Uncommon Filaggrin Variants Are Associated with Persistent Atopic Dermatitis in African Americans

Abstract

Atopic dermatitis (AD) is a common illness that has been associated with filaggrin gene (FLG) loss of function (LoF) variation. In African Americans, a group that commonly has AD and has not been well studied, FLG LoF variation is rarely found. Our objective was to use massively parallel sequencing to evaluate FLG LoF variation in children of African ancestry to evaluate the association between FLG LoF variation and AD and AD persistence. We studied 262 African American children with AD. Nine unique FLG exon 3 LoF variants were identified for an overall minor variant frequency of 6.30% (95% confidence interval [CI] = 4.37-8.73). The most common variants were p.R501X (1.72%, 95% CI = 0.79-3.24), p.S3316X (1.34%, 95% CI = 0.54-2.73), and p.R826X (0.95%, 95% CI = 0.31-2.2). Over an average follow-up period of 96.4 (95% CI = 92.0-100.8) months, African American children with FLG LoF were less likely to be symptom free (odds ratio = 0.36, 95% CI = 0.14-0.89, P = 0.027) compared with a FLG wild-type child. In contrast to previous reports, uncommon FLG LoF variants in African American children exist and are associated with AD and more persistent AD. In contrast to Europeans, no FLG LoF variants predominate in African American children. Properly determining FLG LoF status requires advanced sequencing techniques.

Tiled array‐based sequencing identifies enrichment of loss‐of‐function variants in the highly homologous filaggrin gene in African‐American children with severe atopic dermatitis

“…c.488delG and p.S3101* are novel FLG LOF as they have not been reported in dbSNP, ExAC, and ESP variant databases. p.S3316* (also known as rs149484917) was found in 3 unrelated patients and had been previously reported in a separate AA AD group [13]. The higher proportion of FLG LOF in our AA AD group (11.5%) compared to the 2.5% African ExAC frequency indicated an enrichment for FLG LOF for AA AD and was statistically significant (p=4.3E-04, Fisher’s Exact Test).…”

“…We discovered 2 pathogenic FLG LOF not previously reported for AD (c.488delG and p.S3101*). The overlap of our p.S3316* findings in our cohort, in an independent AA AD study [13], and in African individuals (ExAC, ESP, and 1000G) supports p.S3316* as a population-specific FLG LOF variant for African ancestry. Our discovery of five pathogenic FLG LOF variants (including 2 newly discovered) in African American pediatric patients with severe AD has brought forth a hypothesis for the wider research community to test, FLG LOF variants among the African American population are enriched in AD, and thus justifies more precision medicine efforts for this health disparity group.…”

“…We sought to further investigate the distribution and frequency of rs149484917 that results in FLG LOF S3316* using ExAC, ESP, and 1000G population datasets given the concurrent findings for AA AD in our cohort and a previous study [13]. rs149484917 has been reported primarily in African individuals with 96% and 100% of the minor allele reported in Africans in ExAC and ESP, respectively.…”

“…The conventional human reference allele for FLG , ENSG00000143631, to which most LOF mutations are mapped, is the 10-repeat allele. A recent exome sequencing study in African American children with AD with high read depth (185X) reported a 6.3% proportion of FLG LOF alleles, including 6 newly reported and 3 previously described for AD to suggest multiple and perhaps rare FLG LOF in this ethnic group [13] (Supplemental Table 1). In support of this finding, the allele frequency for the total number of FLG LOF is 2.5% for African individuals in the Exome Aggregation Consortium (ExAC) (whereby each LOF is <1%) and 1.7% in the Exome Variant Server (ESP) for African Americans with no documented knowledges of AD in these datasets [14] (Supplementary Tables 2, 3).…”

Recent evolution of the human skin barrier

“…By contrast, data from 1000 Genomes Project identify a cumulative FLG LOF variant frequency for Africans exceeding that of Europeans (17% vs. 5%, respectively) [46] . This is likely an underestimation, as more recent work with exome sequencing and careful consideration of next generation sequencing short read alignments revealed that the alignment method used affected the sensitivity of variant identification [52,54] .…”