A Case–Control Study Supports Genetic Contribution of the <i>PON</i> Gene Family in Obesity and Metabolic Dysfunction Associated Steatotic Liver Disease
Evelien Van Dijck,
Sara Diels,
Erik Fransen,
Tycho Canter Cremers,
An Verrijken,
Eveline Dirinck,
Alexander Hoischen,
Geert Vandeweyer,
Wim Vanden Berghe,
Luc Van Gaal,
Sven Francque,
Wim Van Hul
Affiliations
Evelien Van Dijck
Centre of Medical Genetics, University of Antwerp and Antwerp University Hospital, 2650 Edegem, Belgium
Sara Diels
Centre of Medical Genetics, University of Antwerp and Antwerp University Hospital, 2650 Edegem, Belgium
Erik Fransen
Centre of Medical Genetics, University of Antwerp and Antwerp University Hospital, 2650 Edegem, Belgium
Tycho Canter Cremers
Centre of Medical Genetics, University of Antwerp and Antwerp University Hospital, 2650 Edegem, Belgium
An Verrijken
Department of Endocrinology, Diabetology and Metabolic Diseases, Antwerp University Hospital, 2650 Edegem, Belgium
Eveline Dirinck
Department of Endocrinology, Diabetology and Metabolic Diseases, Antwerp University Hospital, 2650 Edegem, Belgium
Alexander Hoischen
Department of Human Genetics and Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
Geert Vandeweyer
Centre of Medical Genetics, University of Antwerp and Antwerp University Hospital, 2650 Edegem, Belgium
Wim Vanden Berghe
Cell Death Signaling–Epigenetics Lab, Department Biomedical Sciences, University of Antwerp, 2610 Wilrijk, Belgium
Luc Van Gaal
Department of Endocrinology, Diabetology and Metabolic Diseases, Antwerp University Hospital, 2650 Edegem, Belgium
Sven Francque
Department of Gastroenterology and Hepatology, Antwerp University Hospital, 2650 Edegem, Belgium
Wim Van Hul
Centre of Medical Genetics, University of Antwerp and Antwerp University Hospital, 2650 Edegem, Belgium
The paraoxonase (PON) gene family (including PON1, PON2, and PON3), is known for its anti-oxidative and anti-inflammatory properties, protecting against metabolic diseases such as obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). 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.
