PO.PR02.02 · 预防研究
尼古丁依赖部分介导了吸烟者中IP6K3遗传变异与肺鳞状细胞癌风险之间的关联
Nicotine dependence partially mediates the association between IP6K3 genetic variation and risk of lung squamous cell carcinoma among smokers
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摘要 Abstract
中文摘要
引言：尼古丁依赖是一种可遗传的性状，可能介导对肺癌的遗传易感性。在此前一项整合基因组研究的基础上——该研究识别出位于纯合区段（TOH）内、与肺组织中差异甲基化区域（DMRs）重叠的显著SNPs及其注释基因——我们考察了这些甲基化驱动基因内的SNPs和单倍型是否通过涉及吸烟者尼古丁依赖的通路与非小细胞肺癌（NSCLC）风险相关联。
方法：本研究纳入了来自一项全基因组关联研究（GWAS）的肺腺癌（LUAD）、肺鳞状细胞癌（LUSC）患者以及基于人群的对照。在肿瘤与邻近正常组织之间表现出差异表达（绝对log₂倍数变化≥2）的基因被保留为SNP和单倍型介导模型的候选位点。在候选基因内，界定连锁不平衡区块以构建单倍型。采用校正年龄和性别的多变量logistic回归模型，按亚型估计SNP和单倍型水平与NSCLC风险的关联。携带显著单倍型的个体被编码为暴露。采用因果中介分析估计每个SNP或单倍型对NSCLC风险的效应中由尼古丁依赖介导的比例，尼古丁依赖以Fagerström尼古丁依赖测试（FTND）测量。结构方程模型（SEM）进一步量化了年龄、性别、癌症状态、戒烟状态、吸烟包年数、尼古丁依赖（FTND）及显著单倍型携带状态之间的直接和间接关联。
结果：IP6K3单倍型"GTGTG"（rs649775-rs2966-10947433-rs4713668-rs6457740）与LUSC风险呈负相关，其保护性关联中约39%由尼古丁依赖介导（平均因果中介效应[ACME]=-0.023，95% CI：-0.039，-0.010）。与此模式一致，IP6K3 rs2966（TT vs CC；CT vs CC）和rs4713668（TT vs CC；CT vs CC）表现出经尼古丁依赖的显著间接效应（ACME范围为-0.023至-0.027；p值介于0.004和0.024之间），占其对LUSC风险总保护效应的33-38%。
结论：这些发现将IP6K3确定为尼古丁相关肺癌发生中的潜在候选基因，并凸显了神经生物学依赖通路在个体化戒烟和肺癌预防策略中的相关性。
查看英文原文 English abstract
INTRODUCTION : Nicotine dependence is a heritable trait that may mediate genetic susceptibility to lung cancer. Building on a prior integrative genomic study that identified significant SNPs and their annotated genes located within tracts of homozygosity (TOH) overlapping differentially methylated regions (DMRs) in lung tissue, we investigated whether these SNPs and haplotypes within these methylation-driven genes were associated with Non-Small Cell Lung Cancer (NSCLC) risk through pathways involving nicotine dependence among smokers.
METHODS : The study included individuals with lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), and population-based controls from a genome-wide association study (GWAS). Genes exhibiting differential expression with an absolute log₂ fold-change ≥2 between tumor and adjacent normal tissues were retained as candidate loci for SNP- and haplotype-based mediation models. Within candidate genes, linkage disequilibrium blocks were defined to construct haplotypes. Multivariable logistic regression models adjusted for age and sex were used to estimate SNP- and haplotype-level associations with NSCLC risk by subtypes. Individuals carrying a significant haplotype were coded as exposed. Causal mediation analyses were used to estimate the proportion of each SNP or haplotype's effect on NSCLC risk that was mediated by nicotine dependence, measured by the Fagerström Test for Nicotine Dependence (FTND). Structural equation modeling (SEM) further quantified direct and indirect associations among age, sex, cancer status, smoking cessation status, smoking pack years, nicotine dependence (FTND), and carrier status for the significant haplotypes.
RESULTS : The IP6K3 haplotype “GTGTG” (rs649775-rs2966-10947433-rs4713668-rs6457740) was inversely associated with LUSC risk, with approximately 39% of its protective association mediated by nicotine dependence (average causal mediation effect [ACME]=-0.023, 95% CI: -0.039, -0.010). Consistent with this pattern, IP6K3 rs2966 (TT vs CC; CT vs CC) and rs4713668 (TT vs CC; CT vs CC) exhibited significant indirect effects via nicotine dependence (ACME ranges from -0.023 to -0.027; p -values between 0.004 and 0.024), accounting for 33-38% of their total protective effects on LUSC risk.
CONCLUSION : These findings identify IP6K3 as a potential candidate gene in nicotine-related lung carcinogenesis and highlight the relevance of neurobiological dependence pathways in personalized smoking cessation and lung cancer prevention strategies.
利益披露 Disclosure
J. Jin, None..
Y. Rahmatallah, None..
H. Gomez-Acevedo, None..
Y. Park, None..
D. Ussery, None..
M. Orloff, None.