基于生活方式与肝胆恶性肿瘤发生发展因果关系的孟德尔随机化研究

doi:10.13481/j.1671-587X.20240322

摘要/Abstract

摘要：

目的探讨使用孟德尔随机化研究方法分析生活方式与肝胆恶性肿瘤发生发展的因果关系，为肝胆恶性肿瘤预防和治疗提供潜在临床证据。方法纳入相互独立的大规模全基因组关联研究（GWAS）汇总数据，设定七步纳入标准进行工具变量筛选。暴露的生活方式包括饮食中碳水化合物摄入百分率、脂肪摄入百分率、蛋白质摄入百分率、咖啡摄入量、每周饮酒次数、闲暇时电子屏幕接触时间、闲暇时中高强度体育运动（MVPA）、工作时的久坐行为、首次吸烟年龄、每日吸烟数量、目前吸烟状态和既往吸烟状态共12种表型。采用逆方差加权法（IVW）的随机效应模型作为主分析方法，采用Cochrane’s Q检验评估异质性，采用MR-Egger截距法检验水平多效性。结果目前吸烟状态与易患肝外胆管癌呈显著因果关系（OR=1.607，95%CI：1.113~2.322，P=0.011）。咖啡摄入量较高与患肝癌及肝内胆管癌的较高风险有显著因果关系（OR=1.000，95%CI：0.999~1.000，P=0.012）。在体育活动中，较多的MVPA与患肝癌及肝内胆管癌的较低风险具有显著因果关系（OR=0.998，95%CI：0.996~0.999，P=0.002）。Cochrane’s Q 检验提示MVPA与肝外胆管癌（Q=18.354，P=0.049）和蛋白质摄入百分率与肝癌及肝内胆管癌（Q=12.715，P=0.026）具有轻度异质性，MR-Egger截距法显示本研究无水平多效性。结论目前吸烟状态与患肝外胆管癌的高风险具有因果关系，较多的MVPA与患肝癌及肝内胆管癌的较低风险具有因果关系。对患者进行适当的戒烟劝导和体育运动教育可能会为预防肝胆恶性肿瘤提供潜在益处。

关键词: 生活方式, 肝内胆管肿瘤, 胆管肿瘤, 肝肿瘤, 孟德尔随机化研究

Abstract:

Objective To analyze the causal relationship between lifestyle-based factors and the occurrence and development of hepatobiliary malignancies by Mendelian randomization study method， and to provide the potential clinical evidence for the prevention and treatment of hepatobiliary malignancies. Methods The data from large-scale， independent genome-wide association studies （GWAS） were selected， and seven-step inclusion criteria for the instrumental variable screening were set up. The exposure lifestyles included the percentage of carbohydrate intake， percentage of fat intake， percentage of protein intake in the diet， coffee intake， weekly alcohol consumption times， leisure electronic screen exposure time， moderate to vigorous intensity physical activity （MVPA） during leisure time， sedentary behavior at work， age at first smoking， daily smoking quantity， current smoking status， and past smoking status， totaling 12 phenotypes. The primary analysis method used was the random effect model of the inverse variance weighted （IVW） method， and the heterogeneity was detected by Cochrane’s Q test and the horizontal pleiotropy was detected by MR-Egger intercept method. Results The current smoking status was significantly positively correlated with the increasing risk of extrahepatic cholangiocarcinoma （OR=1.607， 95% CI： 1.113-2.322， P=0.011）. Higher coffee intake was causally linked to a higher risk of liver cancer and intrahepatic cholangiocarcinoma （OR=1.000， 95% CI： 0.999-1.000， P=0.012）. In the physical activity， more MVPA was associated with the lower risk of liver cancer and intrahepatic cholangiocarcinoma （OR=0.998， 95% CI： 0.996-0.999， P=0.002）. The Cochrane’s Q test results showed that there was mild heterogeneity between MVPA and extrahepatic cholangiocarcinoma（Q=18.354，P=0.049） as well as the percentage of protein intake and intraphepatic cholangiocarainoma（Q=12.715，P=0.026）， and the MR-Egger intercept method results showed there was no horizontal pleiotropy. Conclusion There is a causal relationship between current smoking status and extrahepatic cholangiocarcinoma， and there is a causal relationship between more MVPA and the lower risk of liver cancer and intrahepatic cholangiocarcinoma. Education on smoking and physical activity for the patients may offer potential benefits for the prevention of hepatobiliary malignancies.

