基于甾醇酯与肝内导管、胆道和胆囊恶性肿瘤发生的因果关系的孟德尔随机化分析

doi:10.13481/j.1671-587X.20250424

Abstract

Abstract:

Objective To discuss the causal association between sterol esters and intrahepatic duct， biliary tract， and gallbladder malignancies using two-sample Mendelian randomization （MR） analysis， and to clarify the biological mechanisms of sterol esters， and to provide the a basis for early prevention and treatment of these malignancies. Methods The instrumental variable data for 15 different types of sterol ester traits were obtained from the Finnish database （FinnGen）. The genome-wide association study （GWAS） data for intrahepatic duct， biliary tract， and gallbladder malignancies were retrieved from the GWAS database using the keywords “sterol ester” and “intrahepatic duct， biliary tract， and gallbladder malignancies”（accession numbers： ICD-O-3 and GCST90277238-GCST9027725）. The inverse-variance weighted （IVW） method， MR-Egger regression， and weighted median （WM） method were used to assess the causal association between sterol esters and the risk of these malignancies. Pleiotropy was tested using the MR-Egger intercept method； heterogeneity was evaluated using Cochran’s Q test； and sensitivity analysis was performed using the leave-one-out approach to comprehensively assess the reliability and robustness of the results. Results The IVW analysis results showed that Sterol ester （27：1/14：0） odds ratio（OR）=2.349， 95% confidence interval （CI）=1.371-4.025， P=0.002）， Sterol ester（27：1/16：0）（OR=1.248， 95%CI=1.018-1.523， P=0.033）， Sterol ester （27：1/18：2）（OR=1.361， 95%CI=1.078-1.718， P=0.009）， and Sterol ester （27：1/22：6）（OR=1.339， 95%CI=1.001-1.791， P=0.049） were associated with an increased risk of intrahepatic duct， biliary tract， and gallbladder malignancies. The MR-Egger regression analysis results indicated that Sterol ester （27：1/18：2）（OR=2.038， 95%CI=1.337-3.105， P=0.011） was a risk factor for these malignancies. The WM analysis results revealed that Sterol ester （27：1/14：0）（OR=2.786， 95%CI=1.419-5.468， P=0.003） and Sterol ester （27：1/18：2）（OR=1.548， 95%CI=1.148-2.088， P=0.004） were also risk factors. The MR-Egger intercept analysis and Cochran’s Q test results indicated no significant horizontal pleiotropy or heterogeneity. The leave-one-out sensitivity analysis did not identify any influential outlier single nucleotide polymorphism （SNPs）， confirming the reliability of the study. Conclusion Sterol ester （27：1/14：0）， Sterol ester （27：1/16：0）， Sterol ester （27：1/18：2）， and Sterol ester （27：1/22：6） exhibit causal associations with intrahepatic duct， biliary tract， and gallbladder malignancies and may promote their development.

Key words: Sterol ester, Intrahepatic duct, Biliary tract, Gallbladder, Malignancy, Mendelian randomization

CLC Number:

R735

Xianlei ZHOU,Zimo YAN,Liwen GUO,Xuemei ZHANG. Mendelian randomization analysis based on causal association of sterol esters with occurrence of intrahepatic ductal, biliary, and gallbladder malignancy[J].Journal of Jilin University(Medicine Edition), 2025, 51(4): 1084-1093.

Figures/Tables 6

Tab.1

Informations of instrumental variables related to sterol esters"

