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 in... More
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.