[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-433047-105":59,"doc-detail-433047-en":134},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":127,"head_meta":129,"extra_data":131,"updated_unix":133},105,"en","pnpla3-and-tm6sf2-exacerbate-the-impact-of-alcohol-and-metabolic-dysfunction-on-liver-fibrosis","PNPLA3 and TM6SF2 exacerbate the impact of alcohol and metabolic dysfunction on liver fibrosis","","Genetic predisposition and lifestyle factors drive steatotic liver disease (SLD) risk, but the clinical importance of how genetic variants interact with alcohol use and metabolic dysfunction for fibrosis progression is not fully defined. Using two cohorts, multivariable regression with interaction terms tested PNPLA3 and TM6SF2 with alcohol intake and metabolic measures (BMI, insulin resistance) against liver stiffness. Results show gene-environment effects that amplify fibrosis risk rather than independent genetic determinants, supporting tailored patient counselling and risk stratification.",{"@graph":69,"@context":126},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/pnpla3-and-tm6sf2-exacerbate-the-impact-of-alcohol-and-metabolic-dysfunction-on-liver-fibrosis/433047/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/pnpla3-and-tm6sf2-exacerbate-the-impact-of-alcohol-and-metabolic-dysfunction-on-liver-fibrosis/433047.png","ImageObject",300,407,{"name":92,"@type":93},"Mafia Boss","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-29","2026-09-29",true,{"@type":102,"interactionType":103,"userInteractionCount":52},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118,122],{"name":109,"@type":110,"acceptedAnswer":111},"What was the main objective of the study?","Question",{"text":112,"@type":113},"To determine the clinical relevance of interaction between genetic variants (especially PNPLA3 and TM6SF2), metabolic dysfunction, and alcohol intake on liver fibrosis severity in SLD-related populations.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"Which study cohorts and measurements were used?",{"text":117,"@type":113},"Two cohorts were analyzed: tertiary liver care (N=1,554) and an at-risk SLD group (N=1,728). Liver fibrosis severity was assessed by liver stiffness measurement (LSM), while metabolic dysfunction used HOMA-IR and BMI and alcohol intake was evaluated as an exposure.",{"name":119,"@type":110,"acceptedAnswer":120},"How did PNPLA3 and TM6SF2 affect fibrosis risk?",{"text":121,"@type":113},"When interaction terms were included, genetic variants no longer acted as independent determinants. Instead, PNPLA3 potentiated associations between metabolic dysfunction and severe alcohol consumption with LSM, and TM6SF2 amplified effects of BMI and severe alcohol consumption in the tertiary-care cohort.",{"name":123,"@type":110,"acceptedAnswer":124},"What are the implications for patient management?",{"text":125,"@type":113},"The findings indicate that gene-environment interactions should inform patient counselling and risk stratification, because fibrosis progression reflects combined environmental risk factors (obesity, insulin resistance, alcohol) and genetic susceptibility.","https://schema.org",{"og:url":83,"og:type":128,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":130,"canonical":83},"index,follow",{"doc_id":132,"site_id":62},433047,1790694190,{"code":4,"msg":5,"data":135},{"doc_id":132,"user_id":136,"nickname":92,"user_avatar":137,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":138,"file_id":139,"file_url":140,"file_type":141,"file_size":142,"view_count":52,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":143,"language":144,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":145,"faqs":146,"seo_title":147,"seo_description":67,"update_tm":148,"read_time":41,"preview_page_count":4},962090760730,"https://ap-avatar.wpscdn.com/davatar_9964176cb1d06d4a9deccf72a44ae3dc","Research article  \nPNPLA3 and TM6SF2 exacerbate the impact of alcohol and metabolic dysfunction on liver fibrosis  \nAuthors  \nSophie Gensluckner, Helle Lindholm Schnefeld, Jan Embacher,…, Elmar Aigner, Maja Thiele, Georg Semmler‡  \nCorrespondence  \n[maja.thiele@rsyd.dk](maja.thiele@rsyd.dk) (M. Thiele), [georg.semmler@meduniwien.ac.at](georg.semmler@meduniwien.ac.at) (G. Semmler).  \nGraphical abstract  \n\n|  | How do genetic variants modify the association between metabolic\u003Cbr>dysfunction, alcohol and liver fibrosis? |  |\n| --- | --- | --- |\n|  |  |  |\n| Methods Tertiary-care cohort\u003Cbr>N = 1,554 (Austria) At-risk cohort N = 1,728 (Denmark)\u003Cbr>\u003Cbr>Exposures\u003Cbr>Genetic variants PNPLA3 + TM6SF2\u003Cbr>Alcohol\u003Cbr>Metabolic dysfunction (BMI, insulin resistance)\u003Cbr>|  |  |\n\n\n| PNPLA3 and TM6SF2 potentiate the risk of liver fibrosis associated with alcohol & metabolic dysfunction |  |\n| --- | --- |\n|  |  |\n| \u003Cbr>PNPLA3 x\u003Cbr>TM6SF2 x\u003Cbr>\u003Cbr>\u003Cbr>*Only in Tertiary-care cohort |  |\n\nAbsolute risk difference  \nHighlights:  \n• Fibrosis in steatotic liver disease is mediated by environmental risk factors and genetic predisposition (PNPLA3 and TM6SF2).  \n• Genetic variants amplify the effects of obesity, insulin resistance, and alcohol use, synergistically increasing fibrosis risk.  \n• These gene-environment interactions should be considered for patient counselling and risk stratification.  \nImpact and implications:  \nOur findings indicate that fibrosis progression in steatotic liver disease is mediated by an interaction of environmental risk factors (obesity, insulin resistance, alcohol consumption) and genetic risk variants, such as PNPLA3 and TM6SF2 , but not by genetic variants alone. This highlights the importance of acknowledging these gene–environment interactions for patient counselling and risk stratification.  \n[https://doi.org/10.1016/j.jhepr.2025.101649](https://doi.org/10.1016/j.jhepr.2025.101649)  \n© 2025 The Author(s) . Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL) . This is an open access article under the CC BY license ([http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/)). JHEP Reports, 2026, 8, 1–11  \nResearch article  \nPNPLA3 and TM6SF2 exacerbate the impact of alcohol and  \nmetabolic dysfunction on liver fibrosisq  \nSophie Gensluckner1 ,†, Helle Lindholm Schnefeld2 ,3 ,†, Jan Embacher1 ,4 ,5 , Camilla Dalby Hansen2 ,3 , Lorenz Balcar4 ,5 , Katrine Tholstrup Bech2 ,3 , Paul Thöne4 ,5 , Nikolaj Torp2 ,3 , Bernhard Wernly1 , Laura Maarit Pikkupeura6 , Stephan Zandanell1 , Christian Datz7 , Michael Strasser1 , Mads Israelsen2 ,3 , Mattias Mandorfer4 ,5 , Torben Hansen6 , Aleksander Krag2 ,3 , Elmar Aigner1 , Maja Thiele2 ,3 ,* ,‡, Georg Semmler2 ,3 ,4 ,5 ,* ,‡  \nJHEP Reports 2026. vol. 8 | 1–11  \nBackground & Aims: Genetic predisposition (especially variants in PNPLA3 and TM6SF2), metabolic dysfunction, and alcohol consumption are established risk factors for steatotic liver disease (SLD) and progression of fibrosis. However, the clinical relevance of their interaction and its implications for patient management remain unclear.  \nMethods: We cross-sectionally analyzed data from two cohorts: patients referred to tertiary liver care (N = 1,554) and individuals at risk for SLD (N = 1,728) . Multivariable regression models with and without interaction terms were used to assess the independent and interactive effects of genetic risk variants, metabolic dysfunction (HOMA-IR, BMI), and alcohol intake on liver fibrosis severity as assessed by liver stiffness measurement (LSM) .  \nResults: Mean age was 52 and 56 years in the Tertiary-care cohort and the At-risk cohort, respectively. Most participants were male, 23% and 53% suffered from obesity, and 39% and 58% were categorized as insulin resistant, respectively. Median LSM was 5.5 kPa and 4.7 kPa, with 21% and 9.6% having LSM 8 kPa, respectively. In total, 48% and 44% carried at least one PNPLA3 G-alle","cbCaibCcGyMSm2ft","https://ap.wps.com/l/cbCaibCcGyMSm2ft","pdf",1254407,12,"English","# Background & Aims\n# Methods\n# Results\n# Conclusions\n# Introduction","[{\"question\":\"What was the main objective of the study?\",\"answer\":\"To determine the clinical relevance of interaction between genetic variants (especially PNPLA3 and TM6SF2), metabolic dysfunction, and alcohol intake on liver fibrosis severity in SLD-related populations.\"},{\"question\":\"Which study cohorts and measurements were used?\",\"answer\":\"Two cohorts were analyzed: tertiary liver care (N=1,554) and an at-risk SLD group (N=1,728). Liver fibrosis severity was assessed by liver stiffness measurement (LSM), while metabolic dysfunction used HOMA-IR and BMI and alcohol intake was evaluated as an exposure.\"},{\"question\":\"How did PNPLA3 and TM6SF2 affect fibrosis risk?\",\"answer\":\"When interaction terms were included, genetic variants no longer acted as independent determinants. Instead, PNPLA3 potentiated associations between metabolic dysfunction and severe alcohol consumption with LSM, and TM6SF2 amplified effects of BMI and severe alcohol consumption in the tertiary-care cohort.\"},{\"question\":\"What are the implications for patient management?\",\"answer\":\"The findings indicate that gene-environment interactions should inform patient counselling and risk stratification, because fibrosis progression reflects combined environmental risk factors (obesity, insulin resistance, alcohol) and genetic susceptibility.\"}]","PNPLA3 and TM6SF2 exacerbate the impact of alcohol and metabolic dysfunction on liver fibrosis | PDF",1790662453]