Clinical trial NCT06471387: Unraveling the Genetic Basis of Nicotine Addiction for Novel Therapeutic Strategies
Official title: Exploring the Genetic and Molecular Underpinning of Nicotine Addiction for the Development of New Therapeutic Strategies
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Smoking Cessation
Smoking Cessation Intervention
Nicotine Addiction
Epigenetics
Molecular Biology
Genetic Epidemiology
Keywords: Nicotine Addiction
Smoking Cessation
Mendelian Randomization
Methylation
Genetic Epidemiology
Drug Repurposing
Epigenetic Biomarkers
Lead sponsor: University of Cyprus
Sponsor class: OTHER
First posted: 2024-06-24
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The study population will consist of adult daily cigarette smokers recruited from communities across Cyprus who are able to attend study visits at the research facilities in Nicosia. Recruitment will leverage multiple avenues including primary care clinics, community outreach, word-of-mouth referrals, and smoking cessation services throughout the island. The goal is to enroll approximately 200 eligible participants, with equal representation of men and women, from both urban and rural areas of Cyprus. No other specific characteristics beyond meeting eligibility criteria are used to identify or restrict the source population.

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.

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

Primary outcomes:
measure: Novel druggable gene targets for smoking cessation
timeFrame: Upon completion of Mendelian randomization analysis
measure: Association between methylation of candidate genes and nicotine dependence scores
timeFrame: Baseline
measure: Association between DNA methylation of candidate drug target genes and motivation to quit smoking scores
timeFrame: 3 and 6 months post nicotine cessation
measure: Association between methylation and smoking relapse vulnerability
timeFrame: 3 and 6 months post nicotine cessation
Secondary outcomes:
measure: Gender differences in methylation associations
timeFrame: 3 and 6 months post nicotine cessation
Other outcomes:
Locations:
city: Nicosia
country: Cyprus
facility: Center for Applied Neuroscience (CAN)
Study officials:
References:
citation: Karekla M, Savvides SN, Gloster A. An Avatar-Led Intervention Promotes Smoking Cessation in Young Adults: A Pilot Randomized Clinical Trial. Ann Behav Med. 2020 Oct 1;54(10):747-760. doi: 10.1093/abm/kaaa013.