#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Maternal Filaggrin Mutations Increase the Risk of Atopic Dermatitis in Children: An Effect Independent of Mutation Inheritance


Most human diseases are caused by a combination of multiple environmental and genetic influences. The widely used case/control approach aims to identify disease risk genes by comparing the genetic constitution of affected and healthy individuals. Although successful, this approach ignores additional mechanisms influencing disease risk. Here, we studied mutations in the filaggrin gene (FLG), which are strong risk factors for atopic dermatitis (AD) and allergies, in a large number of families with AD. We found that FLG mutations in the mother, not the father, increased the AD risk of the children, even if the child did not inherit the mutation. Thus, our study revealed, for the first time, a direct influence of a maternal mutation on the child’s risk for a common disease. The maternal FLG effect was only found when the mothers were allergic, and was absent in families of non-allergic mothers. This finding suggests that FLG-induced changes in the maternal immune response shape the child’s immune system during pregnancy and increase the child’s risk for AD. Our study indicates that maternal FLG mutations act as strong environmental risk factors for the child and highlights the potential of family-based studies in uncovering novel disease mechanisms in medical genetics.


Vyšlo v časopise: Maternal Filaggrin Mutations Increase the Risk of Atopic Dermatitis in Children: An Effect Independent of Mutation Inheritance. PLoS Genet 11(3): e32767. doi:10.1371/journal.pgen.1005076
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005076

Souhrn

Most human diseases are caused by a combination of multiple environmental and genetic influences. The widely used case/control approach aims to identify disease risk genes by comparing the genetic constitution of affected and healthy individuals. Although successful, this approach ignores additional mechanisms influencing disease risk. Here, we studied mutations in the filaggrin gene (FLG), which are strong risk factors for atopic dermatitis (AD) and allergies, in a large number of families with AD. We found that FLG mutations in the mother, not the father, increased the AD risk of the children, even if the child did not inherit the mutation. Thus, our study revealed, for the first time, a direct influence of a maternal mutation on the child’s risk for a common disease. The maternal FLG effect was only found when the mothers were allergic, and was absent in families of non-allergic mothers. This finding suggests that FLG-induced changes in the maternal immune response shape the child’s immune system during pregnancy and increase the child’s risk for AD. Our study indicates that maternal FLG mutations act as strong environmental risk factors for the child and highlights the potential of family-based studies in uncovering novel disease mechanisms in medical genetics.


Zdroje

1. Brown SJ, McLean WH (2012) One remarkable molecule: filaggrin. J Invest Dermatol 132: 751–762. doi: 10.1038/jid.2011.393 22158554

2. Smith FJ, Irvine AD, Terron-Kwiatkowski A, Sandilands A, Campbell LE et al. (2006) Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet 38: 337–342. 16444271

3. Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H 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. 16550169

4. Sandilands A, Terron-Kwiatkowski A, Hull PR, O'Regan GM, Clayton TH et al. (2007) Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema. Nat Genet 39: 650–654. 17417636

5. Brown SJ, Asai Y, Cordell HJ, Campbell LE, Zhao Y 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. doi: 10.1016/j.jaci.2011.01.031 21377035

6. Fallon PG, Sasaki T, Sandilands A, Campbell LE, Saunders SP et al. (2009) A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming. Nat Genet 41: 602–608. doi: 10.1038/ng.358 19349982

7. Kawasaki H, Nagao K, Kubo A, Hata T, Shimizu A et al. (2012) Altered stratum corneum barrier and enhanced percutaneous immune responses in filaggrin-null mice. J Allergy Clin Immunol 129: 1538–1546. doi: 10.1016/j.jaci.2012.01.068 22409988

8. Lim RH, Kobzik L, Dahl M (2010) Risk for asthma in offspring of asthmatic mothers versus fathers: a meta-analysis. PLoS One 5: e10134. doi: 10.1371/journal.pone.0010134 20405032

9. Goldberg M, Eisenberg E, Elizur A, Rajuan N, Rachmiel M et al. (2013) Role of parental atopy in cow's milk allergy: a population-based study. Ann Allergy Asthma Immunol 110: 279–283. doi: 10.1016/j.anai.2013.01.017 23535093

10. Bisgaard H, Halkjaer LB, Hinge R, Giwercman C, Palmer C et al. (2009) Risk analysis of early childhood eczema. J Allergy Clin Immunol 123: 1355–1360. doi: 10.1016/j.jaci.2009.03.046 19501236

11. Wadonda-Kabondo N, Sterne JA, Golding J, Kennedy CT, Archer CB et al. (2004) Association of parental eczema, hayfever, and asthma with atopic dermatitis in infancy: birth cohort study. Arch Dis Child 89: 917–921. 15383434

