Van Dijck Evelien, Diels Sara, Fransen Erik, Cremers Tycho Canter, Verrijken An, Dirinck Eveline, Hoischen Alexander, Vandeweyer Geert, Vanden Berghe Wim, Van Gaal Luc, Francque Sven, Van Hul Wim
Centre of Medical Genetics, University of Antwerp and Antwerp University Hospital, 2650 Edegem, Belgium.
Department of Endocrinology, Diabetology and Metabolic Diseases, Antwerp University Hospital, 2650 Edegem, Belgium.
Antioxidants (Basel). 2024 Aug 29;13(9):1051. doi: 10.3390/antiox13091051.
The paraoxonase () 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 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 gene displayed significant association with MASLD stage and fibrosis, respectively. Additionally, rare variants were strongly associated with obesity. This study thereby reinforces the genetic foundation of 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 were discovered to be associated with MASLD-related hepatic fibrosis. Notably, we are the first to report an association between naturally occurring rare 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.
对氧磷酶（PON）基因家族（包括PON1、PON2和PON3）以其抗氧化和抗炎特性而闻名，可预防肥胖和代谢功能障碍相关脂肪性肝病（MASLD）等代谢性疾病。在本研究中，研究了常见和罕见变异对这两种疾病的影响。对总共507名体重正常个体和744名肥胖患者（包括433名接受肝脏组织学评估的患者）进行了单分子分子倒置探针（smMIPs）测序，从而能够确定基因对肥胖和MASLD相关肝脏特征的影响。PON基因中的多态性rs705379和rs854552分别与MASLD分期和纤维化显著相关。此外，罕见的PON变异与肥胖密切相关。本研究通过将先前关于常见变异的研究结果扩展到包括罕见变异，从而加强了PON在肥胖和各种MASLD相关肝脏特征中的遗传基础。此外，发现PON中的罕见和极罕见变异与MASLD相关的肝纤维化有关。值得注意的是，我们首次报告了自然发生的罕见PON变异与MASLD相关肝纤维化之间的关联。考虑到肝纤维化在MASLD结局中的关键作用，PON2成为未来研究努力的一个可能候选对象，包括探索其作为生物标志物的潜力。
