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Research Letter |

Low Filaggrin Monomer Repeats in African American Pediatric Patients With Moderate to Severe Atopic Dermatitis FREE

Ashley M. Quiggle, BA1; Zane A. Goodwin, BS1; Twinkal R. Marfatia, PhD1; Monique G. Kumar, MD1; Heather Ciliberto, MD1; Susan J. Bayliss, MD1; Cristina de Guzman Strong, PhD1
[+] Author Affiliations
1Center for Pharmacogenomics, Center for the Study of Itch, Division of Dermatology, Department of Internal Medicine, Washington University School of Medicine, St Louis, Missouri
JAMA Dermatol. 2015;151(5):557-559. doi:10.1001/jamadermatol.2014.4916.
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Published online

The severity of atopic dermatitis (AD) and intragenic filaggrin (FLG; OMIM 135940) copy number variant (CNV) genotypes were assessed in African American pediatric patients, a health disparities group that is disproportionately affected with AD.1

The study was approved by Washington University School of Medicine’s institutional review board. Eligibility criteria for recruited pediatric patients were (1) age 3 months to 18 years, (2) United Kingdom Working Party’s Diagnostic Criteria for Atopic Dermatitis,2 (3) African American ethnicity (self-reported), (4) moderate to severe AD (SCORAD index, ≥25),3 and (5) written informed assent or consent. Common European FLG R501X and 2282del4 mutations and intragenic FLG CNV (3 alleles of either 10, 11, or 12 FLG monomer repeats), upon high-quality DNA assessment, were genotyped4 and correlated with AD severity.

Thirty-nine pediatric African American patients with AD were recruited with a mean (range) age of 6.7 (0.4-15) years (Table 1). Thirty-five patients reported a first-degree family member with atopy, and 30 patients reported AD onset before age 2 years. Of the 31 patients who were 4 years or older at the time of visit, a history of asthma and allergic rhinitis and/or hay fever was reported in 24 (77%) and 16 (52%), respectively. Food allergies were reported as well (51% [n = 20]), most commonly peanut (n = 10) and fish and/or shellfish (n = 10) that were not coincident. All but 1 were either being treated with or had been prescribed topical triamcinolone ointment, 0.1%.

Table Graphic Jump LocationTable 1.  Characteristics of 39 African American Pediatric Patients With Atopic Dermatitis (AD)

The mean (range) SCORAD of the participants was 58.5 (28.0-94.1) (Table 1) with severe pruritis (mean, 7.8) and moderate sleep loss (mean, 5.7) (both scales, 0-10). Twenty-four patients (62%) exhibited severe AD. The mean lesional body extent was 44% and mean lesional intensity was 10 (scale, 0-15; 15 = worst). Lichenification and dryness (both means, 2.2; scale, 0-3; 3 = worst) contributed the most to the lesional intensity (Figure, A).

Place holder to copy figure label and caption
Figure.
Mean Intensity Item Values and Total FLG Repeats vs SCORAD Index

A, Intensity item values that contribute to the collective intensity measure of a representative lesion. B, Distribution of total FLG repeats with respect to SCORAD. The horizontal line in the middle of each box indicates the mean, while the top and bottom borders of the box mark 1 standard deviation above and below the mean. The whiskers above and below the box mark the maximum and minimum values, respectively. Statistics, 2-sided Wilcoxon rank-sum test.

Graphic Jump Location

We sought to explain the associated severe nonlesional skin dryness in our participants by genotyping a previously described European dose-dependent risk factor for AD, intragenic FLG repeats, or CNV.4 Excluding 2 FLG R501X heterozygous patients (no FLG 2282del4 mutations identified), 16 cases (43%) were homozygous for the FLG CNV 10 allele, thus totaling 20 filaggrin monomers (Table 2). Of the total 74 FLG alleles in our cases (n = 37), the FLG CNV 10 allele made up 64% (Table 1). Patients with a total of either 20 or 21 FLG CNV exhibited higher SCORAD (mean, 63.7) and hence severe AD compared with those participants with 22, 23, and 24 FLG CNV (mean SCORAD, 48.5) (P = .01) (Figure, B). Moreover, we found that individuals with 20 total filaggrin monomers are 1.9 times more likely to have severe AD (Table 2). However, this was not statistically significant (P = .33).

