التفاصيل البيبلوغرافية
| العنوان: |
Exome-Wide Association Study on Alanine Aminotransferase Identifies Sequence Variants in the GPAM and APOE Associated With Fatty Liver Disease |
| المؤلفون: |
Jamialahmadi, Oveis, Mancina, Rosellina Margherita, Ciociola, Ester, Tavaglione, Federica, Luukkonen, Panu K., Baselli, Guido, Malvestiti, Francesco, Thuillier, Dorothee, Raverdy, Violeta, Mannisto, Ville, Pipitone, Rosaria Maria, Pennisi, Grazia, Prati, Daniele, Spagnuolo, Rocco, Petta, Salvatore, Pihlajamaki, Jussi, Pattou, Francois, Yki-Järvinen, Hannele, Valenti, Luca, Romeo, Stefano |
| المساهمون: |
HUS Internal Medicine and Rehabilitation, Department of Medicine, Department of Biochemistry and Developmental Biology |
| بيانات النشر: |
W B SAUNDERS CO-ELSEVIER INC |
| سنة النشر: |
2021 |
| المجموعة: |
Helsingfors Universitet: HELDA – Helsingin yliopiston digitaalinen arkisto |
| مصطلحات موضوعية: |
Nonalcoholic Fatty Liver Disease, NAFLD, Transaminase, Metabolic Associated Fatty Liver Disease, MAFLD, RNA-SEQ DATA, ENRICHMENT ANALYSIS, CONFERS SUSCEPTIBILITY, INSULIN-RESISTANCE, HEPATIC STEATOSIS, X-RECEPTOR, GENE, GENOME, PATHOGENICITY, MUTATIONS, 3121 General medicine, internal medicine and other clinical medicine |
| الوصف: |
BACKGROUND & AIMS: Fatty liver disease (FLD) is a growing epidemic that is expected to be the leading cause of end-stage liver disease within the next decade. Both environmental and genetic factors contribute to the susceptibility of FLD. Several genetic variants contributing to FLD have been identified in exome-wide association studies. However, there is still a missing hereditability indicating that other genetic variants are yet to be discovered. METHODS: To find genes involved in FLD, we first examined the association of missense and nonsense variants with alanine amino transferase at an exome-wide level in 425,671 participants from the UK Biobank. We then validated genetic variants with liver fat content in 8930 participants in whom liver fat measurement was available, and replicated 2 genetic variants in 3 independent cohorts comprising 2621 individuals with available liver biopsy. RESULTS: We identified 190 genetic variants independently associated with alanine aminotransferase after correcting for multiple testing with Bonferroni method. The majority of these variants were not previously associated with this trait. Among those associated, there was a striking enrichment of genetic variants influencing lipid metabolism. We identified the variants rs2792751 in GPAM/GPAT1, the gene encoding glycerol-3phosphate acyltransferase, mitochondrial, and rs429358 in APOE, the gene encoding apolipoprotein E, as robustly associated with liver fat content and liver disease after adjusting for multiple testing. Both genes affect lipid metabolism in the liver. CONCLUSIONS: We identified 2 novel genetic variants in GPAM and APOE that are robustly associated with steatosis and liver damage. These findings may help to better elucidate the genetic susceptibility to FLD onset and progression. ; Peer reviewed |
| نوع الوثيقة: |
article in journal/newspaper |
| وصف الملف: |
application/pdf |
| اللغة: |
English |
| العلاقة: |
Stefano Romeo was supported by project grants from the Swedish Research Council (Vetenskapsradet [VR], 2016-01527), the Swedish state under the agreement between the Swedish government and the county councils (the ALF agreement) (SU 2018-04276), the Swedish Diabetes Foundation (DIA 2017-205), the Swedish Heart-Lung Foundation (20120533), the Wallenberg Academy Fellow from the Knut and Alice Wallenberg Foundation (KAW 2017.0203), the Astra Zeneca Agreement for Research, Grant SSF ITM17-0384 Swedish Foundation for Strategic Research, and Novo Nordisk Project Grants in Endocrinology & Metabolism -Nordic Region 2020. Luca Valenti was supported by the following projects grants: the MyFirst Grant AIRC n.16888, Ricerca Finalizzata Ministero della Salute RF-2016-02364358, Ricerca Corrente Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, the European Union Programme Horizon 2020 (under grant agreement no. 777377) for the project LITMUS "Liver Investigation: Testing Marker Utility in Steatohepatitis", Fondazione IRCCS Ca' Granda "Liver BIBLE" PR-0391, and Fondazione IRCCS Ca' Granda core COVID-19 Biobank (RC100017A). Kuopio Obesity Surgery Study (PI JP) was supported by the Finnish Diabetes Research Foundation, Kuopio University Hospital Project grant (EVO/VTR grants 2005-2020), and the Academy of Finland grant (contract No 138006). Panu K. Luukkonen was supported by the Novo Nordisk, Sigrid Juselius, and Instrumentarium Science Foundations.; Jamialahmadi , O , Mancina , R M , Ciociola , E , Tavaglione , F , Luukkonen , P K , Baselli , G , Malvestiti , F , Thuillier , D , Raverdy , V , Mannisto , V , Pipitone , R M , Pennisi , G , Prati , D , Spagnuolo , R , Petta , S , Pihlajamaki , J , Pattou , F , Yki-Järvinen , H , Valenti , L & Romeo , S 2021 , ' Exome-Wide Association Study on Alanine Aminotransferase Identifies Sequence Variants in the GPAM and APOE Associated With Fatty Liver Disease ' , Gastroenterology , vol. 160 , no. 5 , pp. 1634-+ . https://doi.org/10.1053/j.gastro.2020.12.023Test; bc3da21d-731f-44d8-928b-3b7185907ee6; http://hdl.handle.net/10138/331711Test; 000637453900031 |
| الإتاحة: |
http://hdl.handle.net/10138/331711Test |
| حقوق: |
cc_by ; openAccess ; info:eu-repo/semantics/openAccess |
| رقم الانضمام: |
edsbas.7833D5E4 |
| قاعدة البيانات: |
BASE |