12. Kong A, Steinthorsdottir V, Masson G, Thorleifsson G, Sulem P et al. (2009) Parental origin of sequence variants associated with complex diseases. Nature 462: 868–874. doi: 10.1038/nature08625 20016592

13. Lawson HA, Cheverud JM, Wolf JB (2013) Genomic imprinting and parent-of-origin effects on complex traits. Nat Rev Genet 14: 609–617. doi: 10.1038/nrg3543 23917626

14. Hager R, Cheverud JM, Wolf JB (2008) Maternal effects as the cause of parent-of-origin effects that mimic genomic imprinting. Genetics 178: 1755–1762. doi: 10.1534/genetics.107.080697 18245362

15. Exome Aggregation Consortium (ExAC), Cambridge, MA (URL: http://exac.broadinstitute.org) [date (December, 2014) accessed].

16. Marenholz I, Nickel R, Ruschendorf F, Schulz F, Esparza-Gordillo J et al. (2006) Filaggrin loss-of-function mutations predispose to phenotypes involved in the atopic march. J Allergy Clin Immunol 118: 866–871. 17030239

17. Ekelund E, Lieden A, Link J, Lee SP, d'Amato M et al. (2008) Loss-of-function variants of the filaggrin gene are associated with atopic eczema and associated phenotypes in Swedish families. Acta Derm Venereol 88: 15–19. doi: 10.2340/00015555-0383 18176743

18. Howey R, Cordell HJ (2012) PREMIM and EMIM: tools for estimation of maternal, imprinting and interaction effects using multinomial modelling. BMC Bioinformatics 13: 149. doi: 10.1186/1471-2105-13-149 22738121

19. Ainsworth HF, Unwin J, Jamison DL, Cordell HJ (2011) Investigation of maternal effects, maternal-fetal interactions and parent-of-origin effects (imprinting), using mothers and their offspring. Genet Epidemiol 35: 19–45. doi: 10.1002/gepi.20547 21181895

20. Lee YA, Wahn U, Kehrt R, Tarani L, Businco L et al. (2000) A major susceptibility locus for atopic dermatitis maps to chromosome 3q21. Nat Genet 26: 470–473. 11101848

21. Muller S, Marenholz I, Lee YA, Sengler C, Zitnik SE et al. (2009) Association of Filaggrin loss-of-function-mutations with atopic dermatitis and asthma in the Early Treatment of the Atopic Child (ETAC) population. Pediatr Allergy Immunol 20: 358–361. doi: 10.1111/j.1399-3038.2008.00808.x 19538357

22. Ballardini N, Kull I, Soderhall C, Lilja G, Wickman M et al. (2013) Eczema severity in preadolescent children and its relation to sex, filaggrin mutations, asthma, rhinitis, aggravating factors and topical treatment: a report from the BAMSE birth cohort. Br J Dermatol 168: 588–594. doi: 10.1111/bjd.12196 23445315

23. Willer CJ, Li Y, Abecasis GR (2010) METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26: 2190–2191. doi: 10.1093/bioinformatics/btq340 20616382

24. Case A, Paxson C (2001) Mothers and others: who invests in children's health? J Health Econ 20: 301–328. 11373833

25. Su AI, Wiltshire T, Batalov S, Lapp H, Ching KA et al. (2004) A gene atlas of the mouse and human protein-encoding transcriptomes. Proc Natl Acad Sci U S A 101: 6062–6067. 15075390

26. Wu C, Orozco C, Boyer J, Leglise M, Goodale J et al. (2009) BioGPS: an extensible and customizable portal for querying and organizing gene annotation resources. Genome Biol 10: R130. doi: 10.1186/gb-2009-10-11-r130 19919682

27. GTEx Consortium. (2013) The Genotype-Tissue Expression (GTEx) project. Nat Genet 45: 580–585. doi: 10.1038/ng.2653 23715323

28. 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. doi: 10.1136/bmj.b2433 19589816

29. Liu FT, Goodarzi H, Chen HY (2011) IgE, mast cells, and eosinophils in atopic dermatitis. Clin Rev Allergy Immunol 41: 298–310. doi: 10.1007/s12016-011-8252-4 21249468

30. Hamada K, Suzaki Y, Goldman A, Ning YY, Goldsmith C et al. (2003) Allergen-independent maternal transmission of asthma susceptibility. J Immunol 170: 1683–1689. 12574331

31. Fedulov AV, Kobzik L (2011) Allergy risk is mediated by dendritic cells with congenital epigenetic changes. Am J Respir Cell Mol Biol 44: 285–292. doi: 10.1165/rcmb.2009-0400OC 20118218

32. Straubinger K, Paul S, Prazeres da CO, Ritter M, Buch T et al. (2014) Maternal immune response to helminth infection during pregnancy determines offspring susceptibility to allergic airway inflammation. J Allergy Clin Immunol.

