The effect of loss-of-function variants in the Filaggrin gene on food allergy.

Ginkel, C.D. van (2013) The effect of loss-of-function variants in the Filaggrin gene on food allergy. thesis, Medicine.

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Abstract

Introduction: Food allergy is a potentially lethal disease with a high prevalence which reduces quality of life in children. Although the pathway leading to anaphylaxis is quite straight forward, the mechanism which determines the difference between asymptomatic sensitisation and clinical reactivity is as yet unknown. The aim of this study was to determine the effect of loss of function gene variants in the filaggrin gene on clinical reactivity, as diagnosed by the Double Blind, Placebo-Controlled Food Challenge(DBPCFC) in children suspected of being food allergic. Data of their parents was included to improve the quality of the genotyping data and to replicate the analysis. The use of this genotypic data as a new screening tool for food allergy was analysed. Furthermore the effect of these variants on sensitisation and the severity of the test reaction is studied. Materials and Methods: All enrolled children were tested by means of the DBPCFC and cases were identified as children with at least one positive DBPCFC. Parents were defined as food allergic when this is reported in history. IgE was measured by the CAP-FEIA and outcomes >0.35 kU/l were defined as positive. Symptoms of the reaction during the food challenge were recorded and depending on the involved organ systems, a severity score was made ranging from 0 to 12. DNA from the children and their parents was collected by buccal mucosa samples. DNA was extracted, purified and four gene variants were genotyped: R501X, S3247X, 2282Del4 and R2447X. The quality control of the genotypic information was performed with Haploview. Chi-square tests and both logistic and linear regression analysis were used to study the effect of these gene variants on the defined outcomes. The trio analysis was performed by the FBAT toolkit. Results: A total of 173 trios enrolled the study. 18 children were excluded from further analysis due to genotyping errors, non-Caucasian ethnicity, diagnostic irregularities or mendelian errors which indicate unlikely inheritance patterns. Therefore, the results are based on 155 children and their parents. Risk alleles were identified by R501X, S3247X, 2282Del4 and R2447X. From the studied population, 33 children had at least one loss of function variant of the filaggrin gene and of these, 29 were clinically reactive to at least one food. The odds ratio for having at least one loss-of-function gene variant in the filaggrin gene and being clinically reactive was 4.866 (95% CI: 1.6-14.7, p=0.005) and the relative risk is approximately 1.5. No significant confounders were identified for this association. The association between loss-of-function gene variants in the filaggrin gene and food allergy was significantly replicated when including the parents. Based on the data, a significant model was developed with clinical reactivity as outcome and presence of loss-of-function gene variants, gender, specific IgE and eczema ever reported in history as independent variables. With a cut-of value of .90, this model had a specificity of 98.1% to predict food allergy in our high risk population. The model selected 29 patients of which 28 were clinically reactive to at least one food. No association was found between the studied variants of the filaggrin gene and specific IgE values and the severity of the reaction during the DBPCFC. Conclusion: Loss-of-function variants of the filaggrin gene were found to be associated with clinical reactivity to at least one food with an relative risk of 1.5 as confirmed by DBPCFC. This means that in our population, high risk children with loss-of-function gene variants in the filaggrin gene are one and a half times more likely to be clinically reactive to at least one food, compared to high risk children carrying wild type alleles. Our data suggest that the filaggrin gene does not play a role in sensitisation and the severity of food allergy. In our high risk population, we are now able to predict clinical reactivity in a proportion of our population. After validating this model in other populations, this could be the first genetic test to be useful in the diagnosis of food allergy in children. Use of this model could reduce the need for the time-demanding DBPCFC.

Item Type:	Thesis (Thesis)
Supervisor name:	Dubois, Prof. Dr. A.E.J. and Koppelman, Prof. Dr. G.H and Flokstra- de Blok, Dr. B.M.J.
Faculty:	Medical Sciences
Date Deposited:	25 Jun 2020 10:44
Last Modified:	25 Jun 2020 10:44
URI:	https://umcg.studenttheses.ub.rug.nl/id/eprint/511

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