Gene Expression Analysis in Patients with Cocaine-Induced Midline Destructive Lesions.

Matteo Trimarchi,Alessandro Vinciguerra,Dejan Lazarevic,Mario Bussi,Davide Cittaro,Giacomo Bertazzoni,Celia Pardini,Fabio Simeoni

doi:10.3390/medicina57090861

Abstract

Background and Objectives: Cocaine users may present with positive antineutrophil cytoplasmic antibodies (ANCA) and severe midline destructive lesions (CIMDL) which are histologically 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 analyzed. 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 homeostasis, autophagy, and response to oxidative stress. Conclusions: Oxidative stress and rare genetic alterations in the response to reactive oxygen species, apoptosis, autophagy, and tissue regeneration are plausible drivers of damage affecting nasal mucosa exposed to cocaine crystals and, consequently, the pathogenic mechanism behind CIMDL.

Highlights

Cocaine is the most commonly used illicit stimulant drug in Europe [1]
Under the hypothesis that genes linked to the clinical phenotype are induced by cocaine, a rare variants burden test was performed to select genes that were significantly enriched in rare mutations compared to a control population
Our study demonstrated induced expression of a diverse array of pro-apoptotic genes in nasal epithelium exposed to cocaine

Summary

Introduction

Cocaine is the most commonly used illicit stimulant drug in Europe [1]. Estimates of the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) indicate that about 2.6 million young adults (aged 15 to 34) used cocaine during the previous year [1]. 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. Results: We identified 462 genes that were induced by cocaine, mainly related to apoptosis and autophagy in response to oxidative stress. cocaine abusers with CIMDL and no other relevant medical comorbidities underwent exome sequencing, and genes that were significantly enriched in the burden test and present in at least 10 patients were identified. Conclusions: Oxidative stress and rare genetic alterations in the response to reactive oxygen species, apoptosis, autophagy, and tissue regeneration are plausible drivers of damage affecting nasal mucosa exposed to cocaine crystals and, the pathogenic mechanism behind CIMDL

Methods

Results

Discussion

Conclusion