Partitioned polygenic risk scores identify distinct types of metabolic dysfunction-associated steatotic liver disease

Research Square Pub Date : 2024-02-06 DOI:10.21203/rs.3.rs-3878807/v1

Stefano Romeo, O. Jamialahmadi, A. De Vincentis, F. Tavaglione, F. Malvestiti, R. Li-Gao, R. Mancina, Marcus Alvarez, Kyla Gelev, Samantha Maurotti, U. Vespasiani‐Gentilucci, Frits Rosendaal, Julia Kozlitina, P. Pajukanta, François Pattou, Luca Valenti

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Abstract

Abstract Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses an excess of triglycerides in the liver, which can lead to cirrhosis and liver cancer. While there is solid epidemiological evidence of MASLD coexisting with cardiometabolic disease, several leading genetic risk factors for MASLD do not increase the risk of cardiovascular disease, suggesting no causal relationship between MASLD and cardiometabolic derangement. In this work, we leveraged measurements of visceral adiposity and identified 27 novel genetic loci associated with MASLD. Among these loci , we replicated 6 in several independent cohorts. Next, we generated two partitioned polygenic risk scores (PRS) based on the mechanism of genetic association with MASLD encompassing intra-hepatic lipoprotein retention. The two PRS suggest the presence of at least two distinct types of MASLD, one confined to the liver resulting in a more aggressive liver disease and one that is systemic and results in a higher risk of cardiometabolic disease.

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分区多基因风险评分确定了代谢功能障碍相关脂肪肝的不同类型

摘要代谢功能障碍相关性脂肪性肝病（MASLD）包括肝脏中甘油三酯过多，可导致肝硬化和肝癌。虽然有确凿的流行病学证据表明 MASLD 与心血管代谢疾病并存，但 MASLD 的几个主要遗传风险因素并不增加心血管疾病的风险，这表明 MASLD 与心血管代谢紊乱之间没有因果关系。在这项工作中，我们利用内脏脂肪测量结果，确定了 27 个与 MASLD 相关的新基因位点。在这些基因位点中，我们在多个独立队列中复制了 6 个。接下来，我们根据与 MASLD 的遗传关联机制生成了两个分区多基因风险评分（PRS），其中包括肝内脂蛋白潴留。这两个多基因风险评分表明至少存在两种不同类型的 MASLD，一种局限于肝脏，导致更具侵袭性的肝病，另一种是全身性的，导致更高的心血管代谢疾病风险。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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