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Uncommon variants in FLG2 and TCHHL1 are associated with remission of atopic dermatitis in a large longitudinal US cohort

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Abstract

Atopic dermatitis (AD) is a relapsing inflammatory skin disease; filaggrin (FLG) variation has been consistently associated with its pathogenesis. Filaggrin-2 (FLG2) and trichohyalin-like-1 (TCHHL1) are members of the same protein family (S100 fused-type proteins), are similar in structure to FLG, and may be involved in AD pathogenesis. We sought to evaluate the association between variation in FLG2, TCHHL1 and AD remission. We sequenced FLG2 and TCHHL1 in a longitudinal AD cohort using targeted capture-based massively parallel sequencing. Association between individual alleles and AD remission was evaluated with generalized estimating equations for binary outcomes. Association between groups of alleles and AD remission was evaluated using a genetic algorithm to group alleles. We identified two loss-of-function (LoF) mutations in FLG2 (Ser2377Ter, Arg2207Ter) and 2 LoF mutations in TCHHL1 (Gln656Ter, Gln294Ter), none of which were associated with AD remission. Common (MAF > 5%) alleles in FLG2 were similarly unassociated with AD. No common alleles in TCHHL1 were associated with AD remission after multiple testing correction. Among self-described whites, a group of 34 uncommon alleles in FLG2 were associated with increased AD remission (OR 7.64e17; 95% CI 4.41e17–1.32e18; adjusted p < 1.0e–16). Twelve uncommon alleles in TCHHL1 trended toward association with increased AD remission (OR 23.46; 95% CI 7.07–77.89; adjusted p = 0.064). Among self-described African Americans, 13 uncommon FLG2 alleles were associated with increased AD remission (OR 21.01; 95% CI 11.90–37.09; adjusted p < 1.0e–16). No TCHHL1 uncommon allele groups were associated with AD remission among African Americans. Our study supports the role of uncommon alleles in FLG2 and TCHHL1 in AD pathogenesis.

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Data availability

The PEER data (source) is not currently publicly available. The PEER study is an ongoing study sponsored by Valeant in response to a post-marketing commitment with the FDA. A BED file of the probes used for targeted capture is available upon request from the corresponding author.

Code availability

R code for this project is available upon request from the corresponding author.

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Funding

This work was supported in part by a grant from the National Institutes for Health NIAMS R01-AR070873 (PI: Margolis). The PEER study is funded as the Atopic Dermatitis Registry by Valeant Pharmaceuticals International (PI: Margolis).

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Authors and Affiliations

  1. Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Ronald Berna, Ole Hoffstad & David J. Margolis

  2. Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Nandita Mitra & David J. Margolis

  3. Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Bradley Wubbenhorst & Katherine L. Nathanson

Authors
  1. Ronald Berna
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  2. Nandita Mitra
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  3. Ole Hoffstad
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  4. Bradley Wubbenhorst
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  5. Katherine L. Nathanson
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  6. David J. Margolis
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Corresponding author

Correspondence to Ronald Berna.

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Conflict of interest

David Margolis is a consultant for Pfizer with respect to studies of atopic dermatitis and serves on an advisory board for the National Eczema Association. No other authors state financial conflicts of interest with respect to this investigation.

IRB approval

The PEER study was approved by the Institutional Review Board of the University of Pennsylvania, and written informed consent was obtained from all participants from the participant or his or her caregiver.

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Berna, R., Mitra, N., Hoffstad, O. et al. Uncommon variants in FLG2 and TCHHL1 are associated with remission of atopic dermatitis in a large longitudinal US cohort. Arch Dermatol Res 314, 953–959 (2022). https://doi.org/10.1007/s00403-021-02319-7

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  • DOI: https://doi.org/10.1007/s00403-021-02319-7

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