The skin barrier function gene SPINK5 is associated with challenge‐proven IgE‐mediated food allergy in infants

• Published in: Allergy (Copenhagen) Vol. 72; no. 9; pp. 1356 - 1364
• Main Authors: Ashley, S. E., Tan, H.‐T. T., Vuillermin, P., Dharmage, S. C., Tang, M. L. K., Koplin, J., Gurrin, L. C., Lowe, A., Lodge, C., Ponsonby, A.‐L., Molloy, J., Martin, P., Matheson, M. C., Saffery, R., Allen, K. J., Ellis, J. A., Martino, D.
• Format: Journal Article
• Language: English
• Published: Denmark Blackwell Publishing Ltd 01.09.2017
• Subjects: Antigens; Child, Preschool; Children; Food allergies; food allergy; Food Hypersensitivity - immunology; Gene expression; Genetic Predisposition to Disease; Humans; Immunoglobulin E; Immunoglobulin E - immunology; Infant; Infants; lymphoepithelial Kazal‐type‐related inhibitor; Missense mutation; Mucous membrane; Mutation - immunology; Peanuts; Pediatrics; Phenotype; Polymorphism, Single Nucleotide; Predictive Value of Tests; Serine; Serine peptidase; serine peptidase inhibitor Kazal type 5; Serine Peptidase Inhibitor Kazal-Type 5 - genetics; Single-nucleotide polymorphism; Skin; skin barrier; skin barrier function; Water loss; Water Loss, Insensible - genetics; serine peptidase inhibitor Kazal type 5; skin barrier; lymphoepithelial Kazal-type-related inhibitor; skin barrier function; food allergy
• ISSN: 0105-4538; 1398-9995
• DOI: 10.1111/all.13143

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. Method 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.