Uncommon variants in FLG2 and TCHHL1 are associated with remission of atopic dermatitis in a large longitudinal US cohort

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 AD cohort using targeted capture-based massively parallel sequencing. Association between individual alleles and AD remission was evaluated with generalized estimating equations for binary outcomes. Association between groups of alleles and AD remission was evaluated using a genetic algorithm to group alleles. We identified two loss-of-function (LoF) mutations in FLG2 (Ser2377Ter, Arg2207Ter) and 2 LoF mutations in TCHHL1 (Gln656Ter, Gln294Ter), none of which were associated with AD remission. Common (MAF > 5%) alleles in FLG2 were similarly unassociated with AD. No common alleles in TCHHL1 were associated with AD remission after multiple testing correction. Among self-described whites, 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). Twelve uncommon alleles in TCHHL1 trended toward association with increased AD remission (OR 23.46; 95% CI 7.07–77.89; adjusted p = 0.064). Among self-described African Americans, 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 among African Americans. Our study supports the role of uncommon alleles in FLG2 and TCHHL1 in AD pathogenesis.