The Causal relationship between gastroesophageal reflux disease and hepatobiliary-pancreatic diseases: a Mendelian randomization study

doi:10.3877/cma.j.issn.2095-8765.2024.03.006

Abstract

Abstract:

Objective

To explore the causal relationship between gastroesophageal reflux disease（GERD） and hepatobiliary-pancreatic diseases.

Methods

Both the exposure factors and outcome events were selected from the European population. The exposure data on GERD were obtained from the genome-wide association studies （GWAS） database, and data on 11 hepatobiliary-pancreatic diseases were obtained from the FinnGen database. The selection criteria for instrumental variables were single nucleotide polymorphisms with P＜5×10⁸, r²＜0.001, genetic distance of 10,000kb, and F＞10. The statistical methods for Mendelian randomization included inverse variance weighting, weighted median method, MR-Egger, weighted mode,and simple model method. Among these, the results from the inverse variance weighting method were taken as the main basis, with other methods used as supplementary evidence and validation, followed by sensitivity analysis.

Results

GERD increases the incidence of acute pancreatitis, cholecystitis, cholelithiasis, chronic pancreatitis, pancreatic malignancy, non-alcoholic fatty liver disease, and primary sclerosing cholangitis, with OR values and 95%CI of 1.431 （1.237-1.656）, 1.235 （1.028-1.484）, 1.262 （1.169-1.363）, 1.481 （1.194-1.838）, 1.517 （1.114-2.065）, 1.519 （1.205-1.914）, 1.524 （1.182-1.965）, respectively. Sensitivity analysis showed no horizontal pleiotropy among the data. There is no causal relationship between GERD and benign liver tumors, liver cirrhosis, hepatocellular carcinoma, or cholangiocarcinoma.

Conclusion

GERD increases the risk of certain hepatobiliary-pancreatic diseases, providing new insights for the prevention and treatment of these diseases and contributing to more comprehensive health management.

Key words: Gastroesophageal reflux disease, Hepatobiliary and pancreatic system diseases, Mendelian randomization analysis, Causal relationship

Xunfeng Gao, Xiaolu Xu, Jinhui Zhang, Liquan Cai, Heng Zhang, Qinwen Tai. The Causal relationship between gastroesophageal reflux disease and hepatobiliary-pancreatic diseases: a Mendelian randomization study[J]. Chinese Journal of Gastroesophageal Reflux Disease(Electronic Edition), 2024, 11(03): 143-152.

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Figures/Tables 6

References 30

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暴露/结局	病例组（例）	对照组（例）	种族	数据来源
胃食管反流病	129 080	473 524	欧洲	GWAS数据库 ebi-a-GCST90000514
急性胰腺炎	6787	361 641	欧洲	芬兰数据库finngen_R10_K11_ACUTPANC
肝脏良性肿瘤	566	411 541	欧洲	芬兰数据库finngen_R10_CD2_BENIGN_LIVER
原发性硬化性胆管炎	1843	361 641	欧洲	芬兰数据库finngen_R10_K11_CHOLANGI
胆囊炎	4697	361 641	欧洲	芬兰数据库finngen_R10_K11_CHOLECYST
胆石症	40 191	361 641	欧洲	芬兰数据库finngen_R10_K11_CHOLELITH
慢性胰腺炎	3875	361 641	欧洲	芬兰数据库finngen_R10_K11_CHRONPANC
肝硬化	1266	407 801	欧洲	芬兰数据库finngen_R10_CHIRHEP_NAS
肝细胞癌	500	314 193	欧洲	芬兰数据库finngen_R10_C3_HEPATOCELLU_CARC_EXALLC
胆道恶性肿瘤	1207	314 193	欧洲	芬兰数据库finngen_R10_C3_BILIARY_GALLBLADDER_EXALLC
胰腺恶性肿瘤	1626	314 193	欧洲	芬兰数据库finngen_R10_C3_PANCREAS_EXALLC
非酒精性脂肪肝	2568	409 613	欧洲	芬兰数据库 finngen_R10_NAFLD

