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In this study, the influence of common and rare PON variants on both conditions was investigated. A total of 507 healthy weight individuals and 744 patients with obesity including 433 with histological liver assessment, were sequenced with single-molecule molecular inversion probes (smMIPs), allowing the identification of genetic contributions to obesity and MASLD-related liver features. Polymorphisms rs705379 and rs854552 in the PON1 gene displayed significant association with MASLD stage and fibrosis, respectively. Additionally, rare PON1 variants were strongly associated with obesity. This study thereby reinforces the genetic foundation of PON1 in obesity and various MASLD-related liver features, by extending previous findings from common variants to include rare variants. Additionally, rare and very rare variants in PON2 were discovered to be associated with MASLD-related hepatic fibrosis. Notably, we are the first to report an association between naturally occurring rare PON2 variants and MASLD-related liver fibrosis. Considering the critical role of liver fibrosis in MASLD outcome, PON2 emerges as a possible candidate for future research endeavors including exploration of biomarker potential.<\/jats:p>","DOI":"10.3390\/antiox13091051","type":"journal-article","created":{"date-parts":[[2024,8,29]],"date-time":"2024-08-29T11:12:13Z","timestamp":1724929933000},"page":"1051","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A Case\u2013Control Study Supports Genetic Contribution of the PON Gene Family in Obesity and Metabolic Dysfunction Associated Steatotic Liver Disease"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9597-0373","authenticated-orcid":false,"given":"Evelien","family":"Van Dijck","sequence":"first","affiliation":[{"name":"Centre of Medical Genetics, University of Antwerp and Antwerp University Hospital, 2650 Edegem, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Diels","sequence":"additional","affiliation":[{"name":"Centre of Medical Genetics, University of Antwerp and Antwerp University Hospital, 2650 Edegem, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Fransen","sequence":"additional","affiliation":[{"name":"Centre of Medical Genetics, University of Antwerp and Antwerp University Hospital, 2650 Edegem, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tycho Canter","family":"Cremers","sequence":"additional","affiliation":[{"name":"Centre of Medical Genetics, University of Antwerp and Antwerp University Hospital, 2650 Edegem, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"An","family":"Verrijken","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Diabetology and Metabolic Diseases, Antwerp University Hospital, 2650 Edegem, Belgium"},{"name":"Laboratory for Experimental Medicine and Paediatrics, Translational Sciences in Inflammation and Immunology, University of Antwerp, 2610 Wilrijk, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5211-2210","authenticated-orcid":false,"given":"Eveline","family":"Dirinck","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Diabetology and Metabolic Diseases, Antwerp University Hospital, 2650 Edegem, Belgium"},{"name":"Laboratory for Experimental Medicine and Paediatrics, Translational Sciences in Inflammation and Immunology, University of Antwerp, 2610 Wilrijk, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Hoischen","sequence":"additional","affiliation":[{"name":"Department of Human Genetics and Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geert","family":"Vandeweyer","sequence":"additional","affiliation":[{"name":"Centre of Medical Genetics, University of Antwerp and Antwerp University Hospital, 2650 Edegem, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0161-7355","authenticated-orcid":false,"given":"Wim","family":"Vanden Berghe","sequence":"additional","affiliation":[{"name":"Cell Death Signaling\u2013Epigenetics Lab, Department Biomedical Sciences, University of Antwerp, 2610 Wilrijk, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luc","family":"Van Gaal","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Diabetology and Metabolic Diseases, Antwerp University Hospital, 2650 Edegem, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7527-4714","authenticated-orcid":false,"given":"Sven","family":"Francque","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Antwerp University Hospital, 2650 Edegem, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5065-7858","authenticated-orcid":false,"given":"Wim","family":"Van Hul","sequence":"additional","affiliation":[{"name":"Centre of Medical Genetics, University of Antwerp and Antwerp University Hospital, 2650 Edegem, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/j.cgh.2021.11.038","article-title":"An Observational Data Meta-analysis on the Differences in Prevalence and Risk Factors between MAFLD vs NAFLD","volume":"21","author":"Lim","year":"2023","journal-title":"Clin. 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