatitis 77:1–16PubMedCrossRefGoogle Scholar
  23. Landeck L, Visser M, Kezic S, John SM (2012a) Impact of tumour necrosis factor-α polymorphisms on irritant contact dermatitis. Contact Dermatitis 66:221–227PubMedCrossRefGoogle Scholar
  24. Landeck L, Visser M, Skudlik C, Brans R, Kezic S, John SM (2012b) Clinical course of occupational irritant contact dermatitis of the hands in relation to filaggrin genotype status and atopy. Br J Dermatol 167:1302–1309PubMedCrossRefGoogle Scholar
  25. Landeck L, Visser M, Kezic S, John SM (2013) IL1A-889 C/T gene polymorphism in irritant contact dermatitis. J Eur Acad Dermatol Venereol 27:1040–1043PubMedCrossRefGoogle Scholar
  26. Landeck L, Visser M, Skudlik C, Brans R, Kezic S, John SM (2014) No remarkable differences in rates of sensitization to common type I and IV allergens between FLG loss-of-function mutation carriers and wild-type subjects. Contact Dermatitis 70:27–34PubMedCrossRefGoogle Scholar
  27. Lerbaek A, Bisgaard H, Agner T, Ohm Kyvik K, Palmer CN, Menné T (2007) Filaggrin null alleles are not associated with hand eczema or contact allergy. Br J Dermatol 157:1199–1204PubMedCrossRefGoogle Scholar
  28. Molin S, Vollmer S, Weiss EH, Ruzicka T, Prinz JC (2009) Filaggrin mutations may confer susceptibility to chronic hand eczema characterized by combined allergic and irritant contact dermatitis. Br J Dermatol 161:801–807PubMedCrossRefGoogle Scholar
  29. Molin S, Vollmer S, Weiss EH, Weisenseel P, Ruzicka T, Prinz JC (2011) Deletion of the late cornified envelope genes LCE3B and LCE3C may promote chronic hand eczema with allergic contact dermatitis. J Investig Allergol Clin Immunol 21:472–479PubMedGoogle Scholar
  30. Nacak M, Erbagci Z, Aynacioglu AS (2006) Human arylamine N-acetyltransferase 2 polymorphism and susceptibility to allergic contact dermatitis. Int J Dermatol 45:323–326PubMedCrossRefGoogle Scholar
  31. Najim RA, Al-waizt M, Al-Razzuqi RA (2005) Acetylator phenotype in Iraqi patients with allergic contact dermatitis. Ann Saudi Med 25:473–476PubMedPubMedCentralCrossRefGoogle Scholar
  32. Novak N, Baurecht H, Schafer T, Rodriguez E, Wagenpfeil S, Klopp N, Heinrich J, Behrendt H, Ring J, Wichmann E, Illig T, Weidinger S (2008) Loss-of-function mutations in the filaggrin gene and allergic contact sensitization to nickel. J Invest Dermatol 128:1430–1435PubMedCrossRefGoogle Scholar
  33. Pastore S, Mascia F, Mariotti F, Dattilo C, Girolomoni G (2004) Chemokine networks in inflammatory skin diseases. Eur J Dermatol 14:203–208PubMedGoogle Scholar
  34. Pot LM, Alizadeh BZ, Ahrenberg D, Coenraads PJ, Snieder H, Blömeke B (2011) No major role for glutathione S-transferase gene polymorphisms in sensitization to para-phenylenediamine and other xenobiotics: a study of association and a meta-analysis. Br J Dermatol 164:890–892PubMedCrossRefGoogle Scholar
  35. Proksch E, Brandner JM, Jensen JM (2008) The skin – an indispensable barrier. Exp Dermatol 17:1063–1072PubMedCrossRefGoogle Scholar
  36. Reich K, Westphal G, Konig IR, Mossner R, Kruger U, Ziegler A, Neumann C, Schnuch A (2003) Association of allergic contact dermatitis with a promoter polymorphism in the IL16 gene. J Allergy Clin Immunol 112:1191–1194PubMedCrossRefGoogle Scholar
  37. Ross-Hansen K, Linneberg A, Johansen JD, Hersoug LG, Brasch-Andersen C, Menné T, Thyssen JP (2013) The role of glutathione S-transferase and claudin-1 gene polymorphisms in contact sensitization: a cross-sectional study. Br J Dermatol 168:762–770PubMedCrossRefGoogle Scholar
