Filaggrin Associated Risk for Atopic Dermatitis Is Offset By Protective Missense Variants in Rptn and LCE1B Genes in the Epidermal Differentiation Complex.
Sunday, March 6, 2016: 2:00 PM
Room 515A (Convention Center)
Rasika A. Mathias, ScD, , , , , , , , , , , , , , , , ,
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; p=0.0005, OR=0.53) an extracellular epidermal matric protein, and late cornified envelope 1B (LCE1B, p=0.0002, OR=0.29) were both strongly protective. Importantly, the risk for AD in individuals that were carriers of FLG variants and RPTN or LCE1B variants was lower (OR=2.36) as compared to carriers of FLGvariants only (OR= 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.