Research Report 2010 - MDC

Figure 1. Study designFigure 2. Association results and LD structure in the AD associatedregion on 11q13.5. (a) Association results for all GWA markers tested in theregion. Physical positions are based in the NCBI build 36. (b) Genes in theregion from the UniGene database. (c) LD in the CEU Hapmap population.Disequilibrium coefficient values for Hapmap Phase II data (v. 22)were generated with Haploview. The lead SNP is indicated by a green line.were identified to be a strong genetic risk factors foreczema and eczema-associated asthma. We investigatedin the population-based Multicenter Allergy Study(MAS cohort) whether the predictive value of the FLGmutations for asthma was related to infantile eczema.Furthermore, we investigated the role of allergic sensitizationto food allergens which represents the earliestserologic marker for atopy and is a recognized risk factorfor chronic asthma.We found that, in infants with eczema and sensitizationto food allergens within the first three years of life,the presence of a FLG loss of function mutation predictsthe future development of asthma with a specificityand a positive predictive value of 100%. The combinationof FLG mutations and early sensitization to foodallergens, predicted a sizeable proportion (17.2%) of theinfants with eczema who made the transition to asthmalater in childhood. Furthermore, longitudinal pulmonaryfunction measurements demonstrated thatthis subgroup of asthma children identified by the FLGmutations carried a poor prognosis with a steadydecline in pulmonary function until puberty. Hence, thissubgroup might particularly benefit from early predictionof the disease. Our findings indicate that assessmentof the FLG carrier status could improve the predictionof eczema-associated asthma considerably. Themagnitude of the predictive power surpasses the utilityof mutations in the breast cancer susceptibilitygenes BRCA1 and BRCA2 that account for only 2-4% ofall breast cancer cases and for 15-20% among the highrisk group of women with a strong family history andearly onset of the disease in whom targeted genetictesting was recommended. Analogously, in the highrisk group of children with eczema and early food sensitizationthe genotyping of the FLG mutations wouldidentify 35.7% of future asthmatics.In this study, we demonstrate that the determinationof the FLG carrier status in infants with eczema andsensitization to food allergens within the first threeyears of life would allow the early prediction of asthmabefore the onset of symptoms and at a critical time ofimmune development when preventive interventionsare likely to be effective. We suggest our findings couldbe of diagnostic and subsequent therapeutic utility.Selected PublicationsEsparza-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. A common variant onchromosome 11q13 is associated with atopic dermatitis. Nat Genet 41[5],596-601. 2009. * corresponding authorMarenholz I, Kerscher T, Bauerfeind A, Esparza-Gordillo J, Nickel R, Keil T,Lau S, Rohde K, Wahn U, Lee YA. An interaction between filaggrinmutations and early food sensitization improves the prediction ofchildhood asthma. J Allergy Clin Immunol 123[4], 911-916. 2009.Muller S, Marenholz I, Lee YA, Sengler C, Zitnik S, Griffioen RW, Meglio P,Wahn U, Nickel R. Association of Filaggrin loss-of-function mutationswith atopic dermatitis and asthma in the Early Treatment of the AtopicChild (ETAC) population. Pediatr Allergy Immunol . 2009.Pasternack SM, von Kugelgen I, Aboud KA, Lee YA, Ruschendorf F, Voss K,Hillmer AM, Molderings GJ, Franz T, Ramirez A, Nurnberg P, Nothen MM,Betz RC. G protein-coupled receptor P2Y5 and its ligand LPA are involvedin maintenance of human hair growth. Nat Genet 40[3], 329-334. 2008.Schulz F, Marenholz I, Folster-Holst R, Chen C, Sternjak A, Baumgrass R,Esparza-Gordillo J, Gruber C, Nickel R, Schreiber S, Stoll M, Kurek M,Ruschendorf F, Hubner N, Wahn U, Lee YA. A common haplotype of the IL-31 gene influencing gene expression is associated with nonatopiceczema. J Allergy Clin Immunol 120[5], 1097-1102. 2007.Cardiovascular and Metabolic Disease Research 55