A comprehensive genome-wide association study has identified potential genetic factors that could influence the effectiveness of varenicline in smoking cessation.
The study, published in Nicotine and Tobacco Research, analyzed data from more than 4,000 participants across multiple European cohorts.
The investigators assessed short-term and long-term varenicline effectiveness (SVE and LVE) based on smoking status at 3 and 12 months following treatment initiation. Although no variants reached genome-wide significance, 15 sentinel variants were identified at a suggestive significance threshold (P < 5 × 10−6). These variants implicated genes that are involved in transcriptional regulation (GLI2, LMO7), RNA modification (MTPAP, UTP23, THUMPD2), and cilium assembly (TTLL3, TBC1D22A). Specifically, TTLL3, TBC1D22A might affect addiction-related signaling pathways.
The study included 1,405 cases and 2,074 controls for SVE and 1,576 cases and 2,555 controls for LVE. The participants with high nicotine dependence were less likely to achieve smoking cessation. Additionally, genes such as DPP4, linked to glucose metabolism, and TNFAIP8, associated with apoptosis regulation, suggested broader physiologic connections. DPP4 may influence varenicline's efficacy through metabolic regulation. These findings highlighted potential biomarkers for tailoring cessation therapies.
"Leveraging electronic health records, we undertook the largest genetic study of varenicline-aided smoking cessation to date, and the only such study to test genome-wide associations," wrote lead study author Kayesha Coley, PhD, of the Department of Population Health Sciences at the University of Leicester, and colleagues.
The investigators indicated that expanding biobank resources and utilizing denser genotyping arrays could improve future analyses. Replication in multiethnic cohorts would enhance generalizability and address the current study's demographic limitations. Functional studies exploring the biological mechanisms of these genetic variants may provide deeper insights into varenicline response variability.
While the identified genetic variants did not reach the threshold for genome-wide significance, this study offered a foundation for understanding the genetic basis of varenicline response. Detailed analyses of GLI2, LMO7, DPP4, and TNFAIP8 could inform future pharmacogenomic strategies. Large-scale studies integrating clinical and genetic data may pave the way for personalized smoking cessation therapies and optimize treatment efficacy based on individual genetic profiles.
No conflicts of interest were disclosed in the study.
