101 Uncommon alleles in FLG2 and TCHHL1 are associated with remission of atopic dermatitis

Abstract

Atopic dermatitis (AD) is a relapsing inflammatory skin disease; filaggrin (FLG) variation has been consistently associated with its pathogenesis. Filaggrin-2 (FLG2) and trichohyalin-like-1 (TCHHL1) are members of the same protein family (S100 fused type proteins), are similar in structure to FLG, and may be involved in AD pathogenesis. We sought to evaluate the association between variation in FLG2, TCHHL1 and AD remission. We sequenced FLG2 and TCHHL1 in a longitudinal cohort of individuals with AD using targeted capture based massively parallel sequencing. The association between individual alleles and AD remission was evaluated with generalized estimating equations (GEE) for binary outcomes, assuming an exchangeable working correlation structure with empirical standard errors. The association between groups of alleles and AD remission was evaluated using a genetic algorithm, implemented via the rbga.bin function in R, to group alleles and GEE models to evaluate group associations with AD remission. We identified 3 loss-of-function (LoF) mutations in FLG2 (Ser2377Ter, Ter2392Ser, Arg2207Ter) and 2 LoF mutations in TCHHL1 (Gln656Ter, Gln294Ter), none of which were associated with AD remission. Common (MAF>5%), non-LoF alleles in FLG2 were similarly unassociated with AD. One common allele in TCHHL1, 152057002A>G, was associated with increased AD remission (OR 1.48; 95%CI 1.06-2.06; p=0.022). Within the self-described white population, a group of 34 uncommon alleles in FLG2 were associated with increased AD remission (OR 7.64e17; 95%CI 4.41e17-1.32e18; adjusted p<1.0e-16). 12 uncommon alleles in TCHHL1 were associated with increased AD remission (OR 23.46; 95%CI 7.07-77.89; adjusted p=0.064). Within the self-described African American population, 13 uncommon FLG2 alleles were associated with increased AD remission (OR 21.01; 95%CI 11.90-37.09; adjusted p<1.0e-16). No TCHHL1 uncommon allele groups were associated with AD remission. Our study supports the role of uncommon alleles in FLG2 and TCHHL1 in AD pathogenesis.