暴露/结局	病例组（例）	对照组（例）	种族	数据来源
胃食管反流病	129 080	473 524	欧洲	GWAS数据库 ebi-a-GCST90000514
急性胰腺炎	6787	361 641	欧洲	芬兰数据库finngen_R10_K11_ACUTPANC
肝脏良性肿瘤	566	411 541	欧洲	芬兰数据库finngen_R10_CD2_BENIGN_LIVER
原发性硬化性胆管炎	1843	361 641	欧洲	芬兰数据库finngen_R10_K11_CHOLANGI
胆囊炎	4697	361 641	欧洲	芬兰数据库finngen_R10_K11_CHOLECYST
胆石症	40 191	361 641	欧洲	芬兰数据库finngen_R10_K11_CHOLELITH
慢性胰腺炎	3875	361 641	欧洲	芬兰数据库finngen_R10_K11_CHRONPANC
肝硬化	1266	407 801	欧洲	芬兰数据库finngen_R10_CHIRHEP_NAS
肝细胞癌	500	314 193	欧洲	芬兰数据库finngen_R10_C3_HEPATOCELLU_CARC_EXALLC
胆道恶性肿瘤	1207	314 193	欧洲	芬兰数据库finngen_R10_C3_BILIARY_GALLBLADDER_EXALLC
胰腺恶性肿瘤	1626	314 193	欧洲	芬兰数据库finngen_R10_C3_PANCREAS_EXALLC
非酒精性脂肪肝	2568	409 613	欧洲	芬兰数据库 finngen_R10_NAFLD