Exposed sterol ester	SNP count	SNP exposure			SNP outcome
Exposed sterol ester	SNP count	β	SE	P	β	SE	P
(27:1/14:0)	3	-0.186	0.038	1.15E-08	-0.187	0.103	0.070
		0.142	0.021	7.00E-11	0.163	0.058	0.005
		-0.087	0.017	5.87E-09	-0.025	0.043	0.556
(27:1/16:0)	16	-0.010	0.019	1.39E-08	0.057	0.052	0.270
		-0.085	0.017	8.48E-09	-0.025	0.043	0.569
		-0.390	0.046	7.69E-13	-0.213	0.118	0.072
		-0.105	0.019	2.34E-09	0.062	0.050	0.220
		-0.209	0.028	7.31E-12	0.046	0.072	0.528
		0.109	0.018	4.73E-10	-0.004	0.048	0.930
		0.330	0.051	9.26E-11	0.133	0.122	0.276
		-0.206	0.017	5.93E-16	0.000	0.044	0.995
		-0.222	0.037	4.60E-10	-0.187	0.103	0.070
		-0.286	0.053	2.74E-09	-0.008	0.140	0.955
		0.086	0.017	6.15E-09	-0.020	0.044	0.642
		-0.010	0.019	1.09E-08	-0.042	0.050	0.400
		-0.407	0.037	4.31E-15	-0.227	0.089	0.011
		0.247	0.044	1.57E-09	0.018	0.118	0.879
		0.224	0.041	2.17E-09	0.043	0.109	0.690
		-0.085	0.017	1.30E-08	-0.103	0.044	0.019
(27:1/16:1)	6	0.084	0.017	1.41E-08	-0.053	0.044	0.236
		-0.259	0.052	1.39E-08	0.149	0.150	0.319
		-0.090	0.017	6.07E-09	-0.032	0.046	0.478
		-0.204	0.037	2.14E-09	-0.187	0.103	0.070
		-0.108	0.021	7.78E-09	0.175	0.054	0.001
		-0.156	0.026	4.10E-10	-0.111	0.068	0.105
(27:1/17:0)	4	-0.125	0.024	6.15E-09	0.117	0.062	0.059
		0.086	0.017	1.10E-08	-0.025	0.044	0.571
		-0.085	0.017	1.24E-08	-0.018	0.044	0.686
		0.122	0.022	1.33E-09	0.163	0.058	0.005
(27:1/17:1)	1	-0.198	0.037	3.71E-09	-0.187	0.103	0.070
(27:1/18:0)	8	0.495	0.090	1.91E-09	-0.009	0.230	0.968
		0.097	0.018	2.08E-09	-0.096	0.047	0.039
		-0.109	0.020	1.75E-09	0.057	0.051	0.265
		-0.111	0.017	7.09E-11	-0.018	0.044	0.686
		0.134	0.021	2.11E-10	0.163	0.058	0.005
		-0.104	0.019	1.63E-09	0.004	0.049	0.936
		-0.154	0.021	7.95E-12	-0.006	0.054	0.917
		-0.104	0.019	2.52E-09	-0.042	0.050	0.400
(27:1/18:1)	11	-0.106	0.019	2.51E-09	0.057	0.052	0.270
		0.234	0.045	5.23E-09	-0.045	0.118	0.704
		0.295	0.060	1.38E-08	0.095	0.156	0.544
		-0.298	0.047	1.24E-10	-0.213	0.118	0.072
		-0.172	0.028	2.96E-10	0.046	0.072	0.528
		-0.210	0.037	1.25E-09	-0.187	0.103	0.070
		0.338	0.053	1.29E-10	-0.142	0.138	0.304
		-0.290	0.057	8.41E-09	0.081	0.153	0.596
		-0.107	0.020	2.65E-09	-0.051	0.051	0.318
		-0.281	0.037	5.37E-12	-0.227	0.089	0.011
		0.263	0.044	4.77E-10	0.018	0.118	0.879
(27:1/18:2)	10	-0.358	0.047	4.08E-12	-0.213	0.118	0.072
		-0.097	0.019	9.25E-09	0.062	0.050	0.220
		0.346	0.051	4.10E-11	0.135	0.122	0.272
		-0.194	0.028	3.32E-11	0.046	0.072	0.528
		0.239	0.047	9.88E-09	0.058	0.128	0.654
		0.104	0.019	1.74E-09	-0.023	0.049	0.638
		-0.216	0.037	7.93E-10	-0.187	0.103	0.070
		-0.464	0.037	3.51E-16	-0.227	0.089	0.011
		0.284	0.041	2.71E-11	0.043	0.109	0.690
		-0.123	0.022	2.10E-09	-0.052	0.059	0.378
(27:1/18:3)	8	-0.217	0.089	4.00E-09	0.089	0.103	0.389
		-0.105	-0.032	3.65E-10	-0.032	0.046	0.478
		-0.183	-0.006	6.09E-15	-0.006	0.044	0.890
		-0.240	-0.187	1.12E-10	-0.187	0.103	0.070
		0.093	-0.046	2.11E-09	-0.046	0.045	0.300
		0.259	0.049	1.65E-08	0.049	0.133	0.711
		-0.191	-0.227	7.28E-09	-0.227	0.089	0.011
		-0.085	-0.025	8.53E-09	-0.025	0.043	0.556
(27:1/20:2)	6	-0.102	0.020	8.69E-09	0.057	0.047	0.227
		-0.256	0.022	1.20E-15	0.013	0.052	0.806
		0.162	0.024	3.73E-11	0.163	0.058	0.005
		-0.211	0.032	6.61E-11	-0.132	0.072	0.066
		0.099	0.020	1.20E-08	0.095	0.046	0.039
		0.106	0.020	3.35E-09	-0.016	0.047	0.731
(27:1/20:3)	11	0.289	0.059	1.62E-08	-0.047	0.134	0.728
		-0.226	0.018	2.96E-16	-0.038	0.047	0.412
		-0.239	0.037	1.21E-10	-0.187	0.103	0.070
		0.285	0.053	3.09E-09	-0.142	0.138	0.304
		-0.236	0.038	2.05E-10	-0.520	0.085	0.000
		-0.245	0.042	5.95E-10	-0.109	0.107	0.309
		0.112	0.018	3.06E-10	0.006	0.047	0.893
		0.083	0.017	1.28E-08	-0.008	0.044	0.863
		0.085	0.017	9.67E-09	0.016	0.044	0.707
		-0.203	0.037	2.51E-09	-0.227	0.089	0.011
		0.272	0.054	9.26E-09	-0.033	0.137	0.812
(27:1/20:4)	9	-0.101	0.018	1.04E-09	-0.038	0.047	0.412
		-0.297	0.046	1.12E-10	-0.213	0.118	0.072
		0.178	0.035	9.57E-09	0.068	0.102	0.503
		-0.659	0.015	2.35E-26	0.000	0.044	0.995
		0.296	0.052	1.30E-09	-0.142	0.138	0.304
		-0.414	0.077	3.23E-09	0.252	0.237	0.286
		0.165	0.021	2.92E-12	0.005	0.056	0.924
		-0.344	0.066	4.66E-09	0.412	0.181	0.023
		-0.310	0.037	7.25E-13	-0.227	0.089	0.011
(27:1/20:5)	5	-0.086	0.017	7.53E-09	-0.025	0.043	0.569
		-0.411	0.016	6.02E-22	-0.001	0.044	0.987
		-0.085	0.017	6.97E-09	0.021	0.043	0.622
		-0.158	0.029	1.84E-09	-0.193	0.071	0.007
		0.110	0.020	1.56E-09	-0.034	0.051	0.503
(27:1/22:6)	8	-0.205	0.038	3.31E-09	-0.025	0.043	0.569
		-0.238	0.047	8.55E-09	-0.001	0.044	0.987
		-0.175	0.035	1.39E-08	0.021	0.043	0.622
		-0.201	0.017	9.93E-16	-0.193	0.071	0.007
		-0.093	0.017	2.87E-09	-0.034	0.051	0.503
		-0.269	0.037	1.31E-11	-0.025	0.043	0.569
		0.259	0.050	5.90E-09	-0.001	0.044	0.987
		-0.268	0.054	1.11E-08	0.021	0.043	0.622

