常规血/尿生化指标与胰腺癌风险因果关联的孟德尔随机化分析

Routine blood and urine biochemical biomarkers in relation to pancreatic cancer risk: a Mendelian randomization analysis

摘要:

背景与目的 胰腺癌（PC）早期诊断困难，现有标志物（如CA19-9）难以满足人群筛查需求。常规血/尿生化指标具备可及性强、可重复检测等优势，但其与PC风险的因果关系尚不明确。本研究基于两样本孟德尔随机化（MR）方法，系统评估35项常规生化指标与PC风险的潜在因果关联。方法 暴露数据来源于英国生物样本库（UK Biobank）相关GWAS汇总数据，结局数据来自FinnGen R12数据库。以逆方差加权法（IVW）为主要分析方法，并结合MR-Egger、加权中位数及加权模式方法进行验证，同时开展异质性、多效性及稳健性分析。结果 MR分析显示，肾功能相关指标与PC风险存在稳定因果关联：遗传预测的血肌酐每升高1个标准差，PC风险增加18%（OR=1.18，95% CI=1.03~1.36，P=0.019）；估算肾小球滤过率（eGFR）每升高1个标准差，PC风险降低17%（OR=0.83，95% CI=0.72~0.97，P=0.016）。多种敏感性分析结果一致，未发现显著异质性或水平多效性。结论 本研究提供了肾功能相关指标与PC风险之间的遗传学因果证据，提示“肾功能轴”可能参与PC发生发展。血肌酐与eGFR有望作为PC风险分层及早期识别的潜在宿主标志物，仍需进一步机制研究与前瞻性验证。

Abstract:

Background and Aims Early detection of pancreatic cancer (PC) remains challenging, and conventional biomarkers such as CA19-9 are inadequate for population screening. Routine blood and urine biochemical markers are widely accessible and reflect systemic physiological status; however, their causal relationships with PC risk remain unclear. Therefore, this study aimed to systematically evaluate the potential causal associations between 35 routine biochemical biomarkers and pancreatic cancer risk using a two-sample Mendelian randomization (MR) framework.Methods A two-sample MR study was conducted using genome-wide association study (GWAS) summary data from the UK Biobank for 35 biochemical traits. Outcome data for PC were obtained from the FinnGen consortium (release R12). The inverse-variance weighted (IVW) method was used as the primary analysis, complemented by MR-Egger, weighted median, and weighted mode approaches. Sensitivity analyses were performed to assess robustness.Results Two kidney function-related traits showed consistent causal associations with PC risk. Genetically predicted higher serum creatinine levels were associated with an 18% increased risk of PC per 1-standard deviation increment (OR=1.18, 95% CI=1.03-1.36, P=0.019), whereas higher estimated glomerular filtration rate (eGFR) was associated with a 17% reduced risk (OR=0.83, 95% CI=0.72-0.97, P=0.016). Sensitivity analyses supported the robustness of these findings, with no evidence of substantial heterogeneity or horizontal pleiotropy.Conclusions This MR study provides genetic evidence supporting a potential causal role of kidney function-related pathways in pancreatic cancer. Serum creatinine and eGFR may serve as promising host-related biomarkers for risk stratification and early detection, warranting further mechanistic and prospective validation.