孟德尔随机化分析方法在非酒精性脂肪性肝病病因探索中的应用

郭紫薇; 武庆娟; 叶永安; 陈兰羽; 吕文良

doi:10.12449/JCH240325

孟德尔随机化分析方法在非酒精性脂肪性肝病病因探索中的应用

DOI: 10.12449/JCH240325

1.
中国中医科学院广安门医院感染疾病科，北京 100053
2.
北京中医药大学东直门医院脾胃科，北京 100700

基金项目:

中国中医科学院科技创新工程 (CI2021A00801);

中国中医科学院科技创新工程 (CI2021A00802)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：郭紫薇参与选题，撰写论文；武庆娟参与检索文献，数据提取，修改论文；叶永安、陈兰羽、吕文良负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
吕文良， lvwenliang@sohu.com （ORCID： 0000-0002-6866-4394）

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- 被引次数: 0
出版历程
- 收稿日期: 2023-06-28
- 录用日期: 2023-07-20
- 出版日期: 2024-03-20

Application of Mendelian randomization analysis in exploring the etiology of nonalcoholic fatty liver disease

1.
Department of Infectious Diseases，Guang’anmen Hospital，Chinese Academy of Chinese Medical Sciences，Beijing 100053，China
2.
Department of Spleen and Stomach，Dongzhimen Hospital，Beijing University of Chinese Medicine，Beijing 100700，China

Research funding:

Science and Technology Innovation Project of the Chinese Academy of Traditional Chinese Medicine (CI2021A00801);

Science and Technology Innovation Project of the Chinese Academy of Traditional Chinese Medicine (CI2021A00802)

More Information

Corresponding author: LYU Wenliang， lvwenliang@sohu.com （ORCID： 0000-0002-6866-4394）

摘要

摘要: 非酒精性脂肪性肝病（NAFLD）是以肝内脂质大量堆积为特点的肝脂质代谢异常类疾病，是目前世界范围内最常见的肝脏疾病。孟德尔随机化（MR）将基因组数据纳入传统的流行病学研究设计中，以推断暴露因素与疾病风险之间的因果关系。近年来，MR在NAFLD的病因推断研究中得到了较为广泛的应用，本文将系统总结MR在NAFLD研究中的应用进展，为认识疾病本质和科学化干预提供新思路。
- 非酒精性脂肪性肝病 /
- 孟德尔随机化分析 /
- 因果律 /
- 工具变量
Abstract: Nonalcoholic fatty liver disease （NAFLD） is an abnormal lipid metabolic disorder of the liver characterized by accumulation of a large amount of lipids in the liver， and it is currently the most common liver disease around the world. Mendelian randomization （MR） incorporates genomic data into traditional epidemiological study designs to infer the causal relationship between exposure factors and disease risk. In recent years， MR has been widely used in studies on inference of the etiology of NAFLD. This article systematically summarizes the advances in the application of MR in NAFLD research， so as to provide new ideas for understanding the nature of the disease and scientific interventions.
- Non-alcoholic Fatty Liver Disease /
- Mendelian Randomization Analysis /
- Causality /
- Instrumental Variables

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参考文献(48)

[1]	POWELL EE, WONG VW, RINELLA M. Non-alcoholic fatty liver disease[J]. Lancet, 2021, 397( 10290): 2212- 2224. DOI: 10.1016/S0140-6736(20)32511-3.
[2]	PATERNOSTRO R, TRAUNER M. Current treatment of non-alcoholic fatty liver disease[J]. J Intern Med, 2022, 292( 2): 190- 204. DOI: 10.1111/joim.13531.
[3]	TIAN AP, YANG YF. Diagnosis of nonalcoholic fatty liver disease: The importance of pathology[J]. J Clin Hepatol, 2023, 39( 3): 491- 497. DOI: 10.3969/j.issn.1001-5256.2023.03.002. 田爱平, 杨永峰. 非酒精性脂肪性肝病诊断——病理的重要性[J]. 临床肝胆病杂志, 2023, 39( 3): 491- 497. DOI: 10.3969/j.issn.1001-5256.2023.03.002.
[4]	LE MH, LE DM, BAEZ TC, et al. Global incidence of non-alcoholic fatty liver disease: A systematic review and meta-analysis of 63 studies and 1,201,807 persons[J]. J Hepatol, 2023, 79( 2): 287- 295. DOI: 10.1016/j.jhep.2023.03.040.
[5]	ESLAM M, NEWSOME PN, SARIN SK, et al. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement[J]. J Hepatol, 2020, 73( 1): 202- 209. DOI: 10.1016/j.jhep.2020.03.039.
[6]	MA L, HAO AH, HU XX, et al. Association of fat mass-and obesity-associated gene(FTO)polymorphisms with susceptibility to nonalcoholic fatty liver disease[J]. J Clin Hepatol, 2022, 38( 12): 2723- 2727. DOI: 10.3969/j.issn.1001-5256.2022.12.009. 马磊, 郝岸华, 胡欣欣, 等. 脂肪量和肥胖相关基因多态性与非酒精性脂肪性肝病易感性的关系[J]. 临床肝胆病杂志, 2022, 38( 12): 2723- 2727. DOI: 10.3969/j.issn.1001-5256.2022.12.009.
[7]	RICHMOND RC, DAVEY SMITH G. Mendelian randomization: concepts and scope[J]. Cold Spring Harb Perspect Med, 2022, 12( 1): a040501. DOI: 10.1101/cshperspect.a040501.
[8]	EMDIN CA, KHERA AV, KATHIRESAN S. Mendelian randomization[J]. JAMA, 2017, 318( 19): 1925- 1926. DOI: 10.1001/jama.2017.17219.
[9]	JONES DS, PODOLSKY SH. The history and fate of the gold standard[J]. Lancet, 2015, 385( 9977): 1502- 1503. DOI: 10.1016/S0140-6736(15)60742-5.
[10]	GAO X, XUE FZ, HUANG LH, et al. Statistical consensus on Mendelian randomization models and their normative applications[J]. Chin J Health Statistics, 2021, 38( 3): 471- 475. DOI: 10.3969/j.issn.1002-3674.2021.03.042. 高雪, 薛付忠, 黄丽红, 等. 孟德尔随机化模型及其规范化应用的统计学共识[J]. 中国卫生统计, 2021, 38( 3): 471- 475. DOI: 10.3969/j.issn.1002-3674.2021.03.042.
[11]	HE SM, ZHANG Y, PENG LQ, et al. Research progress of propensity score and Mendelian randomization in China[J]. Chin J Dis Control Prev, 2022, 26( 3): 325- 330. DOI: 10.16462/j.cnki.zhjbkz.2022.03.014. 和思敏, 张雨, 彭刘庆, 等. 倾向性评分与孟德尔随机化国内研究现状[J]. 中华疾病控制杂志, 2022, 26( 3): 325- 330. DOI: 10.16462/j.cnki.zhjbkz.2022.03.014.
[12]	HARPER S. A future for observational epidemiology: clarity, credibility, transparency[J]. Am J Epidemiol, 2019, 188( 5): 840- 845. DOI: 10.1093/aje/kwy280.
[13]	DAVEY SMITH G, HEMANI G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies[J]. Hum Mol Genet, 2014, 23( R1): R89- R98. DOI: 10.1093/hmg/ddu328.
[14]	KATAN MB. Apolipoprotein E isoforms, serum cholesterol, and cancer[J]. Lancet, 1986, 1( 8479): 507- 508. DOI: 10.1016/s0140-6736(86)92972-7.
[15]	THOMAS DC, CONTI DV. Commentary: the concept of‘Mendelian Randomization’[J]. Int J Epidemiol, 2004, 33( 1): 21- 25. DOI: 10.1093/ije/dyh048.
[16]	YU TQ, XU WT, SU YN, et al. Mendelian randomization: the basic principles, methods and limitations[J]. Chin J Evid-based Med, 2021, 21( 10): 1227- 1234. DOI: 10.7507/1672-2531.202107008. 于天琦, 徐文涛, 苏雅娜, 等. 孟德尔随机化研究基本原理、方法和局限性[J]. 中国循证医学杂志, 2021, 21( 10): 1227- 1234. DOI: 10.7507/1672-2531.202107008.
[17]	CHEN GQ, GU CZ, WANG QL, et al. Advances in Mendelian randomization analysis methods in schizophrenia[J]. J Int Psychiatry, 2022, 49( 3): 385- 387. DOI: 10.13479/j.cnki.jip.2022.03.046. 陈国庆, 谷传正, 王秋玲, 等. 孟德尔随机化分析方法在精神分裂症中的应用进展[J]. 国际精神病学杂志, 2022, 49( 3): 385- 387. DOI: 10.13479/j.cnki.jip.2022.03.046.
[18]	LAURIDSEN BK, STENDER S, KRISTENSEN TS, et al. Liver fat content, non-alcoholic fatty liver disease, and ischaemic heart disease: Mendelian randomization and meta-analysis of 279,013 individuals[J]. Eur Heart J, 2018, 39( 5): 385- 393. DOI: 10.1093/eurheartj/ehx662.
[19]	PARK S, LEE S, KIM Y, et al. Causal effects from non-alcoholic fatty liver disease on kidney function: A Mendelian randomization study[J]. Liver Int, 2022, 42( 2): 412- 418. DOI: 10.1111/liv.15118.
[20]	LIU Z, SUO C, FAN H, et al. Dissecting causal relationships between nonalcoholic fatty liver disease proxied by chronically elevated alanine transaminase levels and 34 extrahepatic diseases[J]. Metabolism, 2022, 135: 155270. DOI: 10.1016/j.metabol.2022.155270.
[21]	REN Z, SIMONS P, WESSELIUS A, et al. Relationship between NAFLD and coronary artery disease: A Mendelian randomization study[J]. Hepatology, 2023, 77( 1): 230- 238. DOI: 10.1002/hep.32534.
[22]	PETERMANN-ROCHA F, GRAY SR, FORREST E, et al. Associations of muscle mass and grip strength with severe NAFLD: A prospective study of 333,295 UK Biobank participants[J]. J Hepatol, 2022, 76( 5): 1021- 1029. DOI: 10.1016/j.jhep.2022.01.010.
[23]	LIU D, GAO X, PAN XF, et al. The hepato-ovarian axis: genetic evidence for a causal association between non-alcoholic fatty liver disease and polycystic ovary syndrome[J]. BMC Med, 2023, 21( 1): 62. DOI: 10.1186/s12916-023-02775-0.
[24]	LI J, TIAN A, ZHU H, et al. Mendelian randomization analysis reveals no causal relationship between nonalcoholic fatty liver disease and severe COVID-19[J]. Clin Gastroenterol Hepatol, 2022, 20( 7): 1553- 1560. e 78. DOI: 10.1016/j.cgh.2022.01.045.
[25]	WU M, ZHA M, LV Q, et al. Non-alcoholic fatty liver disease and stroke: A Mendelian randomization study[J]. Eur J Neurol, 2022, 29( 5): 1534- 1537. DOI: 10.1111/ene.15277.
[26]	YU Y, YU Y, WANG Y, et al. Nonalcoholic fatty liver disease and type 2 diabetes: an observational and Mendelian randomization study[J]. Front Endocrinol(Lausanne), 2023, 14: 1156381. DOI: 10.3389/fendo.2023.1156381.
[27]	QIU S, CAO P, GUO Y, et al. Exploring the causality between hypothyroidism and non-alcoholic fatty liver: a mendelian randomization study[J]. Front Cell Dev Biol, 2021, 9: 643582. DOI: 10.3389/fcell.2021.643582.
[28]	NÄSLUND-KOCH C, BOJESEN SE, GLUUD LL, et al. Non-alcoholic fatty liver disease is not a causal risk factor for psoriasis: A Mendelian randomization study of 108,835 individuals[J]. Front Immunol, 2022, 13: 1022460. DOI: 10.3389/fimmu.2022.1022460.
[29]	LIU Y, XU H, ZHAO Z, et al. No evidence for a causal link between Helicobacter pylori infection and nonalcoholic fatty liver disease: A bidirectional Mendelian randomization study[J]. Front Microbiol, 2022, 13: 1018322. DOI: 10.3389/fmicb.2022.1018322.
[30]	KING SD, VELIGINTI S, BROUWERS M, et al. Genetic susceptibility to nonalcoholic fatty liver disease and risk for pancreatic cancer: mendelian randomization[J]. Cancer Epidemiol Biomarkers Prev, 2023, 32( 9): 1265- 1269. DOI: 10.1158/1055-9965.EPI-23-0453.
[31]	HARRING M, GOLABI P, PAIK JM, et al. Sarcopenia among patients with nonalcoholic fatty liver disease(nafld) is associated with advanced fibrosis[J]. Clin Gastroenterol Hepatol, 2023, 21( 11): 2876- 2888.e5. DOI: 10.1016/j.cgh.2023.02.013.
[32]	ANDERSSON DP, KERR AG, DAHLMAN I, et al. Relationship between a sedentary lifestyle and adipose insulin resistance[J]. Diabetes, 2023, 72( 3): 316- 325. DOI: 10.2337/db22-0612.
[33]	XIE J, HUANG H, LIU Z, et al. The associations between modifiable risk factors and nonalcoholic fatty liver disease: A comprehensive Mendelian randomization study[J]. Hepatology, 2023, 77( 3): 949- 964. DOI: 10.1002/hep.32728.
[34]	LI S, FU Y, LIU Y, et al. Serum uric acid levels and nonalcoholic fatty liver disease: a 2-sample bidirectional mendelian randomization study[J]. J Clin Endocrinol Metab, 2022, 107( 8): e3497, e 3503. DOI: 10.1210/clinem/dgac190.
[35]	YUAN S, LARSSON SC. Inverse association between serum 25-hydroxyvitamin D and nonalcoholic fatty liver disease[J]. Clin Gastroenterol Hepatol, 2023, 21( 2): 398- 405. e 4. DOI: 10.1016/j.cgh.2022.01.021.
[36]	CHEN J, RUAN X, SUN Y, et al. Plasma phospholipid arachidonic acid in relation to non-alcoholic fatty liver disease: Mendelian randomization study[J]. Nutrition, 2023, 106: 111910. DOI: 10.1016/j.nut.2022.111910
[37]	LI L, HUANG L, YANG A, et al. Causal relationship between complement C3, C4, and nonalcoholic fatty liver disease: bidirectional mendelian randomization analysis[J]. Phenomics, 2021, 1( 5): 211- 221. DOI: 10.1007/s43657-021-00023-0.
[38]	ZHANG Y, LIU Z, CHOUDHURY T, et al. Habitual coffee intake and risk for nonalcoholic fatty liver disease: a two-sample Mendelian randomization study[J]. Eur J Nutr, 2021, 60( 4): 1761- 1767. DOI: 10.1007/s00394-020-02369-z.
[39]	SUN Z, JI J, ZUO L, et al. Causal relationship between nonalcoholic fatty liver disease and different sleep traits: a bidirectional Mendelian randomized study[J]. Front Endocrinol(Lausanne), 2023, 14: 1159258. DOI: 10.3389/fendo.2023.1159258.
[40]	WANG X, LIU Z, LIU W. Does cannabis intake protect against non-alcoholic fatty liver disease? a two-sample mendelian randomization study[J]. Front Genet, 2020, 11: 949. DOI: 10.3389/fgene.2020.00949.
[41]	GUO Z, ZHANG T, YUN Z, et al. Assessing the causal relationships between human blood metabolites and the risk of NAFLD: A comprehensive mendelian randomization study[J]. Front Genet, 2023, 14: 1108086. DOI: 10.3389/fgene.2023.1108086.
[42]	YUAN S, CHEN J, DAN L, et al. Homocysteine, folate, and nonalcoholic fatty liver disease: a systematic review with meta-analysis and Mendelian randomization investigation[J]. Am J Clin Nutr, 2022, 116( 6): 1595- 1609. DOI: 10.1093/ajcn/nqac285.
[43]	TREMBLAY M, PERROT N, GHODSIAN N, et al. Circulating Galectin-3 levels are not associated with nonalcoholic fatty liver disease: a mendelian randomization study[J]. J Clin Endocrinol Metab, 2021, 106( 8): e3178, e 3184. DOI: 10.1210/clinem/dgab144.
[44]	KONG L, YE C, WANG Y, et al. Causal effect of lower birthweight on non-alcoholic fatty liver disease and mediating roles of insulin resistance and metabolites[J]. Liver Int, 2023, 43( 4): 829- 839. DOI: 10.1111/liv.15532.
[45]	RUAN X, CHEN J, SUN Y, et al. Depression and 24 gastrointestinal diseases: a Mendelian randomization study[J]. Transl Psychiatry, 2023, 13( 1): 146. DOI: 10.1038/s41398-023-02459-6.
[46]	TILLMANN T, VAUCHER J, OKBAY A, et al. Education and coronary heart disease: mendelian randomisation study[J]. BMJ(Clinical research ed), 2017, 358: j3542. DOI: 10.1136/bmj.j3542
[47]	LI GH, LAM SK, WONG IC, et al. Education attainment, intelligence and COVID-19: A mendelian randomization study[J]. J Clin Med, 2021, 10( 21): 4870. DOI: 10.3390/jcm10214870.
[48]	LI Z, ZHANG B, LIU Q, et al. Genetic association of lipids and lipid-lowering drug target genes with non-alcoholic fatty liver disease[J]. EBioMedicine, 2023, 90: 104543. DOI: 10.1016/j.ebiom.2023.104543.