Epidermal differentiation complex genetic variation in atopic dermatitis and peanut allergy - 05/04/23
, Kanika Kanchan, PhD b, ∗, Henry T. Bahnson, MS c, d, Ingo Ruczinski, PhD e, Gautam Shankar, MS b, Donald Y.M. Leung, MD, PhD f, Carolyn Baloh, MD a, g, George Du Toit, MBBCh h, Gideon Lack, MBBCh h, Gerald T. Nepom, MD, PhD c, d, Rasika A. Mathias, ScD aAbstract |
Background |
Deleterious variation in the epidermal differentiation complex (EDC) on chromosome 1 is a well-known genetic determinant of atopic dermatitis (AD) and has been associated with risk of peanut allergy (PA) in population-based studies.
Objective |
Our aim was to determine the effect of genetic variation in the EDC on AD trajectory and risk of PA in early life.
Methods |
Genome sequencing was used to measure genetic variation in the EDC in the Learning Early about Peanut Allergy (LEAP) study participants. Association tests were done to identify gene- and variant-level predicted deleterious variation associated with AD severity by using the Scoring Atopic Dermatitis (SCORAD) tool (n = 559) at baseline and each follow-up visit, as well as PA and food allergy in peanut avoiders (n = 275). Predicted deleterious variants included missense variants that were frameshift insertions, frameshift deletions, stop-gain mutations, or stop-loss mutations. Associations between variant load, SCORAD score, and PA were tested by using linear and generalized linear regression models.
Results |
The genes FLG, FLG2, HRNR, and TCHH1 harbored the most predicted deleterious variation (30, 6, 3, and 1 variant, respectively). FLG variants were associated with SCORAD score at all time points; 4 variants (R1798X, R501X, S126X, and S761fs) drove the association with SCORAD score at each time point, and higher variant load was associated with greater AD severity over time. There was an association between these variants and PA, which remained significant independent of baseline AD severity (odds ratio = 2.63 [95% CI = 1.11-6.01] [P = .02]).
Conclusions |
Variation in FLG predicted to be deleterious is associated with AD severity at baseline and longitudinally and has an association with PA independent of baseline severity.
Le texte complet de cet article est disponible en PDF.Key words : Atopic dermatitis, eczema, peanut allergy, genetics, filaggrin, epidermal differentiation complex
Abbreviations used : AD, EDC, FLG, LEAP, OR, PA, SCORAD, WGS
Plan
| This research was performed as a project of the Immune Tolerance Network, an international clinical research consortium headquartered at the Benaroya Research Institute, and supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award no. UM1AI109565. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. |
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| Disclosure of potential conflict of interest: H. T. Bahnson reports fees for contract work paid to his institution by Benaroya Research Institute, DBV Technologies, MYOR, King’s College London, and Stanford University, as well as additional salary support paid by King’s College London and Stanford University. D. Y. M. Leung reports consultant fees from Genentech, Sanofi-Genzyme, Leo Pharma, and Incyte Corporation. G. Du Toit reports grants from the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH), Food Allergy & Research Education (FARE), the Medical Research Council-Asthma (MRC-Asthma) UK Centre, UK Department of Health through the National Institute for Health Research (NIHR), and the Action Medical Research and National Peanut Board; service as a member of the scientific advisory board of Aimmune; service as an investigator on pharma-sponsored allergy studies for Aimmune and DBV Technologies; and service as a scientific adviser to Aimmune, DBV, and Novartis. G. Lack reports grants from the National Institute of Allergy and Infectious Diseases (NIAID, NIH); other compensation from FARE, the MRC-Asthma UK Centre, the UK Department of Health through the NIHR, the National Peanut Board (NPB), and the Davis Foundation during the conduct of the study; ownership of shares in DBV Technologies, and Mighty Mission Me; and personal fees from Novartis, Sanofi-Genyzme, Regeneron, ALK-Abelló, and Lurie Children's Hospital outside the submitted work. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 151 - N° 4
P. 1137 - avril 2023 Retour au numéro
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