{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T15:33:25Z","timestamp":1789140805176,"version":"build-2803163510"},"reference-count":34,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2022,10,21]],"date-time":"2022-10-21T00:00:00Z","timestamp":1666310400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Aims\/hypothesis: 20\u201380% of Nonalcoholic Fatty Liver Disease (NAFLD) have been observed to have dyslipidemia. Nevertheless, the probable mechanism of dyslipidemia\u2019s effect on NAFLD remains unclear. Mendelian randomization (MR) was utilized to investigate the relationship between lipids, inflammatory factors, and NAFLD; and also, to determine the proportion mediated by interleukin-17(IL-17) and interleukin-1\u03b2(IL-1\u03b2) for the effect between lipids and NAFLD. Methods: Summary statistics of traits were obtained from the latest and largest genome-wide association study (GWAS). The UK Biobank provided a summary of lipid statistics, which comprised up to 500,000 participants of European descent. And NAFLD GWAS summary statistics were obtained from the FinnGen Biobank which included a total sample size of 218,792 participants of European ancestry. In order to gain an overall picture of how lipids affect NAFLD, MR with two samples was carried out. Multivariable MR determined lipids direct effects on NAFLD after adjusting for inflammatory factors, namely IL-1\u03b2, interleukin-6(IL-6), interleukin-16(IL-16), IL-17, and interleukin-18(IL-18); those lipids comprise HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), triglycerides (TGs), apolipoprotein A1 (ApoA1), and apolipoprotein B (ApoB). For the purpose of determining the MR impact, an inverse variance weighted (IVW) meta-analysis of each Wald Ratio was carried out, while other methods were also performed for sensitivity analysis. Results: We discovered a positive association between genetically predicted TGs levels and a 45.5% elevated risk of NAFLD, while genetically predicted IL-1\u03b2 [(IVW: OR 1.315 (1.060\u20131.630), p = 0.012) and IL-17 [(IVW: OR 1.468 (1.035\u20132.082), p = 0.032] were positively associated with 31.5% and 46.8% increased risk of NAFLD, respectively. Moreover, TG was positively associated with 10.5% increased risk of IL-1\u03b2 and 17.3% increased risk of IL-17. The proportion mediated by IL-17 and IL-1\u03b2 respectively and both was 2.6%, 3.1%, 14.1%. Conclusion: Genetically predicted TGs, IL-1\u03b2, and IL-17 were positively associated with increased risk of NAFLD, with evidence that IL-1\u03b2 and IL-17 mediated TGs effect upon NAFLD risk. It indicated that early diet management, weight management, lipid-lowering and anti-inflammatory treatment should be carried out for patients with hyperlipidemia to prevent the NAFLD.<\/jats:p>","DOI":"10.3390\/nu14204434","type":"journal-article","created":{"date-parts":[[2022,10,24]],"date-time":"2022-10-24T08:19:06Z","timestamp":1666599546000},"page":"4434","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Role of Inflammatory Factors in Mediating the Effect of Lipids on Nonalcoholic Fatty Liver Disease: A Two-Step, Multivariable Mendelian Randomization Study"],"prefix":"10.3390","volume":"14","author":[{"given":"Junhong","family":"Chen","sequence":"first","affiliation":[{"name":"Hepatopancreatobiliary Department, General Surgery Center, First Hospital of Jilin University, Changchun 130061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Zhou","sequence":"additional","affiliation":[{"name":"Hepatopancreatobiliary Department, General Surgery Center, First Hospital of Jilin University, Changchun 130061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hengwei","family":"Jin","sequence":"additional","affiliation":[{"name":"Hepatopancreatobiliary Department, General Surgery Center, First Hospital of Jilin University, Changchun 130061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8323-5021","authenticated-orcid":false,"given":"Kai","family":"Liu","sequence":"additional","affiliation":[{"name":"Hepatopancreatobiliary Department, General Surgery Center, First Hospital of Jilin University, Changchun 130061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"itc65","DOI":"10.7326\/AITC201811060","article-title":"Nonalcoholic Fatty Liver Disease","volume":"169","author":"Wang","year":"2018","journal-title":"Ann. Intern. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2263","DOI":"10.1001\/jama.2015.5370","article-title":"Nonalcoholic fatty liver disease: A systematic review","volume":"313","author":"Rinella","year":"2015","journal-title":"JAMA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1055\/a-1862-9088","article-title":"Nonalcoholic Fatty Liver Disease: Current Global Burden","volume":"42","author":"Cabezas","year":"2022","journal-title":"Semin. Liver Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1161\/HYPERTENSIONAHA.122.17982","article-title":"Nonalcoholic Fatty Liver Disease and Cardiovascular Disease: A Review of Shared Cardiometabolic Risk Factors","volume":"79","author":"Peng","year":"2022","journal-title":"Hypertension"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1590\/S0004-28032012000100015","article-title":"Metabolic syndrome and risk factors for non-alcoholic fatty liver disease","volume":"49","author":"Souza","year":"2012","journal-title":"Arq. Gastroenterol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"880298","DOI":"10.3389\/fimmu.2022.880298","article-title":"Association of Inflammatory Cytokines With Non-Alcoholic Fatty Liver Disease","volume":"13","author":"Duan","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"k601","DOI":"10.1136\/bmj.k601","article-title":"Reading Mendelian randomisation studies: A guide, glossary, and checklist for clinicians","volume":"362","author":"Davies","year":"2018","journal-title":"BMJ"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1093\/ije\/dyr036","article-title":"Avoiding bias from weak instruments in Mendelian randomization studies","volume":"40","author":"Burgess","year":"2011","journal-title":"Int. J. Epidemiol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Richardson, T.G., Sanderson, E., Palmer, T.M., Ala-Korpela, M., Ference, B.A., Smith, G.D., and Holmes, M.V. (2020). Evaluating the relationship between circulating lipoprotein lipids and apolipoproteins with risk of coronary heart disease: A multivariable Mendelian randomisation analysis. PLoS Med., 17.","DOI":"10.1371\/journal.pmed.1003062"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1038\/s41592-018-0245-2","article-title":"The UK Biobank","volume":"15","author":"Rusk","year":"2018","journal-title":"Nat. Methods"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1038\/s42255-020-00287-2","article-title":"Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals","volume":"2","author":"Folkersen","year":"2020","journal-title":"Nat. Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.ajhg.2016.11.007","article-title":"Genome-wide Association Study Identifies 27 Loci Influencing Concentrations of Circulating Cytokines and Growth Factors","volume":"100","author":"Havulinna","year":"2017","journal-title":"Am. J. Hum. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2816","DOI":"10.1093\/eurheartj\/ehab291","article-title":"Atrial fibrillation and kidney function: A bidirectional Mendelian randomization study","volume":"42","author":"Park","year":"2021","journal-title":"Eur. Heart J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1007\/s10654-021-00757-1","article-title":"Mendelian randomisation for mediation analysis: Current methods and challenges for implementation","volume":"36","author":"Carter","year":"2021","journal-title":"Eur. J. Epidemiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2167","DOI":"10.1093\/rheumatology\/keab654","article-title":"The impact of education inequality on rheumatoid arthritis risk is mediated by smoking and body mass index: Mendelian randomization study","volume":"61","author":"Zhao","year":"2022","journal-title":"Rheumatology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1161\/CIRCRESAHA.116.304846","article-title":"Remnant cholesterol, low-density lipoprotein cholesterol, and blood pressure as mediators from obesity to ischemic heart disease","volume":"116","author":"Varbo","year":"2015","journal-title":"Circ. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1038\/nrcardio.2017.78","article-title":"Mendelian randomization in cardiometabolic disease: Challenges in evaluating causality","volume":"14","author":"Holmes","year":"2017","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1985","DOI":"10.1093\/ije\/dyx102","article-title":"Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption","volume":"46","author":"Hartwig","year":"2017","journal-title":"Int. J. Epidemiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1002\/gepi.21965","article-title":"Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator","volume":"40","author":"Bowden","year":"2016","journal-title":"Genet. Epidemiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1093\/ije\/dyv080","article-title":"Mendelian randomization with invalid instruments: Effect estimation and bias detection through Egger regression","volume":"44","author":"Bowden","year":"2015","journal-title":"Int. J. Epidemiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1742","DOI":"10.1214\/19-AOS1866","article-title":"Statistical inference in two-sample summary-data Mendelian randomization using robust adjusted profile score","volume":"48","author":"Zhao","year":"2020","journal-title":"Ann. Stat."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1001\/jamapsychiatry.2018.4175","article-title":"Assessment of Bidirectional Relationships Between Physical Activity and Depression Among Adults: A 2-Sample Mendelian Randomization Study","volume":"76","author":"Choi","year":"2019","journal-title":"JAMA Psychiatry"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1007\/s10654-017-0255-x","article-title":"Interpreting findings from Mendelian randomization using the MR-Egger method","volume":"32","author":"Burgess","year":"2017","journal-title":"Eur. J. Epidemiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1111\/j.1743-6109.2010.01991.x","article-title":"Testosterone and metabolic syndrome: A meta-analysis study","volume":"8","author":"Corona","year":"2011","journal-title":"J. Sex. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1016\/0016-5085(88)90183-7","article-title":"Alcohollike liver disease in nonalcoholics. A clinical and histologic comparison with alcohol-induced liver injury","volume":"95","author":"Diehl","year":"1988","journal-title":"Gastroenterology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1007\/s00535-013-0758-5","article-title":"Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease","volume":"48","author":"Kawano","year":"2013","journal-title":"J. Gastroenterol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.gtc.2016.07.003","article-title":"Nonalcoholic Fatty Liver Disease: Pathophysiology and Management","volume":"45","author":"Carr","year":"2016","journal-title":"Gastroenterol. Clin. N. Am."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1097\/TP.0000000000002480","article-title":"Nonalcoholic Fatty Liver Disease: Basic Pathogenetic Mechanisms in the Progression From NAFLD to NASH","volume":"103","author":"Pierantonelli","year":"2019","journal-title":"Transplantation"},{"key":"ref_29","first-page":"1","article-title":"Triglyceride Metabolism in the Liver","volume":"8","author":"Cohen","year":"2017","journal-title":"Compr. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1038\/s41591-018-0104-9","article-title":"Mechanisms of NAFLD development and therapeutic strategies","volume":"24","author":"Friedman","year":"2018","journal-title":"Nat. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.cytogfr.2011.10.001","article-title":"Understanding the mechanism of IL-1\u03b2 secretion","volume":"22","author":"Brough","year":"2011","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_32","first-page":"cm2","article-title":"Interleukin-1beta (IL-1beta) processing pathway","volume":"3","author":"Weber","year":"2010","journal-title":"Sci. Signal."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/j.it.2017.01.006","article-title":"IL-17 Signaling: The Yin and the Yang","volume":"38","author":"Amatya","year":"2017","journal-title":"Trends Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.cellimm.2018.09.001","article-title":"IL-17 and limits of success","volume":"339","author":"Omidian","year":"2019","journal-title":"Cell. Immunol."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/14\/20\/4434\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:00:31Z","timestamp":1760144431000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/14\/20\/4434"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,21]]},"references-count":34,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["nu14204434"],"URL":"https:\/\/doi.org\/10.3390\/nu14204434","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,21]]}}}