Key words: Lifestyle, Intrahepatic cholangiocarcinoma, Cholangiocarcinoma, Liver neoplasm, Mendelian randomization study

中图分类号:

R735

刘华青,陈庆凯,陈永新,邱润昊,丁绪鹏,宋奉京,王岩,王葆林,曹宏. 基于生活方式与肝胆恶性肿瘤发生发展因果关系的孟德尔随机化研究[J]. 吉林大学学报(医学版), 2024, 50(3): 778-785.

Huaqing LIU,Qingkai CHEN,Yongxin CHEN,Runhao QIU,Xupeng DING,Fengjing SONG,Yan WANG,Baolin WANG,Hong CAO. Mendelian randomization study based on relationship between lifestyle and occurrence and development of hepatobiliary malignancies[J]. Journal of Jilin University(Medicine Edition), 2024, 50(3): 778-785.

图/表 5

表1

表2

图1

图2

表3

参考文献 35

1	ALJIFFRY M， ABDULELAH A， WALSH M， et al. Evidence-based approach to cholangiocarcinoma： a systematic review of the current literature［J］. J Am Coll Surg， 2009， 208（1）： 134-147.
2	KOAY E J， ODISIO B C， JAVLE M， et al. Management of unresectable intrahepatic cholangiocarcinoma： how do we decide among the various liver-directed treatments？［J］. Hepatobiliary Surg Nutr， 2017， 6（2）： 105-116.
3	BRINDLEY P J， BACHINI M， ILYAS S I， et al. Cholangiocarcinoma［J］. Nat Rev Dis Primers， 2021， 7： 65.
4	OSATAPHAN S， MAHANKASUWAN T， SAENGBOONMEE C. Obesity and cholangiocarcinoma： a review of epidemiological and molecular associations［J］. J Hepatobiliary Pancreat Sci， 2021， 28（12）： 1047-1059.
5	SONG Y H， CAI M T， LI Y H， et al. The focus clinical research in intrahepatic cholangiocarcinoma［J］. Eur J Med Res， 2022， 27（1）： 116.
6	BAUMEISTER S E， SCHLESINGER S， ALEKSANDROVA K， et al. Association between physical activity and risk of hepatobiliary cancers： a multinational cohort study［J］. J Hepatol， 2019， 70（5）： 885-892.
7	KUBO S， SHINKAWA H， ASAOKA Y， et al. Liver cancer study group of Japan clinical practice guidelines for intrahepatic cholangiocarcinoma［J］. Liver Cancer， 2022， 11（4）： 290-314.
8	LAN Q Y， ZHANG Y J， LIAO G C， et al. The association between dietary vitamin A and carotenes and the risk of primary liver cancer： a case-control study［J］. Nutrients， 2016， 8（10）： 624.
9	SCHERÜBL H. Alcohol use and gastrointestinal cancer risk［J］. Visc Med， 2020， 36（3）： 175-181.
10	CHO I R， YI S W， CHOI J S， et al. Comparison of risk factors for cholangiocarcinoma and hepatocellular carcinoma： a prospective cohort study in Korean adults［J］. Cancers， 2022， 14（7）： 1709.
11	HOU L， JIANG J M， LIU B Q， et al. Is exposure to tobacco associated with extrahepatic cholangiocarcinoma epidemics？ A retrospective proportional mortality study in China［J］. BMC Cancer， 2019， 19（1）： 348.
12	MADRID-VALERO J J， GREGORY A M. Behaviour genetics and sleep： a narrative review of the last decade of quantitative and molecular genetic research in humans［J］. Sleep Med Rev， 2023， 69： 101769.
13	MOHAMMADI-SHEMIRANI P， SOOD T， PARÉ G. From’omics to multi-omics technologies： the discovery of novel causal mediators［J］. Curr Atheroscler Rep， 2023， 25（2）： 55-65.
14	丁佳豪，章梦琦，郝明霞，等. 孟德尔随机化研究精神分裂症与自杀或故意自残的因果关系［J］. 中华精神科杂志， 2023， 56（1）： 32-39.
15	刘宇兴，苗雨阳，赵明辉，等. 双样本孟德尔随机化研究精神疾病和阻塞性睡眠呼吸暂停的关系［J］. 中华老年医学杂志， 2022， 41（10）： 1146-1149.
16	张晓宇，刘天一，朱文豪，等. 孟德尔随机化研究及其在脑卒中病因探索中应用进展［J］. 中国老年学杂志， 2022， 42（23）： 5885-5888.
17	吴思佳，李洪凯，薛付忠，等. 血压表型、脂质成分与2型糖尿病的跨种族孟德尔随机化研究［J］. 中华内分泌代谢杂志， 2023， 9（1）： 19-25.
