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Filaggrin gene loss-of-function variants differ by race in children with atopic dermatitis

Variant frequency in the filaggrin gene was strongly associated with race among pediatric patients with atopic dermatitis.

“The difference [in variants] can be profound in that very common variants in one race may be absent or very rare in another, and their location within exon 3 may also vary widely,” David J. Margolis, MD, PhD, of the Perelman School of Medicine at the University of Pennsylvania, and colleagues wrote.

The researchers sought to compare results from targeted sequencing of filaggrin gene (FLG) loss-of-function (LoF) variants in children of African and European ancestry and the association of the variants with atopic dermatitis (AD).

Researchers utilized the genetic subcohort of the Pediatric Eczema Elective Registry, which included 741 patients; 394 children (53.2%) were female, and 394 children (53.2%) were white, 326 (44%) were African American and 21 (2.8%) were of other ancestries. Four hundred twenty-one participants were followed up for at least 10 years, and the study is ongoing.

The genetic variants most often associated with skin barrier dysfunction are exon 3 LoF variants in the FLG. However, patients of African ancestry with AD usually do not exhibit FLG LoF variants. The variants are present in about 25% to 30% of AD patients of European and Asian ancestry.

The researchers identified 23 FLG LoF variants in children with AD.

The prevalence of the most frequently studied FLG LoF variants was 134 (18.1%) in the full cohort, 115 (29.2%) in white individuals and 18 (5.5%) in African American individuals. Using massively parallel sequencing technology, the prevalence of any FLG LoF variants was 177 (23.9%) in the full cohort, 124 (31.5%) in white individuals and 50 (15.3%) in African American individuals, the researchers found.

The four classic variants most often evaluated captured 92.6% of the prevalence of FLG LoF in white children but only 36.1% in children of African ancestry. The researchers determined that some variants are only found in children from a specific ancestry.

Children with an FLG LoF variant were more likely to have persistent AD (OR = 0.67; 95% CI, 0.56-0.80).

The odds ratio for carrying any FLG LoF variant in a white child compared with an African American child was 2.44 (95% CI, 1.76-3.39).

“These findings suggest that using FLG loss-of-function variants to diagnose atopic dermatitis or to estimate the clinical course may be very difficult because very common variants in one race may be absent or very rare in another,” the researchers wrote.

Genetic diagnostic testing for AD based on FLG LoF variants must be more inclusive and not rely solely on the most popular variants. – by Abigail Sutton

Disclosure: Margolis reports receiving research funding as the principal investigator via the trustees of the University of Pennsylvania; receiving funding from the National Institutes of Health, Valeant Pharmaceuticals and Sunovion Pharmaceuticals; and consulting primarily as a member of data monitoring boards or scientific advisory boards with Leo Pharma, Johnson & Johnson, Pfizer, Sanofi, Kerecis and Cell Constructs.