Associations of High-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, total cholesterol (CHL), and triglyceride (TRG) concentrations with risk of biliary tract cancer (BtC) were conflicting in observational studies. We aim to investigate the causal link between circulating lipids and BtC using genetic information. Single nucleotide polymorphisms of the four circulating lipids (n = 34,421) and BtC (418 cases and 159,201 controls) were retrieved from two independent GWAS studies performed in East Asian populations. Two-sample univariate and multivariate Mendelian Randomization (MR) analyses were conducted to determine the causal link between circulating lipids and BtC. No significant horizontal pleiotropy was detected for all circulating lipids according to the MR-PRESSO global test (P = 0.458, 0.368, 0.522, and 0.587 for HDL, LDL, CHL, and TRG, respectively). No significant evidence of heterogeneity and directional pleiotropy was detected by the Cochran’s Q test and MR-Egger regression. Univariate MR estimates from inverse variance weighting method suggested that one standard deviation (1-SD) increase of inverse-normal transformed HDL (OR = 1.38, 95% CI 0.98–1.94), LDL (OR = 1.46, 95% CI 0.96–2.23), and CHL (OR = 1.34, 95% CI 0.83–2.16) were not significantly associated with BtC risk. Whereas 1-SD increase of inverse-normal transformed TRG showed a significantly negative association with BtC risk (OR = 0.48, 95% CI 0.31–0.74). In multivariate MR analyses including all the four lipid traits, we found that 1-SD increase of LDL and TRG was significantly associated with elevated (OR = 1.32, 95% CI 1.04–2.01) and decreased (OR = 0.54, 95% CI 0.42–0.68) risk of BtC, respectively. Circulating lipids, particularly LDL and TRG, may have roles in the development of BtC. However, the results of this study should be replicated in MR with larger GWAS sample sizes for BtC.

中文翻译：

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东亚人循环脂质与胆道癌的孟德尔随机研究


在观察性研究中，高密度脂蛋白 (HDL) 胆固醇、低密度脂蛋白 (LDL) 胆固醇、总胆固醇 (CHL) 和甘油三酯 (TRG) 浓度与胆道癌 (BtC) 风险之间的关系是相互矛盾的。我们的目标是利用遗传信息研究循环脂质与 BtC 之间的因果关系。从在东亚人群中进行的两项独立 GWAS 研究中检索了四种循环脂质（n = 34,421）和 BtC（418 例病例和 159,201 对照）的单核苷酸多态性。进行两个样本单变量和多变量孟德尔随机化 (MR) 分析以确定循环脂质与 BtC 之间的因果关系。根据 MR-PRESSO 全局测试，所有循环脂质均未检测到显着的水平多效性（HDL、LDL、CHL 和 TRG 的 P 值分别为 0.458、0.368、0.522 和 0.587）。 Cochran's Q 检验和 MR-Egger 回归没有检测到异质性和定向多效性的显着证据。逆方差加权法的单变量 MR 估计表明，逆正态变换 HDL（OR = 1.38，95% CI 0.98–1.94）、LDL（OR = 1.46，95% CI 0.96–2.23）增加一个标准差 (1-SD) ）和 CHL（OR = 1.34，95% CI 0.83–2.16）与 BtC 风险没有显着相关性。而逆正态转化 TRG 的 1-SD 增加显示与 BtC 风险显着负相关（OR = 0.48，95% CI 0.31–0.74）。在包括所有四种脂质性状的多变量 MR 分析中，我们发现 LDL 和 TRG 的 1-SD 增加与升高（OR = 1.32，95% CI 1.04–2.01）和降低（OR = 0.54，95% CI 0.42）显着相关。 –0.68) BTC 的风险。 循环脂质，特别是 LDL 和 TRG，可能在 BtC 的形成中发挥作用。然而，这项研究的结果应该在 MR 中得到复制，并且 BtC 的 GWAS 样本量更大。