Table Graphic Jump LocationTable 2.  Total FLG Copy Number Variants (CNVs) and Unadjusted Odds Ratios (ORs) for Participants With Severe Atopic Dermatitis (AD) (SCORAD Index, >50), R501X Excluded

Despite epidemiological data supporting a marked increase in AD in African American children,1 to our knowledge, a quantitative measure of AD severity and an investigation of FLG CNV in this health disparities group have not been reported until now. We identify a significant difference between low FLG CNV (20 or 21) with severe AD vs FLG CNV of 22, 23, or 24 with moderate AD (P = .01). Each FLG repeat encodes 1 posttranslationally modified active filaggrin monomer that is further degraded to metabolites such as urocanic acid that makes up part of the skin’s natural moisturizing factor (NMF).4 Addition of each FLG monomer decreases the odds ratio of disease risk of AD by 0.88.4 A reduction of NMF metabolites was also observed in skin of South African patients with AD.5 Although NMF metabolites were not assessed in this study, the parallels between our study and that of Brown et al4 with respect to low FLG CNV and AD suggest a reduction in filaggrin metabolites contributing to our patients’ skin dryness. Observed low if not absent frequencies of FLG and/or FLG-2 stop-gain mutations in African Americans68 and Africans5 suggest decreased likelihoods for these mutations in AD risk specific to this ancestry. Future case-control studies specific to this health disparities group are warranted to more fully elucidate the genetics of AD.

Corresponding Author: Cristina de Guzman Strong, PhD, Center for Pharmacogenomics, Center for the Study of Itch, Division of Dermatology, Department of Internal Medicine, Washington University School of Medicine, 660 S Euclid Ave, Campus Box 8123, St Louis, MO 63110 (cstrong@dom.wustl.edu).

Accepted for Publication: November 9, 2014.

Published Online: January 7, 2015. doi:10.1001/jamadermatol.2014.4916.

Author Contributions: Drs Bayliss and de Guzman Strong had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Marfatia, de Guzman Strong.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Quiggle, Bayliss, de Guzman Strong.

Critical revision of the manuscript for important intellectual content: Quiggle, Goodwin, Marfatia, Kumar, Ciliberto, de Guzman Strong.

Statistical analysis: Goodwin, de Guzman Strong.

Obtained funding: de Guzman Strong.

Administrative, technical, or material support: All authors.

Study supervision: Bayliss, de Guzman Strong.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported in part by a Dean’s Faculty Diversity Scholar Award (Washington University School of Medicine, Dr de Guzman Strong) and by National Institutes of Health grants T32 HG000045 (Mr Goodwin) and R00AR055948 (Dr de Guzman Strong). The Dean’s Faculty Diversity Funds provided the materials for the study.

Role of the Sponsor: The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Previous Presentation: This study was presented in part at the 73rd Annual Meeting of the Society of Investigative Dermatology; May 8 to 9, 2014; Albuquerque, New Mexico.

Additional Contributions: Emily Beck, MD, Emily Gurnee, MD, Kara J. Gulewicz, MD, and Colleen Cotton, MD, Washington University School of Medicine, assisted with patient recruitment and were not compensated.

