基于孟德尔随机化探讨血清代谢组学与病毒性肝炎的关联-现代医学

基于孟德尔随机化探讨血清代谢组学与病毒性肝炎的关联

单位：1. 山西医科大学附属运城市中心医院感染性疾病科, 山西运城 044000;
2. 山西医科大学附属运城市中心医院急诊医学科, 山西运城 044000

分类号：R512.6

出版年·卷·期（页码）：2024·52·第十期（1498-1507）

摘要：

目的： 病毒性肝炎(VH)可能导致肝功能严重受损。而血清代谢物与VH的关系尚未明确。本研究旨在利用孟德尔随机化(MR)方法探索血清代谢物与VH之间的潜在关联。方法： 利用逆方差加权法(IVW)、加权中位数法、MR-Egger回归法、加权模式以及简单模式5种MR分析方法，对全基因组关联研究(GWAS) Catalog数据库中的血清代谢组数据和FinnGen R 10版本中的VH GWAS数据进行两样本双向MR分析。借助Power统计值来评估当前MR结果的统计功效，采用Cochran's Q检验、MR-Egger回归、MR-PRESSO、Steiger检验和留一法来进行敏感性分析。对正向MR分析中发现与VH有因果关系的血清代谢物进行了单独的反向MR分析。对具有显著因果关系的代谢物进行通路富集分析。结果： 在进行错误发现率(FDR)矫正后，根据IVW结果共发现8种与VH发生风险相关的血清代谢物。其中谷氨酰胺、十四酸盐、缬氨酸及4-甲基-2-氧代戊酸是VH发生的潜在保护性代谢物；而肌醇、胆酸盐、吡哆醇、γ-生育酚与VH存在显著因果关系。同时VH十四酸盐的水平显著升高。所有的结果均不存在异质性及水平多效性。此外，抗坏血酸和丙二酸代谢以及维生素B6通路是代谢物与VH关系的主要作用通路。结论： 血清代谢物与VH存在显著关联，通过对血清代谢物的监测与调控，或许可以对VH进行预防、监测和治疗。

Objective: Viral hepatitis(VH) may lead to severe impairment of liver function. And the relationship between serum metabolites and VH has not been clarified. The aim of this study is to explore the potential association between serum metabolites and VH using Mendelian randomization(MR). Methods: A two-sample bidirectional MR analysis was conducted using serum metabolites data from the Genome-Wide Association Study Catalog(GWAS Catalog) and VH data from the FinnGen R 10. 5 MR methods were applied: inverse variance weighting(IVW), weighted median, MR-Egger regression, weighted mode, and simple mode. The statistical power of the MR results was evaluated using power statistics. Sensitivity analyses were conducted with Cochran's Q test, MR-Egger regression, MR-PRESSO, Steiger's test, and the leave-one-out method. Separate reverse MR analyses were conducted on serum metabolites that demonstrated a causal association with VH in the forward MR analysis. Finally, a pathway enrichment analysis was performed for metabolites with significant causal associations. Results: After applying false discovery rate(FDR) correction, eight serum metabolites were identified as being associated with the risk of VH based on IVW results. Glutamine, tetradecanoate, valine, and 4-methyl-2-oxovaleric acid were identified as potential protective metabolites against VH. In contrast, inositol, cholate, pyridoxine, and γ-tocopherol were significantly associated with an increased risk of VH. The level of tetradecanoate was also significantly elevated post-VH. All findings were free from heterogeneity and pleiotropy. Furthermore, ascorbate and malonate metabolism, as well as the vitamin B6 pathway, were identified as key metabolic pathways linking these metabolites to VH. Conclusion: Serum metabolites show a significant association with VH, suggesting that monitoring and regulating these metabolites could help in the prevention, diagnosis, and treatment of VH.

