PROJECT SUMMARY/ABSTRACT Cigarette smoking remains the leading cause of preventable death. Several effective medications for smoking cessation exist, but uptake of these treatments is low, making it difficult to quit smoking. Difficulty quitting smoking is also driven in part by genetic factors, which have not been incorporated into cessation interventions, marking a major scientific gap. Large genome-wide studies have shown that variation in nicotinic receptor genes impacts the risk of smoking-related diseases and difficulty with quitting smoking. Incorporating genetic information within a risk communication tool may engage current smokers in new quit attempts and motivate treatment use. Genetically-informed interventions may promote cessation by changing health-related cognitions (e.g., personalized benefits of treatment and cessation) and engagement (e.g., personal relevance of the intervention). The overarching goal of this study is to advance the development of a genetically-informed smoking cessation intervention—the RiskProfile—to lay the groundwork for a full-scale efficacy trial. This trial will aim to test preliminary effects of the RiskProfile on medication use and smoking outcomes to estimate effect sizes for a larger trial (Aim 1a), determine effects of the RiskProfile on potential change mechanisms leading to smoking cessation (Aim 1b), and adapt the RiskProfile and evaluate feasibility and acceptability for use in real-world community settings (Aim 2). For Aim 1, we will enroll 128 current smokers to receive genetic testing, randomize participants to either the intervention (genetically-informed RiskProfile) or control (brief cessation advice) group, and assess outcomes up to 6 months post-intervention. In this pilot, parallel-group, randomized controlled trial (RCT), we will test effects of the RiskProfile on primary outcomes of use of smoking cessation pharmacotherapy and average cigarettes smoked per day, and secondary outcomes of readiness to quit smoking and biochemically-verified smoking abstinence. We will then test the effects on health-related cognitions (perceived risk, benefits of treatment use and cessation, self-efficacy) and engagement (personal relevance, comprehension, sharing results). In Aim 2, to explore the potential for transporting the RiskProfile from research to community settings, we will conduct focus groups with individuals who smoke (n=20) and substance abuse counselors (n=10) to adapt the tool for use in a partnering community health agency. Current smokers and counselors (n=20 dyads) will then pilot test the RiskProfile protocol, and quantitative metrics will be used to determine intervention acceptability and feasibility to proceed to a large-scale “real-world” efficacy trial. If successful, this study will (1) incorporate novel genetic information in the development of a behavioral intervention to promote medication use and smoking cessation, (2) reveal potential mechanisms of behavior change to guid...