Filaggrin loss-of-function mutations are associated with persistence of egg and milk allergy

Kalb, Birgit; Marenholz, Ingo; Jeanrenaud, Alexander C. S. N.; Meixner, Lara; Arnau‐Soler, Aleix; Rosillo-Salazar, Oscar D; Ghauri, Ahla; Cibin, Penelope; Blümchen, Katharina; Schlags, Rupert; Hansen, Gesine; Seidenberg, J.; Keil, Thomas; Lau, Susanne; Niggemann, B.; Beyer, Kirsten; Lee, Youngae

doi:10.1016/j.jaci.2022.05.018

Cited by 26 publications

(12 citation statements)

References 49 publications

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“…The post hoc analysis identified eczema at 1 month as a risk factor for EA development. Several cohort studies have consistently reported that eczema in early infancy is a risk factor for the subsequent development of EA . Furthermore, the current trial demonstrated that detecting OVM in breast milk in the early neonatal period was also a risk factor for EA.…”

Section: Discussionsupporting

confidence: 58%

Effect of Maternal Egg Intake During the Early Neonatal Period and Risk of Infant Egg Allergy at 12 Months Among Breastfeeding Mothers

et al. 2023

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ImportanceEgg introduction in infants at age 4 to 6 months is associated with a lower risk of immunoglobulin E–mediated egg allergy (EA). However, whether their risk of EA at age 12 months is affected by maternal intake of eggs at birth is unknown.ObjectiveTo determine the effect of maternal egg intake during the early neonatal period (0-5 days) on the development of EA in breastfed infants at age 12 months.Design, Setting, and ParticipantsThis multicenter, single-blind (outcome data evaluators), randomized clinical trial was conducted from December 18, 2017, to May 31, 2021, at 10 medical facilities in Japan. Newborns with at least 1 of 2 parents having an allergic disease were included. Neonates whose mothers had EA or were unable to consume breast milk after the age of 2 days were excluded. Data were analyzed on an intention-to-treat basis.InterventionsNewborns were randomized (1:1) to a maternal egg consumption (MEC) group, wherein the mothers consumed 1 whole egg per day during the first 5 days of the neonate’s life, and a maternal egg elimination (MEE) group, wherein the mothers eliminated eggs from their diet during the same period.Main Outcomes and MeasuresThe primary outcome was EA at age 12 months. Egg allergy was defined as sensitization to egg white or ovomucoid plus a positive test result in an oral food challenge or an episode of obvious immediate symptoms after egg ingestion.ResultsOf the 380 newborns included (198 [52.1%] female), 367 (MEC: n = 183; MEE: n = 184) were followed up for 12 months. On days 3 and 4 after delivery, the proportions of neonates with ovalbumin and ovomucoid detection in breast milk were higher in the MEC group than in the MEE group (ovalbumin: 10.7% vs 2.0%; risk ratio [RR], 5.23; 95% CI, 1.56-17.56; ovomucoid: 11.3% vs 2.0%; RR, 5.55; 95% CI, 1.66-18.55). At age 12 months, the MEC and MEE groups did not differ significantly in EA (9.3% vs 7.6%; RR, 1.22; 95% CI, 0.62-2.40) or sensitization to egg white (62.8% vs 58.7%; RR, 1.07; 95% CI, 0.91-1.26). No adverse effects were reported.Conclusions and RelevanceIn this randomized clinical trial, EA development and sensitization to eggs were unaffected by MEC during the early neonatal period.Trial RegistrationUMIN Clinical Trials Registry: UMIN000027593

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Section: Discussionsupporting

confidence: 58%

Effect of Maternal Egg Intake During the Early Neonatal Period and Risk of Infant Egg Allergy at 12 Months Among Breastfeeding Mothers

et al. 2023

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“…Filaggrin mutations in patients with atopic dermatitis are a risk factor for severe food-related allergic reactions, and especially to peanuts and hazelnuts [ 45 ]. This class of mutations was also associated with many food allergies irrespective of atopic dermatitis by Kalb et al [ 46 ], who also found that they are associated with the persistence of egg and milk allergies.…”

Section: Natural History Of Hazelnut Allergymentioning

confidence: 85%

Natural History of Hazelnut Allergy and Current Approach to Its Diagnosis and Treatment

et al. 2023

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Hazelnut allergy is the most prevalent type of nut allergy in Europe, with symptoms that can range from mild, such as hives and itching, to severe, such as anaphylaxis, particularly in patients who are sensitized to highly stable allergens, such as storage proteins. Compared to other types of food allergies, allergies to tree nuts, including hazelnuts, tend to persist throughout life. Although symptoms can appear in early childhood, they often continue into adulthood, with a minority of cases improving during adolescence. Currently, there is no curative treatment available for hazelnut allergy, and patients must adhere to a restrictive diet and carry autoinjective epinephrine. However, oral allergen immunotherapy (AIT) is a promising treatment option. Patients can be categorized based on their risk for severe reactions using various clinical, in vivo, and in vitro tests, including component-resolved diagnosis and oral food challenge. This review aims to provide an overview of the current knowledge of the natural history of hazelnut allergy and new approaches for its diagnosis and management.

