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. 2024 Apr 2;9(9):e178258.
doi: 10.1172/jci.insight.178258.

Filaggrin loss-of-function variants are associated with atopic dermatitis phenotypes in a diverse, early-life prospective cohort

Samuel J Virolainen  1   2   3   4 , Latha Satish  4   5 , Jocelyn M Biagini  4   5 , Hassan Chaib  1   4 , Wan Chi Chang  5 , Phillip J Dexheimer  2 , Michael R Dixon  1 , Katelyn Dunn  1   2 , David Fletcher  1 , Carmy Forney  1   2 , Marissa Granitto  1   2 , Matthew S Hestand  6 , Makenna Hurd  5 , Kenneth Kauffman  1   2   4 , Lucinda Lawson  1   2 , Lisa J Martin  1   4 , Loren Dm Peña  1   4 , Kieran J Phelan  5   7 , Molly Shook  1   2 , Matthew T Weirauch  1   2   3   4   8 , Gurjit K Khurana Hershey  4   5   7 , Leah C Kottyan  1   2   3   4   8
Affiliations

Filaggrin loss-of-function variants are associated with atopic dermatitis phenotypes in a diverse, early-life prospective cohort

Samuel J Virolainen et al. JCI Insight. .

Abstract

Loss-of-function (LoF) variants in the filaggrin (FLG) gene are the strongest known genetic risk factor for atopic dermatitis (AD), but the impact of these variants on AD outcomes is poorly understood. We comprehensively identified genetic variants through targeted region sequencing of FLG in children participating in the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children cohort. Twenty FLG LoF variants were identified, including 1 novel variant and 9 variants not previously associated with AD. FLG LoF variants were found in the cohort. Among these children, the presence of 1 or more FLG LoF variants was associated with moderate/severe AD compared with those with mild AD. Children with FLG LoF variants had a higher SCORing for Atopic Dermatitis (SCORAD) and higher likelihood of food allergy within the first 2.5 years of life. LoF variants were associated with higher transepidermal water loss (TEWL) in both lesional and nonlesional skin. Collectively, our study identifies established and potentially novel AD-associated FLG LoF variants and associates FLG LoF variants with higher TEWL in lesional and nonlesional skin.

Keywords: Allergy; Dermatology; Genetics.

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Conflict of interest statement

Conflict of interest: MSH is an employee and shareholder of Pacific Biosciences.

Figures

Figure 1
Figure 1. Phasing of variants to identify individuals with compound heterozygous FLG mutations.
(A) Two possibilities for individuals with more than 1 LoF FLG mutation include full loss of function (top, compound heterozygote) and loss of function in 1 copy of FLG (bottom, with residual functional FLG produced from unimpacted chromosome). (B) Long-read sequencing was used to determine phase of LoF variants. (C–E) IGV visualization of BAM files from individuals 2, 4, and 5 as described in Table 2. The top portion of each screenshot shows the location of reads on chromosome 1 in hg38, with the specific FLG LoF variants labeled next to the corresponding mapped reads in their genomic context. Each “1” and “2” denotes different haplotypes in each individual used for phasing. FLG, filaggrin; LoF, loss of function; IGV, Interactive Genomics Viewer; SNV, single-nucleotide variant.
Figure 2
Figure 2. Demographics of children with FLG LoF variants.
(A) The numbers of children without (blue bar) and with (red bar) LoF FLG variants are shown and further broken down by ancestry. (B) The number of participants with 1, 2, and 3 LoF FLG variants. (C and D) The functional annotation of identified LoF FLG variants. (E) The presence of prior association with AD and prior identification as a genetic variant. LoF, loss of function; FLG, filaggrin; AD, atopic dermatitis; SNV, single-nucleotide variant.
Figure 3
Figure 3. LoF FLG mutations identified in this study.
Identified FLG LoF variants are presented in the context of the FLG genomic coordinates as a lollipop plot. The height of each variant is indicative of the number of individuals with that variant in this study. Each circle represents a variant with the amino acid change and whether the variant was previously annotated as a variant but not previously associated with AD (*) and a novel variant with no previous annotation in gnomAD or 1000 Genomes Project or dbSNP (bold). This plot was generated using the cBioPortal MutationMapper tool to reference genome GRCh38. FLG, filaggrin.
Figure 4
Figure 4. FLG-dependent risk of early-life allergic outcomes in the MPAACH cohort of children with AD.
As described in Table 5, the association (as calculated by a Fisher’s exact test) of LoF FLG mutations with atopic outcomes is shown. All assessments were performed with data from the first MPAACH visit (ages 1.2–2.4 with a median age of 1.9). Outcomes are presented in the order of statistical significance in the full cohort. (A) Graphed odds ratios with 95% confidence intervals are provided for outcomes and annotated with P values (P). Ancestry-specific breakdown of association is provided for those outcomes with statistical significance in the full cohort. (B–D) The individual-level data from SCORAD, lesional TEWL, and nonlesional TEWL are presented for individuals characterized by no LoF FLG variants (blue) and 1 or more LoF FLG variants (red). Mann-Whitney assessments were used to estimate significance throughout the figure. *P < 0.05. All error bars represent ± 1 SD. AD, atopic dermatitis; TEWL, transepidermal water loss; SCORAD, SCORing for Atopic Dermatitis; FLG, filaggrin; AFR, African ancestry; EUR, European ancestry.
Figure 5
Figure 5. Having an FLG LoF variant in the first 1,000 amino acids of the FLG protein is associated with lower FLG expression in nonlesional skin of children with AD.
Individual-level data of FLG mRNA expression values in nonlesional (A) and lesional skin (B). Mann-Whitney assessments were used to estimate significance. *P < 0.05. All error bars represent ± 1 SD.
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