Cholesterol Pathway Gene Variants and Reduced Keratinocyte Cholesterol Support a Final Common Druggable Pathway in...

Hyperproliferative inflammatory skin disease (HISD) is frequently seen in rare monogenic diseases of cholesterol metabolism and responds to topical cholesterol/statin. We hypothesized that aberrant cholesterol metabolism within keratinocytes could be important in HISD more generally, driven by either immunological or lipid pathway genetic variation. Whereas other epidermal lipids have been well-characterized in HISDs, cholesterol and its metabolites have not. In this study, using comprehensive 2-dimensional gas chromatography 3-dimensional mass spectrometry, we found that primary keratinocytes from diverse monogenic HISDs (inflammatory linear verrucous epidermal nevi, n = 14; CHILD [congenital hemidysplasia with ichthyosiform erythroderma and limb defects] syndrome, n = 2) and from plaque psoriasis (n = 2) demonstrate significantly reduced mean cholesterol across all patient groups compared with those across the controls. This striking abnormality appears causally implicated because treatment in vitro with cholesterol and statin rescued the cellular hyperproliferation. Using SNPsea and burden analysis of large international psoriasis cohorts, we went on to show that GWAS hits were significantly enriched in proximity to genes encoding lipid metabolic pathways and that rare variants in lipid metabolic pathway genes were significantly enriched in patients with psoriasis. 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 comorbidity of abnormal serum lipid profile and psoriasis.