Gene expression analysis in patients with cocaine-induced midline destructive lesions

Background and Objectives: Cocaine users may present with positive antineutrophil cy-toplasmic antibodies (ANCA) and severe midline destructive lesions (CIMDL) which are histologi-cally characterized by massive apoptosis. However, histopathological and laboratory studies suggest that autoimmunity may not be the main pathogenic driver. We analyzed gene expression both in cell lines of nasal mucosa exposed to cocaine and in CIMDL patients to determine whether genetic predisposition might cause such lesions, which are observed in a minority of cocaine abusers. Materials and Methods: The genetic expression profile of nasal mucosa exposed to cocaine was ana-lyzed. Rare variants of expressed genes were searched in patients with CIMDL using exome sequencing and bio-informatics. Results: We identified 462 genes that were induced by cocaine, mainly related to apoptosis and autophagy in response to oxidative stress. Under the hypothesis that genes linked to the phenotype are also induced by cocaine itself, a rare variants burden test was performed to select genes that were significantly enriched in rare mutations. Next, 11 cocaine abusers with CIMDL and no other relevant medical comorbidities underwent exome sequencing, and 12 genes that were significantly enriched in the burden test and present in at least 10 patients were identified. An in-depth analysis of these genes revealed their involvement in apoptosis, tissue ho-meostasis, autophagy, and response to oxidative stress. Conclusions: Oxidative stress and rare genetic alterations in the response to reactive oxygen species, apoptosis, autophagy, and tissue regen-eration are plausible drivers of damage affecting nasal mucosa exposed to cocaine crystals and, consequently, the pathogenic mechanism behind CIMDL.