Causal relationship between blood protein ratios and pancreatic neuroendocrine neoplasms:a two-sample Mendelian randomization study

JIANG Zikang; HUANG Yuanpeng

doi:10.13276/j.issn.2097-1656.2025.12.015

Abstract：Objective To investigate the causal relationship between blood protein ratios and pancreatic neuroendocrine neoplasms(PNENs)to provide new theoretical foundations and potential biomarkers for early diagnosis and personalized treatment of PNENs.Methods This study employed a two-sample Mendelian randomization(MR)approach to analyze the causal associations between blood protein ratios and PNENs risk.Exposure data were obtained from a published study of 2 821 blood protein ratios.Outcome data were sourced from FinnGen R11 database.Single nucleotide polymorphisms with P-values less than 5 × 10-8 and F-statistics greater than 10 were selected as instrumental variables for MR analysis and sensitivity analysis.Results The study identified significant causal relationships between blood protein ratios and PNENs,specifically APRT/NSFL1C(OR=7.112,95％ CI=2.319-21.806,P=6.00 × 10-4),KYAT1/PLPBP(OR=3.445,95％ CI=1.747-6.792,P=3.55 × 10-4),PAEP/PROK1(OR=1.913,95％ CI=1.363-2.685,P=1.75 × 10-4),and PAEP/RSPO1(OR=1.826,95％ CI=1.309-2.546,P=3.86 × 10-4),which were associated with increased PNENs risk.Conversely,EIF4EBP1/KYAT1(OR=0.156,95％ CI=0.054-0.447,P=5.52 × 10-4),FKBP4/KYAT1(OR=0.266,95％ CI=0.131-0.540,P=2.42 × 10-4),and GLOD4/KYAT1(OR=0.291,95％ CI=0.142-0.594,P=7.12 × 10-4)exhibited protective effects against PNENs.The MR-Egger intercept test and MR-PRESSO test indicated no evidence of horizontal pleiotropy,while Cochran's Q test showed no significant heterogeneity.Leave-one-out analysis confirmed the robustness of the results.Conclusion This study identifies significant causal relationships between various blood protein ratios and PNENs.These findings provide new potential biomarkers and therapeutic targets for the early diagnosis and personalized treatment of PNENs,with important clinical application value.