体重指数(BMI)已被发现与非小细胞肺癌(NSCLC)风险的降低有关;然而，BMI轨迹以及与遗传变异的潜在相互作用对NSCLC风险的影响仍然未知。

应用Cox比例风险回归模型评估了来自前列腺、肺癌、结直肠癌和卵巢癌(PLCO)筛查试验的138,110名队列参与者的BMI轨迹和NSCLC风险之间的关系。单样本孟德尔随机化(MR)分析进一步用于评估BMI轨迹与NSCLC风险之间的因果关系。此外，使用多基因风险评分(PRS)和全基因组相互作用分析(GWIA)来评估BMI轨迹和NSCLC风险中遗传变异之间的乘法相互作用。

研究表明BMI轨迹、遗传因素和NSCLC风险之间存在关联。有趣的是，我们发现了4个新的基因位点与BMI轨迹在NSCLC风险方面的相互作用，为NSCLC的病因学研究提供了更多的支持。

Abstract

Background: Body mass index (BMI) has been found to be associated with a decreased risk of non-small cell lung cancer (NSCLC); however, the effect of BMI trajectories and potential interactions with genetic variants on NSCLC risk remain unknown.

Methods: Cox proportional hazards regression model was applied to assess the association between BMI trajectory and NSCLC risk in a cohort of 138,110 participants from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. One-sample Mendelian randomization (MR) analysis was further used to access the causality between BMI trajectories and NSCLC risk. Additionally, polygenic risk score (PRS) and genome-wide interaction analysis (GWIA) were used to evaluate the multiplicative interaction between BMI trajectories and genetic variants in NSCLC risk.

Results: Compared with individuals maintaining a stable normal BMI (n = 47,982, 34.74%), BMI trajectories from normal to overweight (n = 64,498, 46.70%), from normal to obese (n = 21,259, 15.39%), and from overweight to obese (n = 4,371, 3.16%) were associated with a decreased risk of NSCLC (hazard ratio [HR] for trend = 0.78, P < 2×10-16). An MR study using BMI trajectory associated with genetic variants revealed no significant association between BMI trajectories and NSCLC risk. Further analysis of PRS showed that a higher GWAS-identified PRS (PRSGWAS) was associated with an increased risk of NSCLC, while the interaction between BMI trajectories and PRSGWAS with the NSCLC risk was not significant (PsPRS= 0.863 and PwPRS= 0.704). In GWIA analysis, four independent susceptibility loci (P < 1×10-6) were found to be associated with BMI trajectories on NSCLC risk, including rs79297227 (12q14.1, located in SLC16A7, Pinteraction = 1.01×10-7), rs2336652 (3p22.3, near CLASP2, Pinteraction = 3.92×10-7), rs16018 (19p13.2, in CACNA1A, Pinteraction = 3.92×10-7), and rs4726760 (7q34, near BRAF, Pinteraction = 9.19×10-7). Functional annotation demonstrated that these loci may be involved in the development of NSCLC by regulating cell growth, differentiation, and inflammation.

Conclusions: Our study has shown an association between BMI trajectories, genetic factors, and NSCLC risk. Interestingly, four novel genetic loci were identified to interact with BMI trajectories on NSCLC risk, providing more support for the aetiology research of NSCLC.

原文链接

pubmed.ncbi.nlm.nih.gov/35658861/

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