β	标准差	P	SNP	效应位点	其他位点	效应位点频率	F
-0.038	0.007	＜0.001	rs569356	G	A	0.141	209.756
0.027	0.005	＜0.001	rs7541875	G	A	0.426	221.295
0.027	0.005	＜0.001	rs2782641	A	G	0.613	209.933
0.039	0.006	＜0.001	rs2815749	G	A	0.801	290.520
0.039	0.006	＜0.001	rs3766823	A	G	0.171	265.369
0.031	0.005	＜0.001	rs1937450	G	T	0.538	299.008
0.053	0.007	＜0.001	rs17379561	T	A	0.144	419.662
-0.027	0.005	＜0.001	rs7527682	G	A	0.537	213.422
0.028	0.005	＜0.001	rs903678	A	G	0.339	207.976
0.032	0.005	＜0.001	rs6711584	A	G	0.452	310.733
-0.028	0.005	＜0.001	rs13409451	G	A	0.392	220.689
0.031	0.005	＜0.001	rs4300861	T	C	0.38208	268.528
0.028	0.005	＜0.001	rs12997558	A	G	0.358	214.634
-0.032	0.005	＜0.001	rs6722661	A	G	0.365	290.632
0.031	0.005	＜0.001	rs1596747	G	A	0.494	291.276
0.034	0.005	＜0.001	rs7600261	T	C	0.306	292.808
-0.042	0.007	＜0.001	rs1011407	G	A	0.122	227.883
0.028	0.005	＜0.001	rs2358016	G	C	0.498	240.907
0.030	0.006	＜0.001	rs6780459	T	A	0.747	212.876
-0.031	0.005	＜0.001	rs2016933	G	C	0.730	228.713
0.030	0.006	＜0.001	rs7612999	A	G	0.245	207.962
-0.047	0.005	＜0.001	rs2240326	A	G	0.474	669.242
-0.033	0.006	＜0.001	rs7675588	A	C	0.795	221.103
-0.028	0.005	＜0.001	rs7685686	G	A	0.422	229.331
0.070	0.0095	＜0.001	rs13107325	T	C	0.074	408.863
-0.026	0.005	＜0.001	rs2164300	T	C	0.523	210.807
-0.039	0.005	＜0.001	rs1510719	C	T	0.383	431.116
-0.027	0.005	＜0.001	rs10010963	T	C	0.616	207.506
0.031	0.005	＜0.001	rs1592757	C	G	0.356	267.379
0.028	0.005	＜0.001	rs11953061	T	C	0.339	214.201
-0.029	0.005	＜0.001	rs329122	A	G	0.420	246.146
0.029	0.005	＜0.001	rs2744961	T	C	0.358	236.412
-0.029	0.005	＜0.001	rs12204714	T	C	0.632	232.798
-0.031	0.006	＜0.001	rs9396740	A	G	0.249	223.485
β	标准差	P	SNP	效应位点	其他位点	效应位点频率	F
-0.038	0.005	＜0.001	rs9372625	A	G	0.383	405.657
0.035	0.005	＜0.001	rs2145318	A	T	0.487	376.332
0.067	0.012	＜0.001	rs3828917	T	G	0.042	217.620
-0.033	0.006	＜0.001	rs9373363	G	A	0.254	243.810
-0.028	0.005	＜0.001	rs4713692	T	C	0.368	213.750
-0.051	0.006	＜0.001	rs11762636	A	C	0.180	472.433
0.027	0.005	＜0.001	rs2043539	A	G	0.419	217.186
0.029	0.005	＜0.001	rs2396133	G	A	0.475	259.110
0.037	0.006	＜0.001	rs2106353	T	G	0.231	289.663
0.032	0.005	＜0.001	rs2396766	A	G	0.473	311.767
-0.033	0.005	＜0.001	rs215614	A	G	0.630	303.482
0.029	0.005	＜0.001	rs903959	A	T	0.399	245.951
0.032	0.005	＜0.001	rs3863241	T	C	0.527	317.456
0.028	0.005	＜0.001	rs7032155	A	C	0.592	224.274
-0.030	0.005	＜0.001	rs4382592	G	T	0.699	232.169
0.027	0.005	＜0.001	rs3793577	G	A	0.538	218.941
0.032	0.005	＜0.001	rs12357321	A	G	0.311	259.925
-0.031	0.005	＜0.001	rs1021363	G	A	0.642	270.060
0.034	0.006	＜0.001	rs761777	G	A	0.254	272.498
0.028	0.005	＜0.001	rs10837002	G	C	0.351	210.015
-0.028	0.005	＜0.001	rs2734839	T	C	0.607	231.189
-0.034	0.006	＜0.001	rs7942368	T	C	0.215	234.522
-0.038	0.005	＜0.001	rs773109	A	G	0.335	389.273
-0.027	0.005	＜0.001	rs324769	T	C	0.449	213.766
0.031	0.005	＜0.001	rs1479405	T	C	0.322	260.801
0.038	0.006	＜0.001	rs1716171	T	C	0.790	294.919
-0.036	0.006	＜0.001	rs9542729	G	C	0.202	256.793
-0.039	0.005	＜0.001	rs1334297	A	G	0.734	354.211
0.027	0.005	＜0.001	rs9529055	A	G	0.476	213.725
0.033	0.005	＜0.001	rs9517313	C	G	0.383	312.533
0.031	0.005	＜0.001	rs942065	A	G	0.634	264.339
0.042	0.006	＜0.001	rs10133111	A	G	0.163	287.253
0.029	0.005	＜0.001	rs957345	G	C	0.540	252.777
0.033	0.005	＜0.001	rs9940128	A	G	0.422	325.150
-0.033	0.005	＜0.001	rs12598916	G	C	0.275	265.831
0.029	0.005	＜0.001	rs7206608	G	C	0.323	224.058
0.030	0.005	＜0.001	rs12453010	T	C	0.395	254.060
0.036	0.006	＜0.001	rs7241572	A	G	0.209	266.398
0.032	0.005	＜0.001	rs1431196	G	A	0.428	310.350
-0.036	0.005	＜0.001	rs12967855	G	A	0.670	355.855
-0.035	0.005	＜0.001	rs9636202	A	G	0.267	289.55
-0.036	0.006	＜0.001	rs2023878	T	C	0.192	246.629
0.031	0.005	＜0.001	rs1883842	G	T	0.279	230.699
0.030	0.005	＜0.001	rs2834005	C	T	0.315	229.473
-0.028	0.005	＜0.001	rs2838771	C	G	0.647	217.478
0.027	0.005	＜0.001	rs9615905	T	C	0.458	227.434

