Filaggrin Associated Risk for Atopic Dermatitis Is Offset By Protective Missense Variants in Rptn and LCE1B Genes in the Epidermal Differentiation Complex

RATIONALE: Null mutations in Filaggrin (FLG) located within the Epidermal Differentiation Complex (EDC; chr1:151972910-153642037) are known to increase risk for atopic dermatitis (AD); but the role of variants within additional genes in the EDC is not well understood. We implemented a whole genome sequencing (WGS) study to fully understand the genetic determinants of AD within the EDC. METHODS: Deep WGS (;30x) was performed on 493 European American AD subjects and 237 non-atopic controls. We assessed association with single nucleotide variants (SNVs) in the EDC, a region rich in genes important for epidermal maturation and examined these associations as a function of FLG carrier status (carrier defined as an individual with 1+ FLGrisk variants). RESULTS: We identified 17,231 SNVs; 14 SNVs had a p <0.001 comparing AD to non-atopic controls, including two functional missense variants. In contrast to the increased risk conferred by FLG variants (OR>_3), the newly identified missense variants in the genes encoding repetin (RPTN; p50.0005, OR50.53) an extracellular epidermal matric protein, and late cornified envelope 1B (LCE1B, p50.0002, OR50.29) were both strongly protective. Importantly, the risk for AD in individuals that were carriers of FLG variants and RPTN or LCE1B variants was lower (OR52.36) as compared to carriers of FLGvariants only (OR5 3.4) supporting an overall protection conferred by these newly identified missense variants in the EDC. CONCLUSIONS: Relying on a sequencing approach, we identify genetic variants within the EDC that confer protection against AD. We demonstrate that these variants may offset the risk conferred by known variants in FLG.