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. 2022 Mar 15;22(1):273.
doi: 10.1186/s12885-022-09382-x.

Mendelian randomization study of circulating lipids and biliary tract cancer among East Asians

Jun Wang #  1 , Jinke Zhuge #  2 , Dongxu Feng #  1 , Bo Zhang  1 , Jianying Xu  3 , Dongkang Zhao  4 , Zhewei Fei  1 , Xia Huang  5 , Wenjie Shi  6
Affiliations

Mendelian randomization study of circulating lipids and biliary tract cancer among East Asians

Jun Wang et al. BMC Cancer. .

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Biliary tract cancer; Cholesterol; HDL; LDL; Lipid; Mendelian randomization; Triglyceride.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Flow chart (A) and schematic representation (B) of Mendelian randomization analysis in this study
Fig. 2
Fig. 2
Scatter plots for Mendelian randomization analyses of the causal effect of circulating lipids on biliary tract cancer in initial practice. A, HDL; B, LDL; C, cholesterol; D, triglyceride. The slope of each line corresponding to the estimated MR effect per method
Fig. 3
Fig. 3
The causal effects of circulating lipids on biliary tract cancer from Mendelian randomization analyses based on four methods. Error bars denote 95% confidence interval of the odds ratio estimates
Fig. 4
Fig. 4
The causal effects of circulating lipids on biliary tract cancer from multivariate Mendelian randomization analyses. A, overlap of genetic instruments among the four lipids; B, causal estimates from multivariate Mendelian randomization analysis. Error bars denote 95% confidence interval of the odds ratio (OR) estimates
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