Data_Sheet_1_Association between dried fruit intake and pan-cancers incidence risk: A two-sample Mendelian randomization study.docx

BackgroundObservational studies have revealed that dried fruit intake may be associated with cancer incidence; however, confounding factors make the results prone to be disturbed. Therefore, we conducted a two-sample Mendelian randomization (MR) study to explore the causal relationship between dried fruit intake and 11 site-specific cancers.
Materials and methodsForty-three single nucleoside polymers (SNPs) with robust genome-wide association study (GWAS) evidence, strongly correlated with dried fruit intake, were used as instrumental variables (IVs) in this study. The summary-level genetic datasets of site-specific cancers were obtained from the Oncoarray oral cavity and oropharyngeal cancer consortium, International Lung Cancer Consortium, Breast Cancer Association Consortium (BCAC), Ovarian Cancer Association Consortium, PanScan1, and GWAS of other scholars. We analyzed the causality between dried fruit intake and 11 site-specific cancers using the inverse-variance-weighted (IVW) and weighted median (WM) methods. For the results of the MR analysis, Cochran’s Q test was used to check for heterogeneity, and multiplicative random effects were used to evaluate the heterogeneity further. Gene pleiotropy was tested using MR-Egger regression and MR-PRESSO methods. In addition, the main results of this study were validated by using the summary statistical data from the FinnGen and UK Biobank databases, and adjusted body mass index (BMI), years of education, fresh fruit intake, and vitamin C using multivariable MR analysis to ensure the stability of the research results.
ResultsThe evidence from IVW analyses showed that each increase of dried fruit intake by one standard deviation was statistically significantly associated with 82.68% decrease of oral cavity/pharyngeal cancer incidence risk (P = 0.0131), 67.01% decrease of lung cancer incidence risk (P = 0.0011), 77% decrease of squamous cell lung cancer incidence risk (P = 0.0026), 53.07% decrease of breast cancer incidence risk (P = 4.62 × 10–5), 39.72% decrease of ovarian cancer incidence risk (P = 0.0183), 97.26% decrease of pancreatic cancer incidence risk (P = 0.0280), 0.53% decrease of cervical cancer incidence risk (P = 0.0482); however, there was no significant effect on lung adenocarcinoma (P = 0.4343), endometrial cancer (P = 0.8742), thyroid cancer (P = 0.6352), prostate cancer (P = 0.5354), bladder cancer (P = 0.8996), and brain cancer (P = 0.8164). In the validation part of the study results, the causal relationship between dried fruit intake and lung cancer (P = 0.0043), squamous cell lung cancer (P = 0.0136), and breast cancer (P = 0.0192) was determined. After adjusting for the potential impact of confounders, the causal relationship between dried fruit intake and lung cancer (P = 0.0034), squamous cell lung cancer (P = 0.046), and breast cancer (P = 0.0001) remained. The sensitivity analysis showed that our results were stable and reliable.
ConclusionThe intake of dried fruits may have a protective effect against some site-specific cancers. Therefore, health education and a reasonable adjustment of dietary proportions may help in the primary prevention of cancer.

**研究背景** 观察性研究已表明，干果摄入可能与癌症发病风险存在关联，但混杂因素易对研究结果造成干扰。为此，本研究开展了两样本孟德尔随机化（Mendelian randomization, MR）研究，以探讨干果摄入与11种部位特异性癌症之间的因果关联。**材料与方法** 本研究选取43个与干果摄入强相关、且具有可靠全基因组关联研究（genome-wide association study, GWAS）证据的单核苷酸多态性（single nucleotide polymorphisms, SNPs）作为工具变量（instrumental variables, IVs）。部位特异性癌症的汇总级遗传数据集来源于Oncoarray口腔癌与口咽癌联盟、国际肺癌联盟、乳腺癌协会联盟（Breast Cancer Association Consortium, BCAC）、卵巢癌协会联盟、PanScan1以及其他学者的GWAS数据。本研究采用逆方差加权（inverse-variance-weighted, IVW）法与加权中位数（weighted median, WM）法分析干果摄入与11种部位特异性癌症之间的因果关联。针对MR分析结果，本研究采用Cochran Q检验（Cochran’s Q test）进行异质性检验，并通过乘性随机效应模型进一步评估异质性；采用MR-Egger回归（MR-Egger regression）与MR-PRESSO方法检测基因多效性。此外，本研究利用FinnGen与英国生物样本库（UK Biobank）数据库的汇总统计数据对主要研究结果进行验证，并通过多变量MR分析校正体重指数（body mass index, BMI）、受教育年限、新鲜水果摄入及维生素C等混杂因素，以确保研究结果的稳定性。**研究结果** 逆方差加权分析结果显示，干果摄入每增加1个标准差，口腔癌/咽癌发病风险降低82.68%（P=0.0131）、肺癌发病风险降低67.01%（P=0.0011）、肺鳞癌发病风险降低77%（P=0.0026）、乳腺癌发病风险降低53.07%（P=4.62×10^-5）、卵巢癌发病风险降低39.72%（P=0.0183）、胰腺癌发病风险降低97.26%（P=0.0280）、宫颈癌发病风险降低0.53%（P=0.0482）；但干果摄入对肺腺癌（P=0.4343）、子宫内膜癌（P=0.8742）、甲状腺癌（P=0.6352）、前列腺癌（P=0.5354）、膀胱癌（P=0.8996）及脑癌（P=0.8164）无显著影响。在研究结果验证环节，本研究证实了干果摄入与肺癌（P=0.0043）、肺鳞癌（P=0.0136）及乳腺癌（P=0.0192）之间的因果关联。校正混杂因素的潜在影响后，干果摄入与肺癌（P=0.0034）、肺鳞癌（P=0.046）及乳腺癌（P=0.0001）之间的因果关联依然存在。敏感性分析结果表明，本研究结果稳定可靠。**研究结论** 干果摄入或许对部分部位特异性癌症具有保护作用。因此，开展健康教育并合理调整膳食结构，或有助于癌症的一级预防。