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

Abstract

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

CLC Number:

R735

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.

Figures/Tables 5

Tab. 1

Tab. 2

Fig. 1

Fig. 2

Tab. 3

References 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]	Haiyao PANG,Jun MENG. Research progress in relationship between 14-3-3ɛ protein and occurrence and development of tumor [J]. Journal of Jilin University(Medicine Edition), 2024, 50(2): 572-578.
[2]	Huijuan SONG,Zhenhua XU,Dongning HE. Effect of apolipoprotein C1 expression on proliferation and apoptosis of human liver cancer HepG2 cells and its mechanism [J]. Journal of Jilin University(Medicine Edition), 2024, 50(1): 128-135.
[3]	Tianyi WANG,Yufeng ZHU,Miao SUN,Wei WANG. Application of three-dimensional reconstruction combined with indocyanine green intraoperative navigation in diagnosis and treatment of liver cancer [J]. Journal of Jilin University(Medicine Edition), 2021, 47(4): 1014-1021.
[4]	Jie YANG,Wubin HE,Ni AN,Wencong KONG,Rongjian SU,Xuezhe WANG. Regulatory effect of glucose-regulating protein 78 on radiotherapy sensitivity of liver cancer cells and its mechanism [J]. Journal of Jilin University(Medicine Edition), 2021, 47(4): 888-895.
[5]	Runhong MU, Xinzhu LIU, Rui LIN, Yupeng LI, Luyao WANG, Chunyu WANG, Xiao GUO. Effect of PRDX6 over-expression of proliferation, invasion and migration of liver cancer cells and its molecular mechanism [J]. Journal of Jilin University(Medicine Edition), 2021, 47(3): 559-565.
[6]	Haiying ZHANG,Wenxin ZHANG,Wenjing ZHAO,Wei LI. Induction effect of gallic acid on apoptosis of human hepatocellular carcinoma HepG-2 cells through regulating mitochondrial oxidative phosphorylation [J]. Journal of Jilin University(Medicine Edition), 2021, 47(1): 125-132.
[7]	CHEN Xi, BAI Lin, WANG Yingying, CAO Shuang, MU Hongping, WANG Yilin, SHI Hao, ZHANG Qian, GAO Xin, ZHANG Chengyi, ZHANG Ruowen. Inhibitory effect of tanshinone ⅡA on proliferation and migration of human liver cancer HepG2 cells and its apoptosis-promoting effect [J]. Journal of Jilin University(Medicine Edition), 2019, 45(03): 531-538.
[8]	XU Zhenhua, SU Rongjian. Inhibitory effects of zingerone combined with sorafenib on migration and invasion of human liver cancer HepG2 cells [J]. Journal of Jilin University(Medicine Edition), 2019, 45(02): 228-233.
[9]	YU Tao, JIAO Xue, FU Changfeng, LI Qin. Selective effects of cyclamin on proliferation and apoptosis of liver cancer cells and their mechanisms [J]. Journal of Jilin University(Medicine Edition), 2019, 45(02): 319-324.
[10]	GU Teng, WANG Jiang, CHEN Xiaoqian, LIU Kai. Hepatic angiomyolipoma: A case report and literature review [J]. Journal of Jilin University(Medicine Edition), 2019, 45(01): 153-155.
[11]	ZHU Deqiang, CHEN Xuejun. Effects of plumbagin on proliferation and apoptosis of hepatocellular carcinoma HepG2R cells resistant to sorafenib and its mechanism [J]. Journal of Jilin University(Medicine Edition), 2018, 44(06): 1223-1229.
[12]	LI Tianzhu, WANG Jiaru, ZHANG Junyi, WANG Hongquan, SHI Tiewei, ZHOU Jing, BAI Chunying, JIN Chenghao. Expression of ELK-3 protein in hepatocellular carcinoma tissue and its effects on migration and invasion abilities of HepG2 cells [J]. Journal of Jilin University Medicine Edition, 2018, 44(04): 736-740.
[13]	LIU Xia, QI Fengjie, DU Xiaoyuan. Effects of silencing expression of CRAF gene on invasion and metastasis of hepatocellular carcinoma cells [J]. Journal of Jilin University Medicine Edition, 2018, 44(03): 521-525.
[14]	XING Shaoji, ZHENG Liansheng, WANG Diandong, ZHANG Xuan, CHI Min. Analysis on association between single nucleotide polymorphism of selenoprotein S gene and risk of liver cancer [J]. Journal of Jilin University Medicine Edition, 2018, 44(03): 558-562.
[15]	ZHANG Yanxia, LI Yuehui, ZHANG Lihong, ZHANG Nianping, YAN Yanyan, YANG Xiaohui, FENG Xiangling. Effects of silencing HOXA13 gene on malignant phenotypes of hepatocellular carcinoma HepG₂ and QGY-7703 cells [J]. Journal of Jilin University Medicine Edition, 2018, 44(02): 315-320.

Mendelian randomization study based on relationship between lifestyle and occurrence and development of hepatobiliary malignancies

RichHTML

PDF (PC)

Like

Knowledge

Abstract

Cite this article

share this article

Figures/Tables 5

References 35

Related Articles 15

Metrics

Comments

Recommended 0