33. von ME, Vercelli D (2010) Farm living: effects on childhood asthma and allergy. Nat Rev Immunol 10: 861–868. doi: 10.1038/nri2871 21060319

34. Brand S, Teich R, Dicke T, Harb H, Yildirim AO 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. doi: 10.1016/j.jaci.2011.04.035 21680015

35. Mott R, Yuan W, Kaisaki P, Gan X, Cleak J et al. (2014) The architecture of parent-of-origin effects in mice. Cell 156: 332–342. doi: 10.1016/j.cell.2013.11.043 24439386

36. Shirakawa T, Li A, Dubowitz M, Dekker JW, Shaw AE et al. (1994) Association between atopy and variants of the beta subunit of the high- affinity immunoglobulin E receptor. Nat Genet 7: 125–129. 7920628

37. Walley AJ, Chavanas S, Moffatt MF, Esnouf RM, Ubhi B et al. (2001) Gene polymorphism in Netherton and common atopic disease. Nat Genet 29: 175–178. 11544479

38. Soderhall C, Marenholz I, Kerscher T, Ruschendorf F, Esparza-Gordillo J et al. (2007) Variants in a novel epidermal collagen gene (COL29A1) are associated with atopic dermatitis. PLoS Biol 5: e242. 17850181

39. Gleason G, Liu B, Bruening S, Zupan B, Auerbach A et al. (2010) The serotonin1A receptor gene as a genetic and prenatal maternal environmental factor in anxiety. Proc Natl Acad Sci U S A 107: 7592–7597. doi: 10.1073/pnas.0914805107 20368423

40. Yan L, Zhao L, Long Y, Zou P, Ji G et al. (2012) Association of the maternal MTHFR C677T polymorphism with susceptibility to neural tube defects in offsprings: evidence from 25 case-control studies. PLoS One 7: e41689. doi: 10.1371/journal.pone.0041689 23056169

41. Gordeeva LA, Voronina EN, Sokolova EA, Ermolenko NA, Gareeva JV et al. (2013) Association GSTT1, GSTM1 and GSTP1 (Ile105Val) genetic polymorphisms in mothers with risk of congenital malformations in their children in Western Siberia: a case-control study. Prenat Diagn 1–7.

42. Hanifin JM, Rajka G (1980) Diagnostic Features of Atopic Dermatitis. Acta Derm (Stockholm) 92 (Suppl.): 44–47.

43. Esparza-Gordillo J, Weidinger S, Folster-Holst R, Bauerfeind A, Ruschendorf F et al. (2009) A common variant on chromosome 11q13 is associated with atopic dermatitis. Nat Genet 41: 596–601. doi: 10.1038/ng.347 19349984

44. Lau S, Illi S, Sommerfeld C, Niggemann B, Bergmann R et al. (2000) Early exposure to house-dust mite and cat allergens and development of childhood asthma: a cohort study. Multicentre Allergy Study Group. Lancet 356: 1392–1397. 11052581

45. Warner JO (2001) A double-blinded, randomized, placebo-controlled trial of cetirizine in preventing the onset of asthma in children with atopic dermatitis: 18 months' treatment and 18 months' posttreatment follow-up. J Allergy Clin Immunol 108: 929–937. 11742270

46. Williams HC, Burney PG, Hay RJ, Archer CB, Shipley MJ et al. (1994) The U.K. Working Party's Diagnostic Criteria for Atopic Dermatitis. I. Derivation of a minimum set of discriminators for atopic dermatitis. Br J Dermatol 131: 383–396. 7918015

47. Weidinger S, O'Sullivan M, Illig T, Baurecht H, Depner M et al. (2008) Filaggrin mutations, atopic eczema, hay fever, and asthma in children. J Allergy Clin Immunol 121: 1203–1209. doi: 10.1016/j.jaci.2008.02.014 18396323

48. Den Dunnen JT, Antonarakis SE (2001) Nomenclature for the description of human sequence variations. Hum Genet 109: 121–124. 11479744

49. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA et al. (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81: 559–575. 17701901

50. Herold C, Becker T (2009) Genetic association analysis with FAMHAP: a major program update. Bioinformatics 25: 134–136. doi: 10.1093/bioinformatics/btn581 19015131

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2015 Číslo 3
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Získaná hemofilie - Povědomí o nemoci a její diagnostika
nový kurz

Eozinofilní granulomatóza s polyangiitidou
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#