孟德尔随机化分析胆石症与原发性硬化性胆管炎因果关系研究*

doi:10.3969/j.issn.1672-5069.2024.06.016

Abstract

Abstract: Objective The aim of this study was to explore causal relationship between cholelithiasis and primary sclerosing cholangitis (PSC). Methods Materials of patients with PSC were retrieved from International PSC Genetics Research Group (IPSCSG) and Finnish Biobank (FinnGen R10), and Mendelian randomization (MR) analysis was conducted by integrating summary data of published genome-wide association studies. Genetic instruments closely associated with cholelithiasis were extracted, and then causal relationship between cholelithiasis and PSC was estimated by using inverse-variance weighted (IVW) and weighted median (WM) methods. Finally, reverse MR was applied to assess whether PSC could lead to altered risk of cholelithiasis. Results Forward MR analysis found that genetic susceptibility to cholelithiasis could increase the risk of PSC (OR_IVW: 1.379, 95%CI: 1.052-1.807, P=0.020; OR_WM: 1.450, 95%CI: 1.014-2.074, P=0.042), and this result was validated in the FinnGen (OR_IVW: 1.989, 95%CI: 1.517-2.610, P=6.76×10^-7; OR_WM: 1.931, 95%CI: 1.302-2.865, P=0.001); reverse MR analysis found that genetically-predicted PSC did not alter the risk of cholelithiasis (OR_IVW: 1.008, 95%CI: 0.991-1.024, P=0.356). Conclusion This MR study find cholelithiasis is an important risk factor for occurrence of PSC, and the reverse causality is not established.

Key words: Primary sclerosing cholangitis, Cholelithiasis, Mendelian randomization, Etiological research

Gao Menghan, Chen Lanlan, Zhang Yuning. Mendelian randomization unveils causal relationship between cholelithiasis and primary sclerosing cholangitis[J]. Journal of Practical Hepatology, 2024, 27(6): 860-865.

References

[1] Dyson J K, Beuers U, Jones D E J, et al. Primary sclerosing cholangitis. Lancet, 2018, 391(10139): 2547-2559.
[2] Hasegawa S, Yoneda M, Kurita Y, et al. Cholestatic liver disease: current treatment strategies and new therapeutic agents. Drugs, 2021, 81(10): 1181-1192.
[3] Visseren T, Erler N S, Polak W G, et al. Recurrence of primary sclerosing cholangitis after liver transplantation-analysing the European Liver Transplant Registry and beyond. Transpl Int, 2021, 34(8): 1455-1467.
[4] Lammert F, Gurusamy K, Ko C W, et al. Gallstones. Nat Rev Dis Primers, 2016, 2: 16024.
[5] Razumilava N, Gores G J. Cholangiocarcinoma. The Lancet, 2014, 383(9935): 2168-2179.
[6] Said K, Glaumann H, Bergquist A. Gallbladder disease in patients with primary sclerosing cholangitis. J Hepatol, 2008, 48(4): 598-605.
[7] Davey Smith G, Hemani G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet, 2014, 23(R1): R89-R98.
[8] Emdin C A, Khera A V, Kathiresan S. Mendelian randomization. JAMA, 2017, 318(19): 1925-1926.
[9] Ji S G, Juran B D, Mucha S, et al. Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease. Nat Genet, 2017, 49(2): 269-273.
[10] Sakaue S, Kanai M, Tanigawa Y, et al. A cross-population atlas of genetic associations for 220 human phenotypes. Nat Genet, 2021, 53(10): 1415-1424.
[11] Chen L, Yang H, Li H, et al. Insights into modifiable risk factors of cholelithiasis: a Mendelian randomization study. Hepatology, 2022, 75(4): 785-796.
[12] Hemani G, Tilling K, Davey Smith G. Orienting the causal relationship between imprecisely measured traits using GWAS summary data. PLoS Genet, 2017, 13(11): e1007081.
[13] Burgess S, Thompson S G. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol, 2017, 32(5): 377-389.
[14] Bowden J, Davey Smith G, Haycock P C, et al. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol, 2016, 40(4): 304-314.
[15] Verbanck M, Chen C Y, Neale B, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet, 2018, 50(5): 693-698.
[16] Burgess S, Bowden J, Fall T, et al. Sensitivity analyses for robust causal inference from Mendelian randomization analyses with multiple genetic variants. Epidemiology, 2017, 28(1): 30-42.
[17] Hemani G, Zheng J, Elsworth B, et al. The MR-Base platform supports systematic causal inference across the human phenome. Elife, 2018, 7:e34408.
[18] Peiseler M, Tacke F. Bile duct-associated macrophages enter the spotlight in inflammatory cholestatic liver disease. Hepatology, 2024, 79(2): 257-260.
[19] Lazaridis K N, Larusso N F. Primary sclerosing cholangitis. N Engl J Med, 2016, 375(12): 1161-1170.
[20] Hov J R, Karlsen T H. The microbiota and the gut-liver axis in primary sclerosing cholangitis. Nat Rev Gastroenterol Hepatol, 2023, 20(3): 135-154.
[21] Christina V, Carl J, Annika B. Treatment of cholangiocarcinoma in patients with primary sclerosing cholangitis: a comprehensive review. eGastroenterology, 2024, 2(1): e100045.
[22] González M I, Vannan D T, Eksteen B, et al. Mast cells in immune-mediated cholangitis and cholangiocarcinoma. Cells, 2022, 11(3):375.
[23] Weiss G A, Hennet T. Mechanisms and consequences of intestinal dysbiosis. Cell Mol Life Sci, 2017, 74(16): 2959-2977.
[24] Di Ciaula A, Wang D Q, Portincasa P. Cholesterol cholelithiasis: part of a systemic metabolic disease, prone to primary prevention. Expert Rev Gastroenterol Hepatol, 2019, 13(2): 157-171.
[25] Yuan S, Gill D, Giovannucci E L, et al. Obesity, type 2 diabetes, lifestyle factors, and risk of gallstone disease: a Mendelian randomization investigation. Clin Gastroenterol Hepatol, 2022, 20(3): e529-e537.
[26] Ebert E C, Nagar M, Hagspiel K D. Gastrointestinal and hepatic complications of sickle cell disease. Clin Gastroenterol Hepatol, 2010, 8(6): 483-489.
[27] Smith G D, Ebrahim S. 'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol, 2003, 32(1): 1-22.
[28] Carter A R, Anderson E L. Correct illustration of assumptions in Mendelian randomization. Int J Epidemiol, 2024, 53(2):dyae050.
[29] Bowden J, Holmes M V. Meta-analysis and Mendelian randomization: a review. Res Synth Methods, 2019, 10(4): 486-496.
[30] 郭银燕, 岳枝, 盖晓冬, 等. 自身免疫性肝炎-原发性胆汁性胆管炎重叠综合征患者临床和肝组织病理学特征分析. 实用肝脏病杂志, 2023, 26(3): 372-375.
[31] 陈慧婷, 周永健. 慢性胆汁淤积性肝病患者肠-肝轴功能变化研究进展. 实用肝脏病杂志, 2023, 26(3): 305-307.
[32] Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol, 2015, 44(2): 512-525.

Mendelian randomization unveils causal relationship between cholelithiasis and primary sclerosing cholangitis

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