Tab.1

Tab.2

Tab.3

Fig. 1

Fig. 2

Fig. 3

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Exposed sterol ester	Methods	β	SE	OR （95%CI）	P
Sterol ester (27:1/14:0)	MR-Egger	1.976	0.948	1.285 (0.695-2.338)	0.424
	WM	1.024	0.344	2.786 (1.419-5.468)	0.003
	IVW	0.854	0.275	2.349 (1.371-4.025)	0.002
Sterol ester (27:1/16:0)	MR-Egger	0.430	0.203	1.537 (1.033-2.289)	0.053
	WM	0.167	0.142	1.158 (0.875-1.532)	0.304
	IVW	0.221	0.104	1.248 (1.018-1.523)	0.033
Sterol ester (27:1/18:2)	MR-Egger	0.712	0.215	2.038 (1.337-3.105)	0.011
	WM	0.437	0.153	1.548 (1.148-2.088)	0.004
	IVW	0.308	0.119	1.361 (1.078-1.718)	0.009
Sterol ester (27:1/22:6)	MR-Egger	0.656	0.455	1.927 (0.790-4.700)	0.200
	WM	-0.017	0.195	1.001 (0.672-1.440)	0.932
	IVW	0.292	0.148	1.339 (1.001-1.791)	0.049

Exposed sterol ester	MR-Egger		Cochran Q test
Exposed sterol ester	Intercept	P	Q	P
Sterol ester (27:1/14:0)	-0.140	0.432	0.335	0.563
Sterol ester (27:1/16:0)	-0.039	0.253	16.913	0.261
Sterol ester (27:1/18:2)	-0.099	0.057	5.150	0.741
Sterol ester (27:1/22:6)	-0.072	0.429	7.516	0.276

Mendelian randomization analysis based on causal association of sterol esters with occurrence of intrahepatic ductal, biliary, and gallbladder malignancy

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