18	LIU H L， WU W， XIANG W， et al. Lifestyle factors， metabolic factors and socioeconomic status for pelvic organ prolapse： a Mendelian randomization study［J］. Eur J Med Res， 2023， 28（1）： 183.
19	SKRIVANKOVA V W， RICHMOND R C， WOOLF B A R， et al. Strengthening the reporting of observational studies in epidemiology using Mendelian randomization： the STROBE-MR statement［J］. JAMA， 2021， 326（16）： 1614-1621.
20	SAKAUE S， KANAI M， TANIGAWA Y， et al. A cross-population atlas of genetic associations for 220 human phenotypes［J］. Nat Genet， 2021， 53（10）： 1415-1424.
21	CHU A Y， WORKALEMAHU T， PAYNTER N P， et al. Novel locus including FGF21 is associated with dietary macronutrient intake［J］. Hum Mol Genet， 2013， 22（9）： 1895-1902.
22	ZHONG V W， KUANG A L， DANNING R D， et al. A genome-wide association study of bitter and sweet beverage consumption［J］. Hum Mol Genet， 2019， 28（14）： 2449-2457.
23	LIU M Z， JIANG Y， WEDOW R， et al. Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use［J］. Nat Genet， 2019， 51（2）： 237-244.
24	WANG Z， EMMERICH A， PILLON N J， et al. Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention［J］. Nat Genet， 2022， 54（9）： 1332-1344.
25	CAI J H， WEI Z X， CHEN M， et al. Socioeconomic status， individual behaviors and risk for mental disorders： a Mendelian randomization study［J］. Eur Psychiatry， 2022， 65（1）： e28.
26	BURGESS S， BUTTERWORTH A， THOMPSON S G. Mendelian randomization analysis with multiple genetic variants using summarized data［J］. Genet Epidemiol， 2013， 37（7）： 658-665.
27	BEHRENS G， MATTHEWS C E， MOORE S C， et al. The association between frequency of vigorous physical activity and hepatobiliary cancers in the NIH-AARP Diet and Health Study［J］. Eur J Epidemiol， 2013， 28（1）： 55-66.
28	MCGEE E E， JACKSON S S， PETRICK J L， et al. Smoking， alcohol， and biliary tract cancer risk： a pooling project of 26 prospective studies［J］. J Natl Cancer Inst， 2019， 111（12）： 1263-1278.
29	林志文，刘红枝，曾永毅，等. 肝内胆管癌新辅助治疗的热点与进展［J］. 临床肝胆病杂志， 2023， 39（9）： 2031-2038.
30	GUO W， GE X Y， LU J， et al. Diet and risk of non-alcoholic fatty liver disease， cirrhosis， and liver cancer： a large prospective cohort study in UK biobank［J］. Nutrients， 2022， 14（24）： 5335.
31	MAKIUCHI T， SOBUE T， KITAMURA T， et al. The relationship between vegetable/fruit consumption and gallbladder/bile duct cancer： a population-based cohort study in Japan［J］. Int J Cancer， 2017， 140（5）： 1009-1019.
32	MAKIUCHI T， SOBUE T， KITAMURA T， et al. Association between green tea/coffee consumption and biliary tract cancer： a population-based cohort study in Japan［J］. Cancer Sci， 2016， 107（1）： 76-83.
33	PETRICK J L， FREEDMAN N D， GRAUBARD B I， et al. Coffee consumption and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma by sex： the liver cancer pooling project［J］. Cancer Epidemiol Biomarkers Prev， 2015， 24（9）： 1398-1406.
34	YIN X， HE X K， WU L Y， et al. Chlorogenic acid， the main antioxidant in coffee， reduces radiation-induced apoptosis and DNA damage via NF-E2-related factor 2 （Nrf2） activation in hepatocellular carcinoma［J］. Oxid Med Cell Longev， 2022， 2022： 4566949.
35	MAKIUCHI T， SOBUE T， KITAMURA T， et al. Smoking， alcohol consumption， and risks for biliary tract cancer and intrahepatic bile duct cancer［J］. J Epidemiol， 2019， 29（5）： 180-186.

