Cholesterol pathway gene variants and reduced keratinocyte cholesterol support a final common druggable pathway in hyperproliferative inflammatory skin diseases.

Hyperproliferative inflammatory skin disease (HISD) is frequently seen in rare monogenic diseases of cholesterol metabolism and responds to topical cholesterol/statin. We hypothesised that aberrant cholesterol metabolism within keratinocytes could be important in HISD more generally, driven by either immunological or lipid pathway genetic variation. Whilst other epidermal lipids have been well characterised in HISDs, cholesterol and its metabolites have not. Using GCxGC 3D mass spectrometry we find here that primary keratinocytes from diverse monogenic HISDs (Inflammatory Linear Verruvous Epidermal Naevus ILVEN n=14, CHILD syndrome n=2), and from plaque psoriasis (n=2), demonstrate significantly reduced mean cholesterol across all patient groups compared to controls. This striking abnormality appears causally implicated, as treatment in vitro with cholesterol and statin rescues the cellular hyperproliferation. Using SNPsea and burden analysis of large international psoriasis cohorts we go on to show that GWAS hits are significantly enriched in proximity to genes encoding lipid metabolic pathways, and that rare variants in lipid metabolic pathway genes are significantly enriched in psoriasis patients. These data identify a final common pathway of aberrant keratinocyte cholesterol metabolism in HISD, which should be drugged topically to avoid first pass metabolism. In parallel we implicate genetic variation in lipid pathway genes in psoriasis susceptibility, potentially explaining the co-morbidity of abnormal serum lipid profile and psoriasis.