食物喜好表型与胰腺癌风险关联的孟德尔随机化研究

Association between food liking phenotypes and pancreatic cancer risk: a Mendelian randomization study

摘要:

背景与目的:饮食因素可能参与胰腺癌发生、发展，但传统观察性研究易受混杂因素、测量误差及反向因果影响，饮食与胰腺癌风险之间的关系尚缺乏稳健的因果证据。食物喜好是影响长期饮食行为的重要上游行为表型，具有一定遗传基础，但其与胰腺癌风险之间的关系尚未得到系统评价。本研究采用遗传流行病学方法，探讨遗传预测的食物喜好表型与胰腺癌风险之间的潜在关联。 方法:采用双样本孟德尔随机化（MR）研究设计。暴露数据来源于May-Wilson等基于UK Biobank欧洲祖源人群开展的食物喜好全基因组关联研究（GWAS），纳入187种食物喜好表型；结局数据来源于3个欧洲祖源胰腺癌GWAS数据集，以FinnGen数据集作为主要分析数据集，ukb-saige-157和ebi-a-GCST90018893作为补充重复验证数据集。采用逆方差加权法（IVW）进行主要MR分析，并结合MR-Egger、加权中位数、加权众数及多种敏感性分析评价结果稳健性。对主分析中筛选出的候选关联进一步开展外部重复估计、随机效应Meta分析及潜在样本重叠校正。 结果:在FinnGen主分析中，11种食物喜好表型与胰腺癌风险达到名义统计学关联。经外部重复估计及Meta分析后，8种食物喜好表型仍保持统计学关联，其中chilli pepper liking和grapefruit liking与胰腺癌风险降低相关，合并OR（95% CI）分别为0.83（0.74~0.93）和0.89（0.81~0.99）；milky sweets liking与胰腺癌风险升高相关，合并OR（95% CI）为1.15（1.04~1.26）。其余5种关联虽经Meta分析获得统计学支持，但在单个外部数据集中的支持相对有限，作为探索性结果解释。另有3种主分析达到名义统计学意义的表型在Meta分析后未获得进一步支持。敏感性分析未发现明显异质性、定向水平多效性或单个单核苷酸多态性驱动效应；MRlap分析显示，潜在样本重叠校正未对效应估计产生实质影响。 结论:遗传流行病学分析提示，部分食物喜好表型可能与胰腺癌风险存在遗传支持的关联。其中，chilli pepper liking、grapefruit liking和milky sweets liking显示出相对稳定的关联信号。由于食物喜好并不等同于实际食物摄入量，本研究结果尚不足以直接转化为针对具体食物摄入的饮食干预建议。上述关联仍需在更大样本、不同祖源人群及更精细的饮食行为表型中进一步验证。

Abstract:

Background and Aims: Dietary factors may contribute to the development of pancreatic cancer, but conventional observational studies are susceptible to confounding, measurement error, and reverse causation. Food liking is an upstream behavioral phenotype that influences long-term dietary behavior and has a genetic component, yet its association with pancreatic cancer risk has not been systematically evaluated. This study investigated the potential associations between genetically predicted food liking phenotypes and pancreatic cancer risk using a genetic epidemiological approach. Methods: A two-sample Mendelian randomization (MR) design was employed. Exposure data were obtained from a genome-wide association study (GWAS) of food liking conducted by May-Wilson et al. in European-ancestry participants from the UK Biobank, covering 187 food liking phenotypes. Outcome data were derived from three European-ancestry pancreatic cancer GWAS datasets, with FinnGen serving as the primary dataset and ukb-saige-157 and ebi-a-GCST90018893 as supplementary replication datasets. The inverse-variance weighted (IVW) method was used for the primary MR analysis, complemented by MR-Egger regression, weighted median, weighted mode, and multiple sensitivity analyses. Candidate associations identified in the primary analysis were further evaluated by external replication, random-effects meta-analysis, and correction for potential sample overlap. Results: In the primary FinnGen analysis, 11 food liking phenotypes showed nominally significant associations with pancreatic cancer risk. After external replication and meta-analysis, eight phenotypes remained statistically associated with pancreatic cancer risk. Genetically predicted liking for chilli pepper and grapefruit was associated with lower pancreatic cancer risk, with pooled OR (95% CI) of 0.83 (0.74-0.93) and 0.89 (0.81-0.99), respectively, whereas milky sweets liking was associated with higher risk, with a pooled OR of 1.15 (1.04-1.26). The other five meta-analysis-supported associations were considered exploratory because of limited support in individual external datasets. Three phenotypes that showed nominal associations in the primary analysis were not supported by meta-analysis. Sensitivity analyses revealed no substantial evidence of heterogeneity, directional horizontal pleiotropy, or single-SNP-driven effects. MRlap analysis indicated that correction for potential sample overlap did not materially alter the effect estimates. Conclusion: Genetic epidemiological analyses suggest that several food liking phenotypes may be genetically associated with pancreatic cancer risk. Liking for chilli pepper, grapefruit, and milky sweets showed relatively consistent association signals. Because food liking does not directly represent actual food intake, these findings do not provide sufficient evidence to support dietary recommendations targeting specific foods. Further validation is warranted in larger samples, populations of diverse ancestries, and studies incorporating more refined dietary behavioral phenotypes.