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

S E Ashley; H-T T Tan; P Vuillermin; S C Dharmage; M L K Tang; J Koplin; L C Gurrin; A Lowe; C Lodge; A-L Ponsonby; J Molloy; P Martin; M C Matheson; R Saffery; K J Allen; J A Ellis; D Martino; HealthNuts team; Barwon Infant Study, the Melbourne Atopy Cohort study, the Peanut Allergen Threshold Study and the Probiotic and Peanut Oral ImmunoTherapy study

doi:10.1111/all.13143

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

Allergy. 2017 Sep;72(9):1356-1364. doi: 10.1111/all.13143. Epub 2017 Apr 4.

Authors

S E Ashley^{1

2}, H-T T Tan^{1

3}, P Vuillermin^{1

4

5}, S C Dharmage^{1

6}, M L K Tang^{1

7

8}, J Koplin^{1

6}, L C Gurrin^{1

6}, A Lowe^{1

6}, C Lodge^{1

6}, A-L Ponsonby^{1

7}, J Molloy^{1

4

5}, P Martin^{1

7}, M C Matheson^{1

6}, R Saffery^{1

2

7}, K J Allen^{1

7

8

9}, J A Ellis^{1

7

10}, D Martino^{1

7

11}; HealthNuts team; Barwon Infant Study, the Melbourne Atopy Cohort study, the Peanut Allergen Threshold Study and the Probiotic and Peanut Oral ImmunoTherapy study

Affiliations

¹ Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Vic., Australia.
² The Hudson Institute, Monash Translational Health Precinct (MTHP), Monash University, Clayton, Vic., Australia.
³ Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Malaysia.
⁴ Child Health Research Unit, Barwon Health, Geelong, Vic., Australia.
⁵ Deakin University, Waurn Ponds, Vic., Australia.
⁶ Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, Vic., Australia.
⁷ Department of Paediatrics, University of Melbourne, Parkville, Vic., Australia.
⁸ Department of Allergy and Immunology, Royal Children's Hospital, Parkville, Vic., Australia.
⁹ Institute of Inflammation and Repair, University of Manchester, Manchester, UK.
¹⁰ Centre for Social and Early Emotional Development, Faculty of Health, Deakin University, Burwood, Vic., Australia.
¹¹ Department of Paediatrics, University of Western Australia, Crawley, WA, Australia.

PMID: 28213955
DOI: 10.1111/all.13143

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.

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.

Keywords: serine peptidase inhibitor Kazal type 5; food allergy; lymphoepithelial Kazal-type-related inhibitor; skin barrier; skin barrier function.

MeSH terms

Child, Preschool
Food Hypersensitivity / immunology*
Genetic Predisposition to Disease
Humans
Immunoglobulin E / immunology*
Infant
Mutation / immunology*
Phenotype
Polymorphism, Single Nucleotide
Predictive Value of Tests
Serine Peptidase Inhibitor Kazal-Type 5 / genetics*
Water Loss, Insensible / genetics

Substances

SPINK5 protein, human
Serine Peptidase Inhibitor Kazal-Type 5
Immunoglobulin E