848 Genes implicated in lipid & metabolic regulation downregulated in CCCA

Abstract

Central centrifugal cicatricial alopecia (CCCA) is the most common form of scarring hair loss in black women. It is characterized by fibrosis out of proportion to the clinical and histologic signs of inflammation, which may lead to progressive end stage fibrosis. Previous work by our group showed that affected CCCA scalp is characterized by an increased expression of profibrotic genes seen in other conditions of aberrant scarring, including hepatic fibrosis. While the cause of this fibrosis is unknown, downregulation of adenosine monophosphate activated protein kinase (AMPK) have been implicated as a primary mediator of hepatic fibrosis, as well as other conditions of scarring. Furthermore, disruption in fatty acid metabolism, including linoleic acid, has been implicated in excess fibrosis including enhanced proliferation of fibroblasts and collagen type I. We performed gene expression microarrays on paired affected and unaffected scalp samples in five patients with CCCA to understand the role of metabolic dysregulation on the pathogenesis of CCCA. Transcriptome-wide analysis of over 20,000 human genes was performed, analyzing all known exons and the 200 (0.9%) most downregulated genes based on fold change were identified. We revealed widespread alterations of genes regulating lipid metabolism (p=2.3 x 10-3) and fatty acid biosynthesis (p=5.3 x 10-6) genes. In particular, the mRNA transcript of protein kinase AMP-activated catalytic subunit alpha 2 (PRKAA2), which partially encodes for the a subunit of AMPK, was shown to be downregulated by 34% in our CCCA affected scalp compared to the unaffected scalp (p=6.4 x 10-3). Linoleic acid metabolism was also disproportionately dysregulated in our dataset (p=9.1 x 10-3). Our work signifies a potential role that metabolic dysregulation may play in the pathogenesis of CCCA.