Filaggrin-2 variation is associated with more persistent atopic dermatitis in African American subjects

Abstract

Background Atopic dermatitis (AD) is a common skin disease that is characterized by recurrent episodes of itching. Genetic variation associated with the persistence of AD has not been described for African-Americans. Objective To evaluate genetic variation of Filaggrin-2 (FLG2) in African-Americans with AD. Methods We evaluated a multiyear prospective cohort study of African-American children with AD with respect to FLG2 variation based on whole exome sequencing followed by a targeted analysis. We ultimately evaluated the association of rs rs12568784 and rs16833974 with the respect to the persistence of AD symptoms over time. Results Whole exome analysis was conducted on 60 subjects revealing premature stop codon in exon 3 at S2377X (rs12568784), X2392S (rs150529054), and a large exon 3 deletion mutation Q2053del224. Based on a priori criteria we then studied rs12568784, rs16833974 (H1249R) and Q2053del224. We noted that S2377X (OR = 0.44; 95% CI: 0.25, 0.46) and H1249R (0.23; 0.12, 0.46) were significantly less likely to be free of symptoms of AD and Q2053del224 (0.54; 0.16, 1.80) trended toward this outcome. S2377X and H1249R were in high linkage disequilibrium (D′=0.95). Conclusions In an African-American cohort with AD, FLG2 mutations were associated with more persistent AD. This is the first finding of genetic variation of a skin barrier protein in those of African ancestry with AD. Clinical Implications FLG2 variation is associated with more persistent AD in children of African ancestry.

The translational revolution and use of biologics in patients with inflammatory skin diseases

“…8 Several AD phenotypes exist based on differences in prevalence, clinical features, and/or response to treatments, including (1) intrinsic and extrinsic AD 8 ; (2) AD among different ethnic groups (ie, European American, Asian, and African American subjects) [126][127][128][129][130] ; and (3) pediatric AD. 131 Further work to define molecular features of clinical variants might help to direct future therapeutic development.…”

Altered Expression of Genes Encoding Cornulin and Repetin in Atopic Dermatitis

“…However, FLG loss-of-function mutations are observed in 20% of AD subjects (and in up to 50% of severe AD subjects), but similar mutations are also observed in ichthyosis vulgaris, and in approximately 9% of the European population, without any concomitant inflammation [11,12] . There are ethnic differences in the frequency of FLG mutations, and local differences exist even within Europeans regions [13,14] . It is worth mentioning that the FLG deficiency in AD is caused not only by gene mutations but also by other exogenous and immunological factors which influence FLG expression [15,16] .…”

Molecular Genetic of Atopic Dermatitis : An Update

“…(55) Their report is from the largest whole-exome sequencing study of African Americans with AD suggesting that S2377X (FLG2) and Q294X (TCHHL1) variants may not be clinically important with respect to incident AD and it seems unlikely that FLG stop-gain mutations have a prominent role with respect to incident AD in African Americans children. (55,56) Whereas, the recent demonstration that FLG2 mutations increase the persistence of AD in African Americans (57) further suggests a pathogenic role for FLG2 mutations (rs12568784 and rs16833974) and supports the sequencing of FLG2in African Americans with IV with or without AD. (44) Polcari data was demonstrated a prevalence of filaggrin mutations including R501X, 2282del4, E2554X, R2447X, 1249insG, R826X, 2767insT, and E2422X in the African American population that exceeds previously published data, although the overall prevalence is still lower than in other populations.…”