title: The skin barrier function gene SPINK5 is associated with challenge-proven IgE-mediated food allergy in infants.
abstract: BACKGROUND
  A defective skin barrier is hypothesized to be an important route of sensitization to dietary antigens and may lead to food allergy in some children. Missense mutations in the serine peptidase inhibitor Kazal type 5 (SPINK5) skin barrier gene have previously been associated with allergic conditions.
  
  
  OBJECTIVE
  To determine whether genetic variants in and around SPINK5 are associated with IgE-mediated food allergy.
  
  
  METHODS
  We genotyped 71 "tag" single nucleotide polymorphisms (tag-SNPs) within a region spanning ~263 kb including SPINK5 (~61 kb) in n=722 (n=367 food-allergic, n=199 food-sensitized-tolerant and n=156 non-food-allergic controls) 12-month-old infants (discovery sample) phenotyped for food allergy with the gold standard oral food challenge. Transepidermal water loss (TEWL) measures were collected at 12 months from a subset (n=150) of these individuals. SNPs were tested for association with food allergy using the Cochran-Mantel-Haenszel test adjusting for ancestry strata. Association analyses were replicated in an independent sample group derived from four paediatric cohorts, total n=533 (n=203 food-allergic, n=330 non-food-allergic), mean age 2.5 years, with food allergy defined by either clinical history of reactivity, 95% positive predictive value (PPV) or challenge, corrected for ancestry by principal components.
  
  
  RESULTS
  SPINK5 variant rs9325071 (A⟶G) was associated with challenge-proven food allergy in the discovery sample (P=.001, OR=2.95, CI=1.49-5.83). This association was further supported by replication (P=.007, OR=1.58, CI=1.13-2.20) and by meta-analysis (P=.0004, OR=1.65). Variant rs9325071 is associated with decreased SPINK5 gene expression in the skin in publicly available genotype-tissue expression data, and we generated preliminary evidence for association of this SNP with elevated TEWL also.
  
  
  CONCLUSIONS
  We report, for the first time, association between SPINK5 variant rs9325071 and challenge-proven IgE-mediated food allergy.
authors.affiliation: Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Vic., Australia.|The Hudson Institute, Monash Translational Health Precinct (MTHP), Monash University, Clayton, Vic., Australia.
authors.forename: S E
authors.identifier: http://orcid.org/0000-0001-9973-9742
authors.initials: SE
authors.lastname: Ashley
authors.affiliation: Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Vic., Australia.|Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Malaysia.
authors.forename: H-T T
authors.initials: HT
authors.lastname: Tan
authors.affiliation: Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Vic., Australia.|Child Health Research Unit, Barwon Health, Geelong, Vic., Australia.|Deakin University, Waurn Ponds, Vic., Australia.
authors.forename: P
authors.initials: P
authors.lastname: Vuillermin
authors.affiliation: Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Vic., Australia.|Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, Vic., Australia.
authors.forename: S C
authors.initials: SC
authors.lastname: Dharmage
authors.affiliation: Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Vic., Australia.|Department of Paediatrics, University of Melbourne, Parkville, Vic., Australia.|Department of Allergy and Immunology, Royal Children's Hospital, Parkville, Vic., Australia.
authors.forename: M L K
authors.initials: MLK
authors.lastname: Tang
authors.affiliation: Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Vic., Australia.|Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, Vic., Australia.
authors.forename: J
authors.initials: J
authors.lastname: Koplin
authors.affiliation: Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Vic., Australia.|Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, Vic., Australia.
authors.forename: L C
authors.initials: LC
authors.lastname: Gurrin
authors.affiliation: Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Vic., Australia.|Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, Vic., Australia.
authors.forename: A
authors.initials: A
authors.lastname: Lowe
authors.affiliation: Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Vic., Australia.|Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, Vic., Australia.
authors.forename: C
authors.initials: C
authors.lastname: Lodge
authors.affiliation: Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Vic., Australia.|Department of Paediatrics, University of Melbourne, Parkville, Vic., Australia.
authors.forename: A-L
authors.initials: AL
authors.lastname: Ponsonby
authors.affiliation: Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Vic., Australia.|Child Health Research Unit, Barwon Health, Geelong, Vic., Australia.|Deakin University, Waurn Ponds, Vic., Australia.
authors.forename: J
authors.identifier: http://orcid.org/0000-0002-6935-0418
authors.initials: J
authors.lastname: Molloy
authors.affiliation: Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Vic., Australia.|Department of Paediatrics, University of Melbourne, Parkville, Vic., Australia.
authors.forename: P
authors.initials: P
authors.lastname: Martin
authors.affiliation: Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Vic., Australia.|Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, Vic., Australia.
authors.forename: M C
authors.initials: MC
authors.lastname: Matheson
authors.affiliation: Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Vic., Australia.|The Hudson Institute, Monash Translational Health Precinct (MTHP), Monash University, Clayton, Vic., Australia.|Department of Paediatrics, University of Melbourne, Parkville, Vic., Australia.
authors.forename: R
authors.initials: R
authors.lastname: Saffery
authors.affiliation: Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Vic., Australia.|Department of Paediatrics, University of Melbourne, Parkville, Vic., Australia.|Department of Allergy and Immunology, Royal Children's Hospital, Parkville, Vic., Australia.|Institute of Inflammation and Repair, University of Manchester, Manchester, UK.
authors.forename: K J
authors.initials: KJ
authors.lastname: Allen
authors.affiliation: Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Vic., Australia.|Department of Paediatrics, University of Melbourne, Parkville, Vic., Australia.|Centre for Social and Early Emotional Development, Faculty of Health, Deakin University, Burwood, Vic., Australia.
authors.forename: J A
authors.initials: JA
authors.lastname: Ellis
authors.affiliation: Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Vic., Australia.|Department of Paediatrics, University of Melbourne, Parkville, Vic., Australia.|Department of Paediatrics, University of Western Australia, Crawley, WA, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Martino
mesh_terms: D002675:Child, Preschool; D005512:Food Hypersensitivity / Q000276:immunology*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology*; D007223:Infant; D009154:Mutation / Q000276:immunology*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D000074163:Serine Peptidase Inhibitor Kazal-Type 5 / Q000235:genetics*; D014870:Water Loss, Insensible / Q000235:genetics
chemical_list: C120650:SPINK5 protein, human; D000074163:Serine Peptidase Inhibitor Kazal-Type 5; D007073:Immunoglobulin E
keywords: 
  serine peptidase inhibitor Kazal type 5
  ; food allergy; lymphoepithelial Kazal-type-related inhibitor; skin barrier; skin barrier function