Exposed lifestyle	PubMed ID	Sample size
Percentage of carbohydrate intake	23372041	33 355
Percentage of fat intake	23372041	33 355
Percentage of protein intake	23372041	33 355
Coffee intake	31046077	39 924
Weekly alcohol consumption times	30643251	630 154
Leisure electronic screen exposure time	36071172	526 725
MVPA during leisure time	36071172	608 595
Sedentary behavior at work	36071172	372 609
Age at first smoking	30643251	216 837
Daily smoking quantity	30643251	216 590
Current smoking status	30643251	378 249
Past smoking status	30643251	848 460

Exposed lifestyle	Extrahepatic cholangiocarcinoma			Liver cancer and intrahepatic cholangiocarcinoma
Exposed lifestyle	Number of SNPs	F	R²（η/%）	Number of SNPs	F	R²（η/%）
Percentage of carbohydrate intake	8	20.25—31.36	0.54	7	20.25—31.36	0.48
Percentage of fat intake	2	19.99—21.60	0.12	2	19.99—21.60	0.12
Percentage of protein intake	6	20.64—27.46	0.42	6	20.64—27.46	0.42
Coffee intake	3	28.73—1 815.28	0.04	3	28.73—1 815.28	0.04
Weekly alcohol consumption times	29	20.80—56.74	0.12	23	20.80—56.74	0.09
Leisure electronic screen exposure time	88	29.34—66.76	0.62	79	29.34—66.76	0.57
MVPA during leisure time	12	30.12—44.31	0.07	8	30.12—44.31	0.05
Sedentary behavior at work	7	29.87—39.69	0.06	6	29.87—38.32	0.05
Age at first smoking	22	21.04—31.29	0.24	14	21.22—31.29	0.15
Daily smoking quantity	30	20.82—503.45	0.60	26	21.04—503.45	0.55
Current smoking status	20	20.79—57.59	0.14	14	20.79—57.59	0.10
Past smoking status	56	20.75—53.17	0.17	46	20.75—53.17	0.14

Exposed lifestyle	Extrahepatic cholangiocarcinoma				Liver cancer and intrahepatic cholangiocarcinoma
Exposed lifestyle	Q	Cochrane’s Q-P	MR-Egger intercept	MR-Egger intercept-P	Q	Cochrane’s Q-P	MR-Egger intercept	MR-Egger intercept-P
Percentage of carbohydrate intake	6.751	0.455	0.040	0.645	4.285	0.638	0.00 016	0.342
Percentage of fat intake	1.288	0.256	—	—	0.798	0.372	—	—
Percentage of protein in diet intake	3.212	0.667	－0.165	0.326	12.715	0.026	－0.00 052	0.159
Coffee intake	2.536	0.281	0.312	0.384	0.123	0.940	0.00 013	0.794
Weekly alcohol consumption time	29.995	0.363	－0.008	0.814	20.088	0.578	－0.0 0010	0.195
Leisure electronic screenex posure time	89.132	0.303	－0.022	0.362	64.966	0.834	－0.00 001	0.885
MVPA during leisure time	18.354	0.049	0.079	0.467	2.687	0.912	0.00 001	0.985
Sedentary behavior at work	3.288	0.772	－0.009	0.910	2.443	0.785	－0.00 005	0.705
Age at first smoking	15.972	0.771	0.005	0.894	17.265	0.187	0.00 006	0.508
Daily smoking quantity	34.499	0.221	0.005	0.819	25.719	0.423	－0.00 001	0.793
Current smoking status	11.899	0.890	0.009	0.790	13.646	0.399	－0.00 004	0.638
Past smoking status	42.277	0.896	－0.015	0.528	42.739	0.568	0.00 003	0.675