β	标准差	P	SNP	效应位点	其他位点	效应位点频率	F
-0.038	0.007	＜0.001	rs569356	G	A	0.141	209.756
0.027	0.005	＜0.001	rs7541875	G	A	0.426	221.295
0.027	0.005	＜0.001	rs2782641	A	G	0.613	209.933
0.039	0.006	＜0.001	rs2815749	G	A	0.801	290.520
0.039	0.006	＜0.001	rs3766823	A	G	0.171	265.369
0.031	0.005	＜0.001	rs1937450	G	T	0.538	299.008
0.053	0.007	＜0.001	rs17379561	T	A	0.144	419.662
-0.027	0.005	＜0.001	rs7527682	G	A	0.537	213.422
0.028	0.005	＜0.001	rs903678	A	G	0.339	207.976
0.032	0.005	＜0.001	rs6711584	A	G	0.452	310.733
-0.028	0.005	＜0.001	rs13409451	G	A	0.392	220.689
0.031	0.005	＜0.001	rs4300861	T	C	0.38208	268.528
0.028	0.005	＜0.001	rs12997558	A	G	0.358	214.634
-0.032	0.005	＜0.001	rs6722661	A	G	0.365	290.632
0.031	0.005	＜0.001	rs1596747	G	A	0.494	291.276
0.034	0.005	＜0.001	rs7600261	T	C	0.306	292.808
-0.042	0.007	＜0.001	rs1011407	G	A	0.122	227.883
0.028	0.005	＜0.001	rs2358016	G	C	0.498	240.907
0.030	0.006	＜0.001	rs6780459	T	A	0.747	212.876
-0.031	0.005	＜0.001	rs2016933	G	C	0.730	228.713
0.030	0.006	＜0.001	rs7612999	A	G	0.245	207.962
-0.047	0.005	＜0.001	rs2240326	A	G	0.474	669.242
-0.033	0.006	＜0.001	rs7675588	A	C	0.795	221.103
-0.028	0.005	＜0.001	rs7685686	G	A	0.422	229.331
0.070	0.0095	＜0.001	rs13107325	T	C	0.074	408.863
-0.026	0.005	＜0.001	rs2164300	T	C	0.523	210.807
-0.039	0.005	＜0.001	rs1510719	C	T	0.383	431.116
-0.027	0.005	＜0.001	rs10010963	T	C	0.616	207.506
0.031	0.005	＜0.001	rs1592757	C	G	0.356	267.379
0.028	0.005	＜0.001	rs11953061	T	C	0.339	214.201
-0.029	0.005	＜0.001	rs329122	A	G	0.420	246.146
0.029	0.005	＜0.001	rs2744961	T	C	0.358	236.412
-0.029	0.005	＜0.001	rs12204714	T	C	0.632	232.798
-0.031	0.006	＜0.001	rs9396740	A	G	0.249	223.485
β	标准差	P	SNP	效应位点	其他位点	效应位点频率	F
-0.038	0.005	＜0.001	rs9372625	A	G	0.383	405.657
0.035	0.005	＜0.001	rs2145318	A	T	0.487	376.332
0.067	0.012	＜0.001	rs3828917	T	G	0.042	217.620
-0.033	0.006	＜0.001	rs9373363	G	A	0.254	243.810
-0.028	0.005	＜0.001	rs4713692	T	C	0.368	213.750
-0.051	0.006	＜0.001	rs11762636	A	C	0.180	472.433
0.027	0.005	＜0.001	rs2043539	A	G	0.419	217.186
0.029	0.005	＜0.001	rs2396133	G	A	0.475	259.110
0.037	0.006	＜0.001	rs2106353	T	G	0.231	289.663
0.032	0.005	＜0.001	rs2396766	A	G	0.473	311.767
-0.033	0.005	＜0.001	rs215614	A	G	0.630	303.482
0.029	0.005	＜0.001	rs903959	A	T	0.399	245.951
0.032	0.005	＜0.001	rs3863241	T	C	0.527	317.456
0.028	0.005	＜0.001	rs7032155	A	C	0.592	224.274
-0.030	0.005	＜0.001	rs4382592	G	T	0.699	232.169
0.027	0.005	＜0.001	rs3793577	G	A	0.538	218.941
0.032	0.005	＜0.001	rs12357321	A	G	0.311	259.925
-0.031	0.005	＜0.001	rs1021363	G	A	0.642	270.060
0.034	0.006	＜0.001	rs761777	G	A	0.254	272.498
0.028	0.005	＜0.001	rs10837002	G	C	0.351	210.015
-0.028	0.005	＜0.001	rs2734839	T	C	0.607	231.189
-0.034	0.006	＜0.001	rs7942368	T	C	0.215	234.522
-0.038	0.005	＜0.001	rs773109	A	G	0.335	389.273
-0.027	0.005	＜0.001	rs324769	T	C	0.449	213.766
0.031	0.005	＜0.001	rs1479405	T	C	0.322	260.801
0.038	0.006	＜0.001	rs1716171	T	C	0.790	294.919
-0.036	0.006	＜0.001	rs9542729	G	C	0.202	256.793
-0.039	0.005	＜0.001	rs1334297	A	G	0.734	354.211
0.027	0.005	＜0.001	rs9529055	A	G	0.476	213.725
0.033	0.005	＜0.001	rs9517313	C	G	0.383	312.533
0.031	0.005	＜0.001	rs942065	A	G	0.634	264.339
0.042	0.006	＜0.001	rs10133111	A	G	0.163	287.253
0.029	0.005	＜0.001	rs957345	G	C	0.540	252.777
0.033	0.005	＜0.001	rs9940128	A	G	0.422	325.150
-0.033	0.005	＜0.001	rs12598916	G	C	0.275	265.831
0.029	0.005	＜0.001	rs7206608	G	C	0.323	224.058
0.030	0.005	＜0.001	rs12453010	T	C	0.395	254.060
0.036	0.006	＜0.001	rs7241572	A	G	0.209	266.398
0.032	0.005	＜0.001	rs1431196	G	A	0.428	310.350
-0.036	0.005	＜0.001	rs12967855	G	A	0.670	355.855
-0.035	0.005	＜0.001	rs9636202	A	G	0.267	289.55
-0.036	0.006	＜0.001	rs2023878	T	C	0.192	246.629
0.031	0.005	＜0.001	rs1883842	G	T	0.279	230.699
0.030	0.005	＜0.001	rs2834005	C	T	0.315	229.473
-0.028	0.005	＜0.001	rs2838771	C	G	0.647	217.478
0.027	0.005	＜0.001	rs9615905	T	C	0.458	227.434

