Exploring the Genetic and Molecular Underpinning of Nicotine Addiction for the Development of New Therapeutic Strategies
Overview
- Phase
- Not Applicable
- Intervention
- Not specified
- Conditions
- Smoking Cessation
- Sponsor
- University of Cyprus
- Enrollment
- 200
- Locations
- 1
- Primary Endpoint
- Novel druggable gene targets for smoking cessation
- Status
- Recruiting
- Last Updated
- last year
Overview
Brief Summary
This case-control study aims to investigate the genetic and molecular bases of nicotine addiction to identify potential therapeutic targets. The project will involve drug repurposing using Mendelian Randomization, a smoking cessation intervention, and the analysis of methylation status in participants undergoing nicotine withdrawal.
Detailed Description
Cigarette smoking remains the largest preventable risk factor for chronic diseases and premature mortality worldwide. While several medications have been approved to aid smoking cessation, most individuals relapse following an initial period of abstinence, with only around 15% achieving long-term abstinence beyond 6-12 months. This highlights a critical need to identify novel drug targets and develop more effective pharmacotherapies to treat nicotine addiction and maintain long-term smoking abstinence. The proposed case-control study aims to leverage an interdisciplinary approach combining genetic epidemiology and molecular biology to: 1) Identify potential novel druggable targets for smoking cessation using a drug repurposing Mendelian randomization (MR) strategy, and 2) Assess whether epigenetic modifications (DNA methylation) of the identified drug target genes are associated with motivation to quit smoking, nicotine dependence severity, and vulnerability to smoking relapse following a cessation attempt. Specifically, NicoGen study utilizes large-scale genomic datasets of expression quantitative trait loci (eQTLs) and protein quantitative trait loci (pQTLs) to identify genetic variants that influence expression/levels of genes encoding druggable proteins (targets of approved drugs/clinical candidates). MR analyses will then determine if genetically-predicted expression of these genes is causally related to smoking cessation outcomes. Additionally, 200 current cigarette smokers (100 men, 100 women) will be recruited prior to smoking cessation for collection of biofluids for DNA extraction. The methylation levels of the top candidate drug target genes identified in will be assessed and compared between: 1) Cases who achieve ≥6 month abstinence vs. relapsed controls, 2) High vs. low motivation to quit groups, and 3) High vs. low nicotine dependence groups. This allows identification of epigenetic biomarkers predictive of cessation outcomes. Additionally, potential gender differences in the associations between gene methylation, motivation, dependence and relapse vulnerability will be explored to identify gender-specific drug targets.
Investigators
Panos Zanos
Assistant Professor
University of Cyprus
Eligibility Criteria
Inclusion Criteria
- •Adults aged 18-60 years old
- •Current daily cigarette smoker
- •Able to understand study procedures and provide informed consent
- •For females, non-pregnant and non-lactating
Exclusion Criteria
- •Presence of significant uncontrolled medical conditions (e.g. cardiovascular disease, respiratory disorders, cancer) that could affect smoking behaviors or study participation
- •Presence of major uncontrolled psychiatric disorders (e.g. schizophrenia, bipolar disorder, severe depression)
- •Current substance use disorder (except nicotine dependence)
- •Taking medications that could significantly interfere with study objectives (e.g. medications for smoking cessation)
- •Significant cognitive impairment that precludes ability to complete study procedures
Outcomes
Primary Outcomes
Novel druggable gene targets for smoking cessation
Time Frame: Upon completion of Mendelian randomization analysis
Genes encoding druggable proteins (targets of approved drugs or clinical candidates) whose genetically predicted expression levels are found to be causally associated with smoking cessation outcomes using Mendelian randomization approaches.
Association between methylation and smoking relapse vulnerability
Time Frame: 3 and 6 months post nicotine cessation
Difference in methylation of top genes between cases achieving 6+ month abstinence vs. controls who relapsed to smoking.
Association between DNA methylation of candidate drug target genes and motivation to quit smoking scores
Time Frame: 3 and 6 months post nicotine cessation
Difference in methylation levels of the top candidate drug target genes between participants with high vs. low scores on a validated motivation to quit smoking questionnaire.
Association between methylation of candidate genes and nicotine dependence scores
Time Frame: Baseline
Difference in methylation levels of top genes between participants with high vs. low scores on the Fagerström Test for Nicotine Dependence.
Secondary Outcomes
- Gender differences in methylation associations(3 and 6 months post nicotine cessation)