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“…An epivariation in filaggrin ( FLG ), a gene expressed in the buccal cavity, has been identified in another study 28 with a little evidence to support a role of DNA methylation in the regulation of FLG expression and oral tolerance. Otherwise, Kalb et al (2022) 43 demonstrated that FLG mutations confer a risk of any food allergy.…”

Section: Discussionmentioning

confidence: 99%

Epigenome alterations in food allergy: A systematic review of candidate gene and epigenome‐wide association studies

Safar

Oussalah

Mayorga

et al. 2023

Clin Experimental Allergy

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Objective:The aim of this study was to systematically review the evidence across studies that assessed DNA methylome variations in association with food allergy (FA).Design: A systematic review of the literature and meta-analysis were carried out within several databases. However, the risk of bias in the included articles was not evaluated.Data sources: PubMed, Cochrane Database of Systematic Reviews, and Web of Science were used to search up to July 2022. Eligibility criteria:We included targeted and epigenome-wide association studies (EWASs) that assessed DNA methylome alterations in association with FA in adult or paediatric populations.Results: Among 366 publications, only 16 were retained, which were mainly focused on FA in children. Seven candidate gene-targeted studies found associations in Th1/ Th2 imbalance (IL4, IL5, IL10, INFG, IL2 and IL12B genes), regulatory T cell function (FOXP3 gene), Toll-like receptors pathway (TLR2, CD14 genes) and digestive barrier integrity (FLG gene). Nine EWAS assessed the association with peanut allergy (n = 3), cow's milk allergy (n = 2) or various food allergens (n = 4). They highlighted 11 differentially methylated loci in at least two studies (RPS6KA2, CAMTA1, CTBP2, RYR2, TRAPPC9, DOCK1, GALNTL4, HDAC4, UMODL1, ZAK and TNS3 genes). Among them, Food allergy (FA) is a current public health issue with an increasing incidence over time, suggesting potential epigenetic triggers. Nearly 8% of children have FA in the United States. 1 Food allergy can produce high alteration of the quality of life. In some cases, it may have a severe presentation with life-threatening complications, including fatal episodes of anaphylaxis. 2 There are more than 170 foods that have been reported to cause FA; among them, eight common foods (i.e., cow's milk, hen's egg, peanut, tree nuts, wheat, soy, fish and crustacean shellfish) are responsible for 90% of the reported FA CAMTA1 and RPS6KA2, and CTBP2 are involved in regulatory T cell function and Th2 cell differentiation, respectively. Gene-functional analysis revealed two enriched gene clusters involved in immune responses and protein phosphorylation. ChIP-X Enrichment Analysis 3 showed eight significant transcription factors (RXRA, ZBTB7A, ESR1, TCF3, MYOD1, CTCF, GATA3 and CBX2). Ingenuity Pathway Analysis identified canonical pathways involved, among other, in B cell development, pathogen-induced cytokine storm signalling pathway and dendritic cell maturation. Conclusion:This review highlights the involvement of epigenomic alterations of loci in Th1/Th2 and regulatory T cell differentiation in both candidate gene studies and EWAS. These alterations provide a better insight into the mechanistic aspects in FA pathogenesis and may guide the development of epigenome-based biomarkers for FA.

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Filaggrin loss-of-function mutations are associated with persistence of egg and milk allergy

Cited by 26 publications

References 49 publications

Effect of Maternal Egg Intake During the Early Neonatal Period and Risk of Infant Egg Allergy at 12 Months Among Breastfeeding Mothers

Effect of Maternal Egg Intake During the Early Neonatal Period and Risk of Infant Egg Allergy at 12 Months Among Breastfeeding Mothers

Natural History of Hazelnut Allergy and Current Approach to Its Diagnosis and Treatment

Epigenome alterations in food allergy: A systematic review of candidate gene and epigenome‐wide association studies

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