DataSheet1_Using multi-omics to explore the genetic causal relationship between colorectal cancer and heart failure in gastrointestinal tumors.docx

BackgroundHeart failure (HF) and colorectal cancer are significant public health concerns with substantial morbidity and mortality. Previous studies have indicated a close association between HF and various tumors, including colorectal cancer. Further understanding the potential causal relationship between them could provide insights into their shared pathophysiological mechanisms and inform strategies for prevention and treatment.
MethodsThis study employed a bidirectional Mendelian randomization (MR) approach using genetic variants from large genome-wide association studies (GWAS) as instrumental variables (IVs). The inverse-variance weighted (IVW) method was employed for the MR analysis. Meta-analyses of IVW results from discovery and validation cohorts were performed to enhance the power of detecting causal effects. Sensitivity analyses, including heterogeneity analysis and tests for horizontal pleiotropy, were conducted to test the robustness of the conclusions.
ResultsResults from the discovery cohort suggest HF is associated with an approximately 30% increased risk of colorectal cancer (OR 1.32, 95% CI 1.03-1.69, P=0.025), although this finding did not reach statistical significance in the validation cohort (OR 1.19, 95% CI 0.97-1.46, P=0.090). However, meta-analysis supports HF as a potential risk factor for colorectal cancer (Pooled OR 1.24, 95% CI 1.06-1.25, P=0.007). Reverse MR analysis found no evidence of colorectal cancer increasing HF risk (Pooled OR 1.03, 95% CI 0.99-1.07, P=0.121). Sensitivity analyses (all P>0.05) indicate robustness against heterogeneity and horizontal pleiotropy.
ConclusionThis comprehensive bidirectional MR study provides genetic evidence supporting a causal link between HF and colorectal cancer. The insights gained enhance understanding of their interconnectedness and may guide future research and clinical practices aimed at mitigating their risks through targeted interventions.

背景 心力衰竭（Heart failure, HF）与结直肠癌（colorectal cancer）均为引发严重发病与死亡的重大公共卫生问题。既往研究已证实，心力衰竭与包括结直肠癌在内的多种肿瘤存在密切关联。进一步明确二者间潜在的因果关联，可为阐释二者共有的病理生理机制提供新思路，并为预防与治疗策略制定提供参考。
方法 本研究采用双向孟德尔随机化（Mendelian randomization, MR）分析方法，以大型全基因组关联研究（genome-wide association studies, GWAS）中的遗传变异作为工具变量（instrumental variables, IVs）。孟德尔随机化分析采用逆方差加权（inverse-variance weighted, IVW）法，通过对发现队列与验证队列的逆方差加权结果进行荟萃分析，以提升因果效应检测效力。本研究同时开展敏感性分析，包括异质性检验与水平多效性检测，以验证研究结论的稳健性。
结果 发现队列结果显示，心力衰竭与结直肠癌风险升高约30%相关（比值比（OR）=1.32，95%置信区间（CI）：1.03~1.69，P=0.025），但该关联在验证队列中未达到统计学显著性（OR=1.19，95%CI：0.97~1.46，P=0.090）。不过荟萃分析结果支持心力衰竭为结直肠癌的潜在危险因素（合并OR=1.24，95%CI：1.06~1.25，P=0.007）。反向孟德尔随机化分析未发现结直肠癌会增加心力衰竭风险的证据（合并OR=1.03，95%CI：0.99~1.07，P=0.121）。敏感性分析结果（所有P>0.05）表明研究结论不受异质性与水平多效性的影响，具备稳健性。
结论 本项综合性双向孟德尔随机化研究提供了遗传学证据，支持心力衰竭与结直肠癌之间存在因果关联。本研究所得结论可加深对二者相互关联机制的理解，并可为未来通过靶向干预手段降低二者发病风险的相关研究与临床实践提供指导。