DataSheet1_Causal relationship between plasma lipidome and four types of pancreatitis: a bidirectional Mendelian randomization study.pdf

BackgroundPancreatitis is a serious and complex inflammatory disease that imposes a severe effect on quality of life. Links between plasma lipidome and pancreatitis have been reported, some of which have not yet been clearly elucidated.
MethodsTherefore, our study aimed to investigate the causal relationships between plasma lipidome and four types of pancreatitis by conducting a bidirectional, two-sample Mendelian randomization (MR) analysis. We obtained genetic variants associated with 179 lipid species from a Genome-wide association analysis of plasma lipidome. The aggregated statistical data of acute pancreatitis (AP), alcohol-induced acute pancreatitis (AAP), chronic pancreatitis (CP), and alcohol-induced chronic pancreatitis (ACP) from the FinnGen consortium were exploited as the outcome. The inverse variance weighted (IVW) technique as the main method was used for MR analysis and sensitivity analyses were used to evaluate heterogeneity and pleiotropy.
ResultsAfter FDR correction, SE (27:1/20:4) (OR = 0.938, 95%CI = 0.906-0.972, P = 4.38 × 10-4, PFDR = 0.039) was identified to be significantly associated with AP risk. Eight lipid species were identified to be significantly associated with CP risk: SE (27:1/20:4) (OR = 0.911, 95%CI = 0.869-0.954, P = 8.89 × 10-5, PFDR = 0.016), LPC (20:4) (OR = 0.892, 95%CI = 0.843-0.945, P = 9.74 × 10-5, PFDR = 0.009), PC (16:0_22:5) (OR = 0.880, 95%CI = 0.818-0.947, P = 6.29 × 10-4, PFDR = 0.028), PC (17:0_20:4) (OR = 0.893, 95%CI = 0.842-0.948, P = 1.76 × 10-4, PFDR = 0.010), PC (18:0_20:4) (OR = 0.920, 95%CI = 0.874-0.969, P = 1.70 × 10-3, PFDR = 0.038), PC (O-16:0/20:4) (OR = 0.871, 95%CI = 0.804-0.943, P = 6.95 × 10-4, PFDR = 0.025), PC (O-16:1/20:4) (OR = 0.890, 95%CI = 0.832-0.953, P = 7.85 × 10-4, PFDR = 0.023), and PE (O-18:1/20:4) (OR = 0.866, 95%CI = 0.791-0.947, P = 1.61 × 10-3, PFDR = 0.041). Furthermore, genetically predicted increased LPC (20:4) (OR = 0.862, 95%CI = 0.796-0.934, P = 3.00 × 10-4, PFDR = 0.027) and SM (34:2;O2) (OR = 0.753, 95%CI = 0.659-0.860, P = 2.97 × 10-5, PFDR = 0.005) levels were associated with decreased risk of ACP.
ConclusionsOur findings provide evidence of causal associations between the specific types of lipidome and pancreatitis, offering new insights into future clinical research.

**背景**：胰腺炎是一种严重且复杂的炎症性疾病，会对患者的生活质量造成严重损害。已有研究报道血浆脂质组（plasma lipidome）与胰腺炎之间存在关联，但其中部分关联的机制尚未得到明确阐明。
**方法**：因此，本研究旨在通过双向两样本孟德尔随机化（Mendelian randomization, MR）分析，探究血浆脂质组与四种胰腺炎亚型之间的因果关系。我们从一项血浆脂质组全基因组关联分析（Genome-wide association analysis）中获取了与179种脂质物种相关的遗传变异。本研究以FinnGen联盟公开的急性胰腺炎（acute pancreatitis, AP）、酒精诱导性急性胰腺炎（alcohol-induced acute pancreatitis, AAP）、慢性胰腺炎（chronic pancreatitis, CP）以及酒精诱导性慢性胰腺炎（alcohol-induced chronic pancreatitis, ACP）的汇总统计数据作为结局指标。本研究以逆方差加权（inverse variance weighted, IVW）法作为MR分析的主要方法，并通过敏感性分析评估异质性（heterogeneity）与多效性（pleiotropy）。
**结果**：经错误发现率（false discovery rate, FDR）校正后，甾醇酯（sterol ester, SE）(27:1/20:4)（比值比OR=0.938，95%置信区间95%CI=0.906~0.972，P=4.38×10⁻⁴，校正后P值PFDR=0.039）被鉴定为与急性胰腺炎（AP）的发病风险显著相关。另有8种脂质物种与慢性胰腺炎（CP）的发病风险显著相关：SE(27:1/20:4)（OR=0.911，95%CI=0.869~0.954，P=8.89×10⁻⁵，PFDR=0.016）、溶血磷脂酰胆碱（lysophosphatidylcholine, LPC）(20:4)（OR=0.892，95%CI=0.843~0.945，P=9.74×10⁻⁵，PFDR=0.009）、磷脂酰胆碱（phosphatidylcholine, PC）(16:0_22:5)（OR=0.880，95%CI=0.818~0.947，P=6.29×10⁻⁴，PFDR=0.028）、PC(17:0_20:4)（OR=0.893，95%CI=0.842~0.948，P=1.76×10⁻⁴，PFDR=0.010）、PC(18:0_20:4)（OR=0.920，95%CI=0.874~0.969，P=1.70×10⁻³，PFDR=0.038）、PC(O-16:0/20:4)（OR=0.871，95%CI=0.804~0.943，P=6.95×10⁻⁴，PFDR=0.025）、PC(O-16:1/20:4)（OR=0.890，95%CI=0.832~0.953，P=7.85×10⁻⁴，PFDR=0.023）以及磷脂酰乙醇胺（phosphatidylethanolamine, PE）(O-18:1/20:4)（OR=0.866，95%CI=0.791~0.947，P=1.61×10⁻³，PFDR=0.041）。此外，遗传预测的LPC(20:4)（OR=0.862，95%CI=0.796~0.934，P=3.00×10⁻⁴，PFDR=0.027）与鞘磷脂（sphingomyelin, SM）(34:2;O2)（OR=0.753，95%CI=0.659~0.860，P=2.97×10⁻⁵，PFDR=0.005）水平升高与酒精诱导性慢性胰腺炎（ACP）的发病风险降低显著相关。
**结论**：本研究结果为特定脂质组与胰腺炎之间的因果关联提供了证据，为未来的临床研究提供了新的思路。