[1]	庞海垚,孟峻. 14-3-3ɛ蛋白与肿瘤发生发展关系的研究进展[J]. 吉林大学学报(医学版), 2024, 50(2): 572-578.
[2]	宋慧娟,徐振华,何东宁. 载脂蛋白C1表达对人肝癌HepG2细胞增殖和凋亡的影响及其机制[J]. 吉林大学学报(医学版), 2024, 50(1): 128-135.
[3]	魏雁虹,杨晨雪,杨广民,宋帅,李明,杨海娇,魏海峰. 下调HMGB2表达对肝癌LM3细胞上皮-间质转化的抑制作用及其AKT/mTOR信号通路机制[J]. 吉林大学学报(医学版), 2024, 50(1): 143-149.
[4]	梁媛媛,赵颂,胡静,安妮,魏验芦,苏荣健. 莫特塞尼与EZH2抑制剂GSK126联合应用对肝癌Huh7细胞增殖和凋亡的影响及其机制[J]. 吉林大学学报(医学版), 2023, 49(4): 896-904.
[5]	牛英杰,查勇,李思嘉,王青,唐诗聪,李红阳. 胆管癌根治性切除术后患者预后相关因素分析和生存预测模型构建[J]. 吉林大学学报(医学版), 2022, 48(4): 979-987.
[6]	冯少青,孟峻. 血清和糖皮质激素诱导蛋白激酶3与肿瘤发生发展关系的研究进展Research progress in relationship between serum and glucocorticoid-induced protein kinase 3 and occurrence and development of tumor[J]. 吉林大学学报(医学版), 2022, 48(2): 540-545.
[7]	倪盟,曾雷. miRNA单核苷酸多态性与HBV感染相关疾病关系的研究进展[J]. 吉林大学学报(医学版), 2021, 47(6): 1588-1593.
[8]	王天一,朱玉峰,孙淼,王巍. 三维重建联合吲哚菁绿术中导航在肝癌诊断和治疗中的应用[J]. 吉林大学学报(医学版), 2021, 47(4): 1014-1021.
[9]	杨洁,贺武斌,安妮,孔雯聪,苏荣健,王学哲. 葡萄糖调节蛋白78对肝癌细胞放射敏感性的调控作用及其机制[J]. 吉林大学学报(医学版), 2021, 47(4): 888-895.
[10]	母润红, 刘馨竹, 林睿, 李雨澎, 王璐瑶, 王春雨, 郭笑. PRDX6过表达对肝癌细胞增殖、侵袭和迁移的影响及其分子机制[J]. 吉林大学学报(医学版), 2021, 47(3): 559-565.
[11]	张海英,张文馨,赵文静,李伟. 五倍子酸通过调节人肝癌HepG-2细胞线粒体氧化磷酸化对细胞凋亡的诱导作用[J]. 吉林大学学报(医学版), 2021, 47(1): 125-132.
[12]	陈曦, 柏林, 王映映, 曹爽, 穆宏平, 王翊霖, 石浩, 张倩, 高鑫, 张成义, 张若文. 丹参酮ⅡA对人肝癌HepG2细胞增殖和迁移的抑制作用及促凋亡作用[J]. 吉林大学学报(医学版), 2019, 45(03): 531-538.
[13]	徐振华, 苏荣健. 姜油酮联合索拉非尼对人肝癌HepG2细胞迁移和侵袭的抑制作用[J]. 吉林大学学报(医学版), 2019, 45(02): 228-233.
[14]	于涛, 焦雪, 付长峰, 李嵚. 仙客来皂苷对肝癌细胞体外增殖和凋亡的选择性作用及其机制[J]. 吉林大学学报(医学版), 2019, 45(02): 319-324.
[15]	顾腾, 王江, 陈晓倩, 刘凯. 肝血管平滑肌脂肪瘤1例报告及文献复习[J]. 吉林大学学报(医学版), 2019, 45(01): 153-155.