Shaw  TE, Currie  GP, Koudelka  CW, Simpson  EL.  Eczema prevalence in the United States: data from the 2003 National Survey of Children’s Health. J Invest Dermatol. 2011;131(1):67-73.
PubMed   |  Link to Article
Williams  HC, Burney  PG, Hay  RJ,  et al.  The UK Working Party's Diagnostic Criteria for Atopic Dermatitis. I. derivation of a minimum set of discriminators for atopic dermatitis. Br J Dermatol. 1994;131(3):383-396.
Link to Article
 Severity scoring of atopic dermatitis: the SCORAD index: Consensus Report of the European Task Force on Atopic Dermatitis. Dermatology. 1993;186(1):23-31.
Link to Article
Brown  SJ, Kroboth  K, Sandilands  A,  et al.  Intragenic copy number variation within filaggrin contributes to the risk of atopic dermatitis with a dose-dependent effect. J Invest Dermatol. 2012;132(1):98-104.
PubMed   |  Link to Article
Thawer-Esmail  F, Jakasa  I, Todd  G,  et al.  South African amaXhosa patients with atopic dermatitis have decreased levels of filaggrin breakdown products but no loss-of-function mutations in filaggrin. J Allergy Clin Immunol. 2014;133(1):280-2.e1, 2.
PubMed   |  Link to Article
Margolis  DJ, Gupta  J, Apter  AJ,  et al.  Exome sequencing of filaggrin and related genes in African-American children with atopic dermatitis. J Invest Dermatol. 2014;134(8):2272-2274.
PubMed   |  Link to Article
Polcari  I, Becker  L, Stein  SL, Smith  MS, Paller  AS.  Filaggrin gene mutations in African Americans with both ichthyosis vulgaris and atopic dermatitis. Pediatr Dermatol. 2014;31(4):489-492.
PubMed   |  Link to Article
Margolis  DJ, Gupta  J, Apter  AJ,  et al.  Filaggrin-2 variation is associated with more persistent atopic dermatitis in African American subjects. J Allergy Clin Immunol. 2014;133(3):784-789.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure.
Mean Intensity Item Values and Total FLG Repeats vs SCORAD Index

A, Intensity item values that contribute to the collective intensity measure of a representative lesion. B, Distribution of total FLG repeats with respect to SCORAD. The horizontal line in the middle of each box indicates the mean, while the top and bottom borders of the box mark 1 standard deviation above and below the mean. The whiskers above and below the box mark the maximum and minimum values, respectively. Statistics, 2-sided Wilcoxon rank-sum test.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1.  Characteristics of 39 African American Pediatric Patients With Atopic Dermatitis (AD)
Table Graphic Jump LocationTable 2.  Total FLG Copy Number Variants (CNVs) and Unadjusted Odds Ratios (ORs) for Participants With Severe Atopic Dermatitis (AD) (SCORAD Index, >50), R501X Excluded

References

Shaw  TE, Currie  GP, Koudelka  CW, Simpson  EL.  Eczema prevalence in the United States: data from the 2003 National Survey of Children’s Health. J Invest Dermatol. 2011;131(1):67-73.
PubMed   |  Link to Article
Williams  HC, Burney  PG, Hay  RJ,  et al.  The UK Working Party's Diagnostic Criteria for Atopic Dermatitis. I. derivation of a minimum set of discriminators for atopic dermatitis. Br J Dermatol. 1994;131(3):383-396.
Link to Article
 Severity scoring of atopic dermatitis: the SCORAD index: Consensus Report of the European Task Force on Atopic Dermatitis. Dermatology. 1993;186(1):23-31.
Link to Article
Brown  SJ, Kroboth  K, Sandilands  A,  et al.  Intragenic copy number variation within filaggrin contributes to the risk of atopic dermatitis with a dose-dependent effect. J Invest Dermatol. 2012;132(1):98-104.
PubMed   |  Link to Article
Thawer-Esmail  F, Jakasa  I, Todd  G,  et al.  South African amaXhosa patients with atopic dermatitis have decreased levels of filaggrin breakdown products but no loss-of-function mutations in filaggrin. J Allergy Clin Immunol. 2014;133(1):280-2.e1, 2.
PubMed   |  Link to Article
Margolis  DJ, Gupta  J, Apter  AJ,  et al.  Exome sequencing of filaggrin and related genes in African-American children with atopic dermatitis. J Invest Dermatol. 2014;134(8):2272-2274.
PubMed   |  Link to Article
Polcari  I, Becker  L, Stein  SL, Smith  MS, Paller  AS.  Filaggrin gene mutations in African Americans with both ichthyosis vulgaris and atopic dermatitis. Pediatr Dermatol. 2014;31(4):489-492.
PubMed   |  Link to Article
Margolis  DJ, Gupta  J, Apter  AJ,  et al.  Filaggrin-2 variation is associated with more persistent atopic dermatitis in African American subjects. J Allergy Clin Immunol. 2014;133(3):784-789.
PubMed   |  Link to Article

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