title: Copy Number Variations in CTNNA3 and RBFOX1 Associate with Pediatric Food Allergy.
abstract: Food allergy is a significant public health concern, especially among children. Previous candidate gene studies suggested a few susceptibility loci for food allergy, but no study investigated the contribution of copy number variations (CNVs) to food allergy on a genome-wide scale. To investigate the genetics of food allergy, we performed CNV assessment using high-resolution genome-wide single nucleotide polymorphism arrays. CNV calls from a total of 357 cases with confirmed food allergy and 3980 controls were analyzed within a discovery cohort, followed by a replication analysis composed of 167 cases and 1573 controls. We identified that CNVs in CTNNA3 were significantly associated with food allergy in both the discovery cohort and the replication cohort. Of particular interest, CTNNA3 CNVs hit exons or intron regions rich in histone marker H3K4Me1. CNVs in a second gene (RBFOX1) showed a significant association (p = 7.35 × 10(-5)) with food allergy at the genome-wide level in our meta-analysis of the European ancestry cohorts. The presence of these CNVs was confirmed by quantitative PCR. Furthermore, knockdown of CTNNA3 resulted in upregulation of CD63 and CD203c in mononuclear cells upon PMA stimulation, suggesting a role in sensitization to allergen. We uncovered at least two plausible genes harboring CNV loci that are enriched in pediatric patients with food allergies. The novel gene candidates discovered in this study by genome-wide CNV analysis are compelling drug and diagnostic targets for food allergy.
authors.affiliation: Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA 19104;
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.affiliation: Division of Allergy and Immunology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104;
authors.forename: Irene
authors.initials: I
authors.lastname: Fung
authors.affiliation: Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA 19104;
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Glessner
authors.affiliation: Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA 19104;
authors.forename: Rahul
authors.initials: R
authors.lastname: Pandey
authors.affiliation: Department of Computer Science, New Jersey Institute of Technology, Newark, NJ 08540;
authors.forename: Zhi
authors.initials: Z
authors.lastname: Wei
authors.affiliation: Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA 19104;
authors.forename: Marina
authors.initials: M
authors.lastname: Bakay
authors.affiliation: Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA 19104;
authors.forename: Frank D
authors.initials: FD
authors.lastname: Mentch
authors.affiliation: Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA 19104;
authors.forename: Renata
authors.initials: R
authors.lastname: Pellegrino
authors.affiliation: Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA 19104;
authors.forename: Tiancheng
authors.initials: T
authors.lastname: Wang
authors.affiliation: Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA 19104;
authors.forename: Cecilia
authors.initials: C
authors.lastname: Kim
authors.affiliation: Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA 19104;
authors.forename: Cuiping
authors.initials: C
authors.lastname: Hou
authors.affiliation: Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA 19104;
authors.forename: Fengxiang
authors.initials: F
authors.lastname: Wang
authors.affiliation: Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA 19104;
authors.forename: Rosetta M
authors.initials: RM
authors.lastname: Chiavacci
authors.affiliation: Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA 19104;
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Thomas
authors.affiliation: Division of Allergy and Immunology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; Center for Pediatric Eosinophilic Disorders, The Children's Hospital of Philadelphia, Philadelphia, PA 19104; and.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Spergel
authors.affiliation: Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA 19104; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104 hakonarson@email.chop.edu sleimanp@email.chop.edu.
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.affiliation: Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA 19104; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104 hakonarson@email.chop.edu sleimanp@email.chop.edu.
authors.forename: Patrick M A
authors.initials: PM
authors.lastname: Sleiman
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000367:Age Factors; D051178:alpha Catenin / Q000235:genetics; D016022:Case-Control Studies; D056915:DNA Copy Number Variations; D005512:Food Hypersensitivity / Q000235:genetics / Q000276:immunology; D017353:Gene Deletion; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results; D000072260:RNA Splicing Factors; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins / Q000235:genetics
chemical_list: D051178:alpha Catenin; C441963:CTNNA3 protein, human; C455479:RBFOX1 protein, human; D000072260:RNA Splicing Factors; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins