孟德尔随机化在肝癌研究中的应用

李凌巍; 秦俊杰; 贾云龙; 吕浩

doi:10.12449/JCH240228

孟德尔随机化在肝癌研究中的应用

DOI: 10.12449/JCH240228

李凌巍^a,
秦俊杰^a,
贾云龙^b,
吕浩^b, , ,

a.
吉林大学第一医院乐群院区消化内科，长春 130021
b.
吉林大学第一医院乐群院区急救医学科，长春 130021

基金项目:

吉林省财政厅项目 (JLSWSRCZX2020-049)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：李凌巍负责课题设计，撰写论文；李凌巍、秦俊杰、贾云龙参与文献搜集，修改论文并最后定稿；吕浩负责拟定写作思路，指导撰写文章。

详细信息

通信作者:
吕浩， 309098144@qq.com （ORCID： 0000-0001-6575-4338）

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- 被引次数: 0
出版历程
- 收稿日期: 2023-05-16
- 录用日期: 2023-06-06
- 出版日期: 2024-02-19

Application of Mendelian randomization in liver cancer

a.
Department of Gastroenterology，Lequn Branch，The First Hospital of Jilin University，Changchun 130021，China
b.
Department of Emergency Medicine，Lequn Branch，The First Hospital of Jilin University，Changchun 130021，China

Research funding:

Finance Department Project of Jilin Province (JLSWSRCZX2020-049)

More Information

Corresponding author: LYU Hao， 309098144@qq.com （ORCID： 0000-0001-6575-4338）

摘要

摘要: 近年来，基于全基因组关联研究的孟德尔随机化研究方法被广泛应用于医学领域的病因探索，以其遗传变异的分配随机性和时序优先性的独特优势，可以有效克服传统观察性研究中的混杂偏倚和反向因果的干扰。本文针对该方法及其在肝癌研究领域的应用进展作一综述，旨在为肝癌的因果关联研究提供新思路。
- 孟德尔随机化分析 /
- 肝肿瘤 /
- 全基因组关联研究
Abstract: In recent years， the research method of Mendelian randomization based on genome-wide association studies has been widely used for etiological exploration in the medical field， which can effectively overcome the confounding biases and interference of reverse causalities in traditional observational researches with its unique advantages of the distributive randomness and timing priority of genetic variants. This article reviews the method of Mendelian randomization and its application in liver cancer， in order to provide new ideas for the research on causal association in liver cancer.
- Mendelian Randomization Analysis /
- Liver Neoplasms /
- Genome-Wide Association Study

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参考文献(65)

[1]	FERLAY J, COLOMBET M, SOERJOMATARAM I, et al. Cancer statistics for the year 2020: An overview[J]. Int J Cancer, 2021. DOI: 10.1002/ijc.33588.[ Online ahead of print]
[2]	FORNER A, REIG M, BRUIX J. Hepatocellular carcinoma[J]. Lancet, 2018, 391( 10127): 1301- 1314. DOI: 10.1016/S0140-6736(18)30010-2.
[3]	ZENG HM, CHEN WQ, ZHENG RS, et al. Changing cancer survival in China during 2003-15: A pooled analysis of 17 population-based cancer registries[J]. Lancet Glob Health, 2018, 6( 5): e555- e567. DOI: 10.1016/S2214-109X(18)30127-X.
[4]	VILLANUEVA A. Hepatocellular carcinoma[J]. N Engl J Med, 2019, 380( 15): 1450- 1462. DOI: 10.1056/nejmra1713263.
[5]	HE J, CHEN WQ, SHEN HB, et al. China guideline for liver cancer screening(2022, Beijing)[J]. J Clin Hepatol, 2022, 38( 8): 1739- 1758. DOI: 10.3969/j.issn.1001-5256.2022.08.007. 赫捷, 陈万青, 沈洪兵, 等. 中国人群肝癌筛查指南(2022, 北京)[J]. 临床肝胆病杂志, 2022, 38( 8): 1739- 1758. DOI: 10.3969/j.issn.1001-5256.2022.08.007.
[6]	SHI JF, CAO MM, WANG YT, et al. Is it possible to halve the incidence of liver cancer in China by 2050?[J]. Int J Cancer, 2021, 148( 5): 1051- 1065. DOI: 10.1002/ijc.33313.
[7]	SUNG H, FERLAY J, SIEGEL RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71( 3): 209- 249. DOI: 10.3322/caac.21660.
[8]	TIAN T, XIAO F, LI HD, et al. Association between serum iron status and primary liver cancer risk: A Mendelian randomization analysis[J]. Ann Transl Med, 2021, 9( 20): 1533. DOI: 10.21037/atm-21-4608.
[9]	MCGLYNN KA, PETRICK JL, EL-SERAG HB. Epidemiology of hepatocellular carcinoma[J]. Hepatology, 2021, 73( Suppl 1): 4- 13. DOI: 10.1002/hep.31288.
[10]	CARRERAS-TORRES R, HAYCOCK PC, RELTON CL, et al. The causal relevance of body mass index in different histological types of lung cancer: A Mendelian randomization study[J]. Sci Rep, 2016, 6: 31121. DOI: 10.1038/srep31121.
[11]	YEUNG SL AU, JIANG CQ, CHENG KK, et al. Is aldehyde dehydrogenase 2 a credible genetic instrument for alcohol use in Mendelian randomization analysis in Southern Chinese men?[J]. Int J Epidemiol, 2013, 42( 1): 318- 328. DOI: 10.1093/ije/dys221.
[12]	RICHMOND RC, ANDERSON EL, DASHTI HS, et al. Investigating causal relations between sleep traits and risk of breast cancer in women: Mendelian randomisation study[J]. BMJ, 2019, 365: l2327. DOI: 10.1136/bmj.l2327.
[13]	KATAN M. Apoupoprotein e isoforms, serum cholesterol, and cancer[J]. Lancet, 1986, 327( 8479): 507- 508. DOI: 10.1016/S0140-6736(86)92972-7.
[14]	WANG LN, ZHANG ZF. Mendelian randomization approach, used for causal inferences[J]. Chin J Epidemiol, 2017, 38( 4): 547- 552. DOI: 10.3760/cma.j.issn.0254-6450.2017.04.027. 王莉娜, 张作风. 孟德尔随机化法在因果推断中的应用[J]. 中华流行病学杂志, 2017, 38( 4): 547- 552. DOI: 10.3760/cma.j.issn.0254-6450.2017.04.027.
[15]	DAVIES NM, HOLMES MV, DAVEY SMITH G. Reading Mendelian randomisation studies: A guide, glossary, and checklist for clinicians[J]. BMJ, 2018, 362: k601. DOI: 10.1136/bmj.k601.
[16]	EMDIN CA, KHERA AV, KATHIRESAN S. Mendelian randomization[J]. JAMA, 2017, 318( 19): 1925. DOI: 10.1001/jama.2017.17219.
[17]	GREENLAND S. An introduction to instrumental variables for epidemiologists[J]. Int J Epidemiol, 2000, 29( 4): 722- 729. DOI: 10.1093/ije/29.4.722.
[18]	BOWDEN J, DAVEY SMITH G, BURGESS S. Mendelian randomization with invalid instruments: Effect estimation and bias detection through Egger regression[J]. Int J Epidemiol, 2015, 44( 2): 512- 525. DOI: 10.1093/ije/dyv080.
[19]	LAWLOR DA. Commentary: Two-sample Mendelian randomization: Opportunities and challenges[J]. Int J Epidemiol, 2016, 45( 3): 908- 915. DOI: 10.1093/ije/dyw127.
[20]	ZHENG J, BAIRD D, BORGES MC, et al. Recent developments in Mendelian randomization studies[J]. Curr Epidemiol Rep, 2017, 4( 4): 330- 345. DOI: 10.1007/s40471-017-0128-6.
[21]	SOMMER F, BÄCKHED F. The gut microbiota: Masters of host development and physiology[J]. Nat Rev Microbiol, 2013, 11( 4): 227- 238. DOI: 10.1038/nrmicro2974.
[22]	THOMAS S, IZARD J, WALSH E, et al. The host microbiome regulates and maintains human health: A primer and perspective for non-microbiologists[J]. Cancer Res, 2017, 77( 8): 1783- 1812. DOI: 10.1158/0008-5472.CAN-16-2929.
[23]	ZHANG L, WU YN, CHEN T, et al. Relationship between intestinal microbial dysbiosis and primary liver cancer[J]. Hepatobiliary Pancreat Dis Int, 2019, 18( 2): 149- 157. DOI: 10.1016/j.hbpd.2019.01.002.
[24]	REN ZG, LI A, JIANG JW, et al. Gut microbiome analysis as a tool towards targeted non-invasive biomarkers for early hepatocellular carcinoma[J]. Gut, 2019, 68( 6): 1014- 1023. DOI: 10.1136/gutjnl-2017-315084.
[25]	MARRA F, SVEGLIATI-BARONI G. Lipotoxicity and the gut-liver axis in NASH pathogenesis[J]. J Hepatol, 2018, 68( 2): 280- 295. DOI: 10.1016/j.jhep.2017.11.014.
[26]	MA J, LI JL, JIN C, et al. Association of gut microbiome and primary liver cancer: A two-sample Mendelian randomization and case-control study[J]. Liver Int, 2023, 43( 1): 221- 233. DOI: 10.1111/liv.15466.
[27]	KHAN SR, CHAKER L, RUITER R, et al. Thyroid function and cancer risk: The Rotterdam study[J]. J Clin Endocrinol Metab, 2016, 101( 12): 5030- 5036. DOI: 10.1210/jc.2016-2104.
[28]	JOURNY NMY, BERNIER MO, DOODY MM, et al. Hyperthyroidism, hypothyroidism, and cause-specific mortality in a large cohort of women[J]. Thyroid, 2017, 27( 8): 1001- 1010. DOI: 10.1089/thy.2017.0063.
[29]	MONDUL AM, WEINSTEIN SJ, BOSWORTH T, et al. Circulating thyroxine, thyroid-stimulating hormone, and hypothyroid status and the risk of prostate cancer[J]. PLoS One, 2012, 7( 10): e47730. DOI: 10.1371/journal.pone.0047730.
[30]	ORTEGA-OLVERA C, ULLOA-AGUIRRE A, ÁNGELES-LLERENAS A, et al. Thyroid hormones and breast cancer association according to menopausal status and body mass index[J]. Breast Cancer Res, 2018, 20( 1): 94. DOI: 10.1186/s13058-018-1017-8.
[31]	HASSAN MM, KASEB A, LI DH, et al. Association between hypothyroidism and hepatocellular carcinoma: A case-control study in the United States[J]. Hepatology, 2009, 49( 5): 1563- 1570. DOI: 10.1002/hep.22793.
[32]	PINTER M, HAUPT L, HUCKE F, et al. The impact of thyroid hormones on patients with hepatocellular carcinoma[J]. PLoS One, 2017, 12( 8): e0181878. DOI: 10.1371/journal.pone.0181878.
[33]	SAHIN T, ORAL A, TURKER F, et al. Can hypothyroidism be a protective factor for hepatocellular carcinoma in cirrhosis?[J]. Medicine, 2020, 99( 11): e19492. DOI: 10.1097/MD.0000000000019492.
[34]	CHU YD, LIN KH, HUANG YH, et al. A novel thyroid function index associated with opposite therapeutic outcomes in advanced hepatocellular carcinoma patients receiving chemotherapy or sorafenib[J]. Asia Pac J Clin Oncol, 2018, 14( 5): e341- e351. DOI: 10.1111/ajco.12983.
[35]	HASSAN MM, CURLEY SA, LI DH, et al. Association of diabetes duration and diabetes treatment with the risk of hepatocellular carcinoma[J]. Cancer, 2010, 116( 8): 1938- 1946. DOI: 10.1002/cncr.24982.
[36]	REDDY A, DASH C, LEERAPUN A, et al. Hypothyroidism: A possible risk factor for liver cancer in patients with no known underlying cause of liver disease[J]. Clin Gastroenterol Hepatol, 2007, 5( 1): 118- 123. DOI: 10.1016/j.cgh.2006.07.011.
[37]	BRUCK R, WEISS S, TRAISTER A, et al. Induced hypothyroidism accelerates the regression of liver fibrosis in rats[J]. J Gastroenterol Hepatol, 2007, 22( 12): 2189- 2194. DOI: 10.1111/j.1440-1746.2006.04777.x.
[38]	OREN R, DOTAN I, PAPA M, et al. Inhibition of experimentally induced cirrhosis in rats by hypothyroidism[J]. Hepatology, 1996, 24( 2): 419- 423. DOI: 10.1053/jhep.1996.v24.pm0008690414.
[39]	YUAN S, KAR S, VITHAYATHIL M, et al. Causal associations of thyroid function and dysfunction with overall, breast and thyroid cancer: A two-sample Mendelian randomization study[J]. Int J Cancer, 2020, 147( 7): 1895- 1903. DOI: 10.1002/ijc.32988.
[40]	LU LK, WAN BB, LI LJ, et al. Hypothyroidism has a protective causal association with hepatocellular carcinoma: A two-sample Mendelian randomization study[J]. Front Endocrinol, 2022, 13: 987401. DOI: 10.3389/fendo.2022.987401.
[41]	WU YM. The Mendelian randomization study of obesity and primary liver cancer risk[D]. Guangzhou: Guangdong Pharmaceutical University, 2021. 吴燕梅. 肥胖与肝癌发生风险的孟德尔随机化研究[D]. 广州: 广东药科大学, 2021.
[42]	ZHANG YY, CHENG JX, ZHONG C, et al. ESR1 regulates the obesity- and metabolism-differential gene MMAA to inhibit the occurrence and development of hepatocellular carcinoma[J]. Front Oncol, 2022, 12: 899969. DOI: 10.3389/fonc.2022.899969.
[43]	SONG SS, CHENG J, YANG S. Research progress on pathogenesis of alcohol related liver cancer[J/CD]. Chin J Liver Dis(Electronic Version), 2023, 15( 3): 1- 5. DOI: 10.3969/j.issn.1674-7380.2023.03.001. 宋姗姗, 成军, 杨松. 酒精相关肝癌发病机制研究进展[J/CD]. 中国肝脏病杂志(电子版), 2023, 15( 3): 1- 5. DOI: 10.3969/j.issn.1674-7380.2023.03.001.
[44]	LIU ZQ, SONG C, SUO C, et al. Alcohol consumption and hepatocellular carcinoma: Novel insights from a prospective cohort study and nonlinear Mendelian randomization analysis[J]. BMC Med, 2022, 20( 1): 413. DOI: 10.1186/s12916-022-02622-8.
[45]	PETRICK JL, CAMPBELL PT, KOSHIOL J, et al. Tobacco, alcohol use and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: The Liver Cancer Pooling Project[J]. Br J Cancer, 2018, 118( 7): 1005- 1012. DOI: 10.1038/s41416-018-0007-z.
[46]	ZHONG LX, CHEN WW, WANG TH, et al. Alcohol and health outcomes: An umbrella review of meta-analyses base on prospective cohort studies[J]. Front Public Health, 2022, 10: 859947. DOI: 10.3389/fpubh.2022.859947.
[47]	DENG YY, HUANG JJ, WONG MCS. Associations between six dietary habits and risk of hepatocellular carcinoma: A Mendelian randomization study[J]. Hepatol Commun, 2022, 6( 8): 2147- 2154. DOI: 10.1002/hep4.1960.
[48]	ALLEN NE, BERAL V, CASABONNE D, et al. Moderate alcohol intake and cancer incidence in women[J]. J Natl Cancer Inst, 2009, 101( 5): 296- 305. DOI: 10.1093/jnci/djn514.
[49]	KENNEDY OJ, RODERICK P, BUCHANAN R, et al. Coffee, including caffeinated and decaffeinated coffee, and the risk of hepatocellular carcinoma: A systematic review and dose-response meta-analysis[J]. BMJ Open, 2017, 7( 5): e013739. DOI: 10.1136/bmjopen-2016-013739.
[50]	ZHAO LG, LI ZY, FENG GS, et al. Coffee drinking and cancer risk: An umbrella review of meta-analyses of observational studies[J]. BMC Cancer, 2020, 20( 1): 101. DOI: 10.1186/s12885-020-6561-9.
[51]	FEDIRKO V, DUARTE-SALLES T, BAMIA C, et al. Prediagnostic circulating vitamin D levels and risk of hepatocellular carcinoma in European populations: A nested case-control study[J]. Hepatology, 2014, 60( 4): 1222- 1230. DOI: 10.1002/hep.27079.
[52]	BUDHATHOKI S, HIDAKA A, YAMAJI T, et al. Plasma 25-hydroxyvitamin D concentration and subsequent risk of total and site specific cancers in Japanese population: Large case-cohort study within Japan public health center-based prospective study cohort[J]. BMJ, 2018, 360: k671. DOI: 10.1136/bmj.k671.
[53]	LANGE CM, MIKI D, OCHI H, et al. Genetic analyses reveal a role for vitamin D insufficiency in HCV-associated hepatocellular carcinoma development[J]. PLoS One, 2013, 8( 5): e64053. DOI: 10.1371/journal.pone.0064053.
[54]	LIU H, JIANG X, QIAO QH, et al. Association of circulating 25-Hydroxyvitamin D and its related genetic variations with hepatocellular carcinoma incidence and survival[J]. Ann Transl Med, 2020, 8( 17): 1080. DOI: 10.21037/atm-20-1637.
[55]	ZHONG X. The Mendelian randomization study of vitamin D levels/vitamin D deficiency with primary liver cancer risk[D]. Guangzhou: Guangdong Pharmaceutical University, 2020. 钟旋. 维生素D水平/缺乏与肝癌发生风险的孟德尔随机化研究[D]. 广州: 广东药科大学, 2020.
[56]	ZHANG XR, NIU WQ. Meta-analysis of randomized controlled trials on vitamin D supplement and cancer incidence and mortality[J]. Biosci Rep, 2019, 39( 11): BSR20190369. DOI: 10.1042/BSR20190369.
[57]	ZHANG Y, FANG F, TANG J, et al. Association between vitamin D supplementation and mortality: systematic review and meta-analysis[J]. BMJ, 2019, 366: l4673. DOI: 10.1136/bmj.l4673.
[58]	SHU Y, HE LL, GAO MX, et al. Immunomodulatory role of transforming growth factor-β in hepatocellular carcinoma and its research progress[J/CD]. Chin J Liver Dis(Electronic Version), 2022, 14( 3): 9- 13. DOI: 10.3969/j.issn.1674-7380.2022.03.003. 舒杨, 何玲玲, 高美欣, 等. 转化生长因子β在肝细胞癌中的免疫调节作用及研究进展[J/CD]. 中国肝脏病杂志(电子版), 2022, 14( 3): 9- 13. DOI: 10.3969/j.issn.1674-7380.2022.03.003.
[59]	TAS F, YASASEVER CT, KARABULUT S, et al. Serum transforming growth factor-beta1 levels may have predictive and prognostic roles in patients with gastric cancer[J]. Tumour Biol, 2015, 36( 3): 2097- 2103. DOI: 10.1007/s13277-014-2817-9.
[60]	LI JX, MU SF, MU LX, et al. Transforming growth factor-beta-1 is a serum biomarker of radiation-induced pneumonitis in esophageal cancer patients treated with thoracic radiotherapy: Preliminary results of a prospective study[J]. Onco Targets Ther, 2015, 8: 1129- 1136. DOI: 10.2147/OTT.S79433.
[61]	RADWAN MI, PASHA HF, MOHAMED RH, et al. Influence of transforming growth factor-β1 and tumor necrosis factor-α genes polymorphisms on the development of cirrhosis and hepatocellular carcinoma in chronic hepatitis C patients[J]. Cytokine, 2012, 60( 1): 271- 276. DOI: 10.1016/j.cyto.2012.05.010.
[62]	LU WQ, QIU JL, HUANG ZL, et al. Enhanced circulating transforming growth factor beta 1 is causally associated with an increased risk of hepatocellular carcinoma: A Mendelian randomization meta-analysis[J]. Oncotarget, 2016, 7( 51): 84695- 84704. DOI: 10.18632/oncotarget.13218.
[63]	YUAN S, CARTER P, VITHAYATHIL M, et al. Iron status and cancer risk in UK biobank: A two-sample Mendelian randomization study[J]. Nutrients, 2020, 12( 2): 526. DOI: 10.3390/nu12020526.
[64]	CHENG Y, YU CX, HUANG MT, et al. Genetic association of telomere length with hepatocellular carcinoma risk: A Mendelian randomization analysis[J]. Cancer Epidemiol, 2017, 50( Pt A): 39- 45. DOI: 10.1016/j.canep.2017.07.011.
[65]	PAN GQ, YANG CC, SHANG XL, et al. The causal relationship between white blood cell counts and hepatocellular carcinoma: A Mendelian randomization study[J]. Eur J Med Res, 2022, 27( 1): 278. DOI: 10.1186/s40001-022-00900-y.