血浆脂质与非酒精性脂肪性肝病及肝酶之间因果关系的孟德尔随机化分析

doi:10.13481/j.1671-587X.20260123

Abstract

Abstract:

Objective To investigate the potential causal associations of specific plasma lipids with nonalcoholic fatty liver disease （NAFLD） and liver enzymes， and elucidate the potential impact of specific plasma lipid on liver health. Methods Two-sample Mendelian randomization （MR） analyses were conducted to investigate potential causal relationships between 179 plasma lipids and both NAFLD and 4 liver enzymes： alanine aminotransferase （ALT）， aspartate aminotransferase （AST）， gamma-glutamyl transferase （GGT）， and alkaline phosphatase （ALP）. The inverse-variance weighted method served as the primary analysis approach， supplemented by MR-Egger， weighted median， weighted mode， and simple mode. Sensitivity analyses including MR-Egger intercept test and MR-PRESSO Global test were conducted to ensure the reliability of the results. Multivariable MR analysis was conducted to adjust for the potential effect of body mass index （BMI） on the association between plasma lipids and NAFLD. Results The analyses revealed that phosphatidylcholine （18：0/20：5）［odd ratio（OR）=0.988， 95% confidence interval（CI）（0.977， 0.999）， P=0.028］ exhibited a protective effect on NAFLD， while phosphatidylinositol （16：0/18：2）［OR=1.016， 95%CI（1.000， 1.032）， P=0.046］ and phosphatidylinositol （18：0/18：2）［OR=1.012， 95%CI （1.002， 1.022）， P=0.021］ increased NAFLD risk. After adjustment for BMI， the association between phosphatidylinositol （18：0/18：2）［OR=1.019， 95%CI （1.007， 1.035）， P=0.008］ and NAFLD remained significant. Elevated levels of phosphatidylcholine （16：0/20：5）［β=0.026， 95%CI（0.015， 0.036）， P=9.93×10^-7］， phosphatidylcholine （O-16：0/22：5）［β=0.057， 95%CI（0.035， 0.078）， P=1.79×10^-7］， triacylglycerol （56：7）［β=0.057， 95%CI （0.035，0.079）， P=2.53×10^-7］ and triacylglycerol （56：8）［β=0.067， 95%CI （0.047，0.087）， P=1.19×10^-10］ were significantly associated with increased ALT levels. Triacylglycerol （53：2）［β=0.160， 95% CI （0.123， 0.197）， P=1.55×10^-17］ showed a significant positive causal association with AST levels. Conclusion Specific plasma lipids were causally associated with NAFLD risk and liver enzyme levels， with some associations independent of BMI.

Key words: Plasma lipidome, Liver enzymes, Nonalcoholic fatty liver disease, Mendelian randomization, Causal association

CLC Number:

R575.5

Zhifei LIU,Yaru BI,Chenglin SUN,Suyan TIAN. Mendelian randomization analysis on causal association between plasma lipids with nonalcoholic fatty liver disease and liver enzymes[J].Journal of Jilin University(Medicine Edition), 2026, 52(1): 219-227.

Figures/Tables 6

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References 28

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Phenotype	Year	Data resources	PubMed ID	GWAS Catalog accession	Sample size	Ancestry
Plasma lipids	2023	GeneRISK	37907536	GCST90277238-GCST90277416	7 174	European
NAFLD	2023	SUN Z, et al	37235137	GCST90275041	32 941	European
ALT	2021	BARTON A R, et al	34226706	GCST90025979	437 724	European
AST	2021	BARTON A R, et al	34226706	GCST90025980	436 275	European
GGT	2021	BARTON A R, et al	34226706	GCST90025966	437 651	European
ALP	2021	BARTON A R, et al	34226706	GCST90025947	437 896	European
BMI	2018	GIANT	30124842	GCST006900	681 275	European

Exposure	nSNP	OR (95%CI)	P	MR-Egger intercept P	MR-PRESSO Global P	Cochran’s Q test P
Phosphatidylcholine (18：0/20：5)	14	0.988(0.977,0.999)	0.028	0.131	0.895	0.921
Phosphatidylcholine (O-16：0/16：1)	11	0.982(0.966,0.999)	0.035	0.071	0.451	0.454
Phosphatidylcholine (O-16：0/18：2)	9	1.020(1.001,1.040)	0.041	0.306	0.887	0.937
Phosphatidylcholine (O-16：0/22：5)	8	0.979(0.961,0.997)	0.023	0.265	0.752	0.757
Phosphatidylcholine (O-16：1/20：4)	11	0.989(0.978,1.000)	0.044	0.769	0.985	0.995
Phosphatidylcholine (O-18：1/20：4)	9	0.981(0.966,0.996)	0.014	0.395	0.645	0.559
Phosphatidylcholine (O-18：2/16：0)	12	1.021(1.004,1.038)	0.013	0.630	0.354	0.299
Phosphatidylinositol (16：0/18：2)	19	1.016(1.000,1.032)	0.046	0.183	0.061	0.065
Phosphatidylinositol (18：0/18：2)	22	1.012(1.002,1.022)	0.021	0.686	0.078	0.098
Sphingomyelin (d40：2)	9	1.020(1.001,1.040)	0.041	0.306	0.887	0.937

Exposure	Without adjustment OR (95%CI)	Adjust for BMI OR (95%CI)	MVMR P
Phosphatidylcholine (18：0/20：5)	0.988(0.977,0.999)	1.000(0.962,1.014)	0.843
Phosphatidylinositol (16：0/18：2)	1.016(1.000,1.032)	0.993(0.944,1.031)	0.147
Phosphatidylinositol (18：0/18：2)	1.012(1.002,1.022)	1.019(1.007,1.035)	0.008

Exposure	Outcome	nSNP	β（95%CI）	P	MR-Egger intercept P	MR-PRESSO Global P	Cochran's Q test P
Sterol ester (27：1/20：5)	ALT	5	0.054(0.030,0.077)	6.96E-06	0.227	0.492	0.379
Phosphatidylcholine (16：0/20：5)	ALT	6	0.026(0.015,0.036)	9.93E-07	0.378	0.444	0.491
Phosphatidylcholine (O-16：0/22：5)	ALT	4	0.057(0.035,0.078)	1.79E-07	0.380	0.396	0.193
Triacylglycerol (56：7)	ALT	7	0.057(0.035,0.079)	2.53E-07	0.657	0.144	0.060
Triacylglycerol (56：8)	ALT	7	0.067(0.047,0.087)	1.19E-10	0.764	0.314	0.124
Triacylglycerol (53：2)	AST	4	0.160(0.123,0.197)	1.55E-17	0.988	0.261	0.339

Mendelian randomization analysis on causal association between plasma lipids with nonalcoholic fatty liver disease and liver enzymes

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