参考文献：

[1] NAGRA N,KOZAREK R A,BURMAN B E.Therapeutic advances in viral hepatitis A-E[J].Adv Ther,2022,39(4):1524-1552.
[2] LIOU J W,MANI H,YEN J H.Viral hepatitis,cholesterol metabolism,and cholesterol-lowering natural compounds[J].Int J Mol Sci,2022,23(7):3897.
[3] RIZZO G E M,CABIBBO G,CRAXÌ A.Hepatitis B virus-associated hepatocellular carcinoma[J].Viruses,2022,14(5):986.
[4] LEONI S,CASABIANCA A,BIAGIONI B,et al.Viral hepatitis:innovations and expectations[J].World J Gastroenterol,2022,28(5):517-531.
[5] LANINI S,USTIANOWSKI A,PISAPIA R,et al.Viral hepatitis:etiology,epidemiology,transmission,diagnostics,treatment,and prevention[J].Infect Dis Clin North Am,2019,33(4):1045-1062.
[6] CHEN Y,LU T,PETTERSSON-KYMMER U,et al.Genomic atlas of the plasma metabolome prioritizes metabolites implicated in human diseases[J].Nat Genet,2023,55(1):44-53.
[7] KETTUNEN J,DEMIRKAN A,WüRTZ P,et al.Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA[J].Nat Commun,2016,7:11122.
[8] HOLMES E,WILSON I D,NICHOLSON J K.Metabolic phenotyping in health and disease[J].Cell,2008,134(5):714-717.
[9] REŽEN T,ROZMAN D,KOVÁCS T,et al.The role of bile acids in carcinogenesis[J].Cell Mol Life Sci,2022,79(5):243.
[10] LOFTFIELD E,ROTHWELL J A,SINHA R,et al.Prospective investigation of serum metabolites,coffee drinking,liver cancer incidence,and liver disease mortality[J].J Natl Cancer Inst,2020,112(3):286-294.
[11] YU M,ZHOU C,TIAN D,et al.Molecular classification and clinical diagnosis of acute-on-chronic liver failure patients by serum metabolomics[J].J Pharm Biomed Anal,2021,198:114004.
[12] HAN J,HAN M L,XING H,et al.Tissue and serum metabolomic phenotyping for diagnosis and prognosis of hepatocellular carcinoma[J].Int J Cancer,2020,146(6):1741-1753.
[13] POMYEN Y,BUDHU A,CHAISAINGMONGKOL J,et al.Tumor metabolism and associated serum metabolites define prognostic subtypes of Asian hepatocellular carcinoma[J].Sci Rep,2021,11(1):12097.
[14] SAITO T,SUGIMOTO M,IGARASHI K,et al.Dynamics of serum metabolites in patients with chronic hepatitis C receiving pegylated interferon plus ribavirin:a metabolomics analysis[J].Metabolism,2013,62(11):1577-1586.
[15] ZUCCOLO L,HOLMES M V.Commentary:Mendelian randomization-inspired causal inference in the absence of genetic data[J].Int J Epidemiol,2017,46(3):962-965.
[16] DAVEY SMITH G,HEMANI G.Mendelian randomization:genetic anchors for causal inference in epidemiological studies[J].Hum Mol Genet,2014,23(R1):R89-98.
[17] 张亦舒,李晓宁,苗晨欣.睡眠障碍与卒中风险的因果关系:孟德尔随机化研究[J].现代医学,2023,51(11):1559-1565.
[18] 董静静,胡攀伟,章晓乐,等.偏头痛与子宫内膜异位症:两样本孟德尔随机化研究[J].现代医学,2023,51(11):1584-1589.
[19] BIRNEY E.Mendelian randomization[J].Cold Spring Harb Perspect Med,2022,12(4):a041302.
[20] SHIN S Y,FAUMAN E B,PETERSEN A K,et al.An atlas of genetic influences on human blood metabolites[J].Nat Genet,2014,46(6):543-550.
[21] YUN Z,GUO Z,LI X,et al.Genetically predicted 486 blood metabolites in relation to risk of colorectal cancer:a Mendelian randomization study[J].Cancer Med,2023,12(12):13784-13799.
[22] PIERCE B L,AHSAN H,VANDERWEELE T J.Power and instrument strength requirements for Mendelian randomization studies using multiple genetic variants[J].Int J Epidemiol,2011,40(3):740-752.
[23] BURGESS S,DUDBRIDGE F,THOMPSON S G.Combining information on multiple instrumental variables in Mendelian randomization:comparison of allele score and summarized data methods[J].Stat Med,2016,35(11):1880-1906.
[24] WANG S,ZHU H,PAN L,et al.Systemic inflammatory regulators and risk of acute-on-chronic liver failure:a bidirectional mendelian-randomization study[J].Front Cell Dev Biol,2023,11:1125233.
[25] RAN B,QIN J,WU Y,et al.Causal role of immune cells in chronic obstructive pulmonary disease:Mendelian randomization study[J].Expert Rev Clin Immunol,2024,20(4):413-421.