  38. Schnuch A, Westphal G, Mössner R, Uter W, Reich K (2011) Genetic factors in contact allergy--review and future goals. Contact Dermatitis 64:2–23PubMedCrossRefGoogle Scholar
  39. Thyssen JP, Kezic S (2014) Causes of epidermal filaggrin reduction and their role in the pathogenesis of atopic dermatitis. J Allergy Clin Immunol 134:792–799PubMedCrossRefGoogle Scholar
  40. Thyssen JP, Johansen JD, Linneberg A, Menné T, Nielsen NH, Meldgaard M, Szecsi PB, Stender S, Carlsen BC (2010) The association between null mutations in the filaggrin gene and contact sensitization to nickel and other chemicals in the general population. Br J Dermatol 162:1278–1285PubMedCrossRefGoogle Scholar
  41. Timmerman JG, Heederik D, Spee T, van Rooy FG, Krop EJ, Koppelman GH, Rustemeyer T, Smit LA (2016) Contact dermatitis in the construction industry: the role of filaggrin loss-of-function mutations. Br J Dermatol 174:348–355PubMedCrossRefGoogle Scholar
  42. Visser MJ, Landeck L, Campbell LE, McLean WHI, Weidinger S, Calkoen F, John SM, Kezic S (2013) Impact of atopic dermatitis and loss-of-function mutations in the filaggrin gene on the development of occupational irritant contact dermatitis. Br J Dermatol 168:326–332PubMedPubMedCentralCrossRefGoogle Scholar
  43. Visser MJ, Verberk MM, Campbell LE, McLean WH, Calkoen F, Bakker JG, van Dijk FJ, Bos JD, Kezic S (2014) Filaggrin loss-of-function mutations and atopic dermatitis as risk factors for hand eczema in apprentice nurses: part II of a prospective cohort study. Contact Dermatitis 70:139–150PubMedCrossRefGoogle Scholar
  44. Wang BJ, Shiao JS, Chen CJ, Lee YC, Guo YL (2007) Tumour necrotizing factor-alpha promoter and GST-T1 genotype predict skin allergy to chromate in cement workers in Taiwan. Contact Dermatitis 57:309–315PubMedCrossRefGoogle Scholar
  45. Weidinger S, Novak N (2016) Atopic dermatitis. Lancet 387:1109–1122CrossRefGoogle Scholar
  46. Westphal GA, Reich K, Schulz TG, Neumann C, Hallier E, Schnuch A (2000a) N-acetyltransferase 1 and 2 polymorphisms in para-substituted arylamine-induced contact allergy. Br J Dermatol 142:1121–1127PubMedCrossRefGoogle Scholar
  47. Westphal GA, Schnuch A, Schulz TG, Reich K, Aberer W, Brasch J, Koch P, Wessbecher R, Szliska C, Bauer A, Hallier E (2000b) Homozygous gene deletions of the glutathione S-transferases M1 and T1 are associated with thimerosal sensitization. Int Arch Occup Environ Health 73:384–388PubMedCrossRefGoogle Scholar
  48. Westphal GA, Schnuch A, Moessner R, Konig IR, Kranke B, Hallier E, Ziegler A, Reich K (2003) Cytokine gene polymorphisms in allergic contact dermatitis. Contact Dermatitis 48:93–98PubMedCrossRefGoogle Scholar
  49. Westphal GA, Rihs HP, Schaffranek A, Zeiler T, Werfel T, Heratizadeh A, Dickel H, Weisshaar E, Bauer A, Schliemann S, Reich K, Breuer K, Schröder-Kraft C, Worm M, Molin S, Brans R, Schäkel K, Schwantes H, Pföhler C, Szliska C, Kreft B, Löffler H, Bünger J, Brüning T, Geier J, Schnuch A (2016) A variant of the CXCL11 gene may influence susceptibility to contact allergy, particularly in polysensitized patients. Contact Dermatitis 75:303–307PubMedCrossRefGoogle Scholar
  50. Wilson AG, Symons JA, McDowell TL, McDevitt HO, Duff GW (1997) Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci U S A 94:3195–3199PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Coronel Institute of Occupational Health, Amsterdam Public Health Research Institute, Academic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands

Personalised recommendations