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[2]	Yimin Xing, Tianfei Zhang, Huiyong Dai. Application of gastrointestinal filling contrast-enhanced ultrasound in the clinical diagnosis of patients with acid reflux and belching [J]. Chinese Journal of Operative Procedures of General Surgery(Electronic Edition), 2024, 18(03): 303-306.
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[8]	Xiaojiu Tang, Man Hu, Bijun Xu, Ya Xiao. Study on the correlation between the severity of obesity combined with gastroesophageal reflux disease patients and their anxiety, depression and nutritional status [J]. Chinese Journal of Digestion and Medical Imageology(Electronic Edition), 2024, 14(04): 360-364.
[9]	Jing Zhang, Yibing Bai, Yaoliang Lai, Yong Liu, Yuanyuan He, Min Su. The different results in side-lying or supine position on high-resolution esophageal pressure in patients with gastroesophageal reflux disease [J]. Chinese Journal of Gastroesophageal Reflux Disease(Electronic Edition), 2024, 11(03): 115-120.
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[11]	Li Hua, Weidong Zhong, Gen Hu, Liying Zhang, Guoyi Shao. Study on the psychological state of patients with gastroesophageal reflux disease before and after surgery [J]. Chinese Journal of Gastroesophageal Reflux Disease(Electronic Edition), 2024, 11(03): 126-129.
[12]	Ming Wen, Li Zhang, Fang Xie, Aili Aikebaier, Abudureyimu Kelimu. Establishment of clinical model for predicting the risk of atrial fibrillation with gastroesophageal reflux disease [J]. Chinese Journal of Gastroesophageal Reflux Disease(Electronic Edition), 2024, 11(03): 130-136.
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