[26] LI P,WANG H,GUO L,et al.Association between gut microbiota and preeclampsia-eclampsia:a two-sample Mendelian randomization study[J].BMC Med,2022,20(1):443.
[27] 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[J].Nat Genet,2018,50(5):693-698.
[28] HEMANI G,TILLING K,DAVEY SMITH G.Orienting the causal relationship between imprecisely measured traits using GWAS summary data[J].PLoS Genet,2017,13(11):e1007081.
[29] BRION M J,SHAKHBAZOV K,VISSCHER P M.Calculating statistical power in Mendelian randomization studies[J].Int J Epidemiol,2013,42(5):1497-501.
[30] BIZZARRI M,MONTI N,PIOMBAROLO A,et al.Myo-Inositol and D-Chiro-Inositol as modulators of ovary steroidogenesis:a narrative review[J].Nutrients,2023,15(8):1875.
[31] FALKENBURGER B H,JENSEN J B,DICKSON E J,et al.Phosphoinositides:lipid regulators of membrane proteins[J].J Physiol,2010,588(Pt 17):3179-3185.
[32] MACFARLANE P M,DI FIORE J M.Myo-inositol effects on the developing respiratory neural control system[J].Adv Exp Med Biol,2018,1071:159-166.
[33] FIUME R,FAENZA I,SHETH B,et al.Nuclear phosphoinositides:their regulation and roles in nuclear functions[J].Int J Mol Sci,2019,20(12):2991.
[34] AWAD A,GASSAMA-DIAGNE A.PI3K/SHIP2/PTEN pathway in cell polarity and hepatitis C virus pathogenesis[J].World J Hepatol,2017,9(1):18-29.
[35] TROTARD M,LEPōRE-DOUARD C,RÉGEARD M,et al.Kinases required in hepatitis C virus entry and replication highlighted by small interference RNA screening[J].Faseb J,2009,23(11):3780-3789.
[36] YU Y,ZHANG L,LIU Q,et al.Endoplasmic reticulum stress preconditioning antagonizes low-density lipoprotein-induced inflammation in human mesangial cells through upregulation of XBP1 and suppression of the IRE1α/IKK/NF-κB pathway[J].Mol Med Rep,2015,11(3):2048-2054.
[37] NERONOV V A.Bile biochemical composition changes in patients with chronic viral hepatitis[J].Ter Arkh,2009,81(11):10-13.
[38] BADMUS O O,HILLHOUSE S A,ANDERSON C D,et al.Molecular mechanisms of metabolic associated fatty liver disease(MAFLD):functional analysis of lipid metabolism pathways[J].Clin Sci(Lond),2022,136(18):1347-1366.
[39] KRENKEL O,PUENGEL T,GOVAERE O,et al.Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis[J].Hepatology,2018,67(4):1270-1283.
[40] RAMZAN R,NAPIWOTZKI J,WEBER P,et al.Cholate disrupts regulatory functions of cytochrome c oxidase[J].Cells,2021,10(7):1579.
[41] COSTEIRA R,EVANGELISTA L,WILSON R,et al.Metabolomic biomarkers of habitual B vitamin intakes unveil novel differentially methylated positions in the human epigenome[J].Clin Epigenetics,2023,15(1):166.
[42] ABRAHAM A,KATTOOR A J,SALDEEN T,et al.Vitamin E and its anticancer effects[J].Crit Rev Food Sci Nutr,2019,59(17):2831-2838.
[43] WAGNER K H,KAMAL-ELDIN A,ELMADFA I.Gamma-tocopherol--an underestimated vitamin?[J].Ann Nutr Metab,2004,48(3):169-188.
[44] VON HERBAY A,STAHL W,NIEDERAU C,et al.Vitamin E improves the aminotransferase status of patients suffering from viral hepatitis C:a randomized,double-blind,placebo-controlled study[J].Free Radic Res,1997,27(6):599-605.
[45] GERNER P,POSSELT H G,KRAHL A,et al.Vitamin E treatment for children with chronic hepatitis B:a randomized placebo controlled trial[J].World J Gastroenterol,2008,14(47):7208-7213.
[46] BOUAYED J,BOHN T.Exogenous antioxidants--double-edged swords in cellular redox state:health beneficial effects at physiologic doses versus deleterious effects at high doses[J].Oxid Med Cell Longev,2010,3(4):228-237.
[47] JAKUBCZYK K,DEC K,KAŁDUŃSKA J,et al.Reactive oxygen species-sources,functions,oxidative damage[J].Pol Merkur Lekarski,2020,48(284):124-127.

服务与反馈：

【文章下载】【发表评论】【查看评论】【加入收藏】

提示：您还未登录，请登录！点此登录