ERLIN1的常见p.Ile291Val变体可增强TM6SF2的功能,并与MASLD的保护相关。

IF 12.8 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Med Pub Date : 2024-08-09 Epub Date: 2024-05-21 DOI:10.1016/j.medj.2024.04.010
Miriam Daphne Rendel, Cecilia Vitali, Kate Townsend Creasy, David Zhang, Eleonora Scorletti, Helen Huang, Katharina Sophie Seeling, Joseph Park, Leonida Hehl, Mara Sophie Vell, Donna Conlon, Sikander Hayat, Michael C Phillips, Kai Markus Schneider, Daniel J Rader, Carolin Victoria Schneider
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引用次数: 0

摘要

背景:ERLIN1 p.Ile291Val单核苷酸多态性(rs2862954)与脂肪性肝病(SLD)的保护相关,但该变异对代谢表型的影响仍不确定:方法:在英国生物库(UKB)、宾夕法尼亚医学生物库(PMBB)和 "我们所有人 "队列中,采用基因组优先方法分析了与ERLIN1 p.Ile291Val相关的代谢表型和结果:结果:在英国生物库中,ERLIN1 p.Ile291Val携带者的血清丙氨酸氨基转移酶和天冬氨酸氨基转移酶水平明显较低,甘油三酯、低密度脂蛋白胆固醇、载脂蛋白B、高密度脂蛋白胆固醇和载脂蛋白A1的水平较高,这些值受ERLIN1 p.Ile291Val的影响呈等位基因剂量依赖性。等位基因ERLIN1 p.Ile291Val携带者罹患代谢功能障碍相关SLD(MASLD,调整比值比[aOR] = 0.92,95%置信区间[CI],0.88-0.96)的风险显著降低。这一变异对酒精性肝病患者的保护作用更强。我们的结果在 PMBB 和 "我们所有人 "队列中得到了验证。令人震惊的是,ERLIN1 p.Ile291Val 的保护作用在携带与 SLD 风险增加相关的 TM6SF2 p.Glu167Lys 变异的个体中并不明显。我们分析了预测的ERLIN1功能缺失变异的效应,发现它们具有相反的效应,即降低血浆脂质,这表明ERLIN1 p.Ile291Val可能是一种功能增益变异:我们的研究通过调查一个编码变异,有助于更好地了解ERLIN1,该变异已成为一种潜在的功能增益变异,对MASLD的发展具有保护作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The common p.Ile291Val variant of ERLIN1 enhances TM6SF2 function and is associated with protection against MASLD.

Background: The ERLIN1 p.Ile291Val single-nucleotide polymorphism (rs2862954) is associated with protection from steatotic liver disease (SLD), but effects of this variant on metabolic phenotypes remain uncertain.

Methods: Metabolic phenotypes and outcomes associated with ERLIN1 p.Ile291Val were analyzed by using a genome-first approach in the UK Biobank (UKB), Penn Medicine BioBank (PMBB), and All of Us cohort.

Findings: ERLIN1 p.Ile291Val carriers exhibited significantly lower serum levels of alanine aminotransferase and aspartate aminotransferase as well as higher levels of triglycerides, low-density lipoprotein cholesterol, Apolipoprotein B, high-density lipoprotein cholesterol, and Apolipoprotein A1 in UKB, and these values were affected by ERLIN1 p.Ile291Val in an allele-dose-dependent manner. Homozygous ERLIN1 p.Ile291Val carriers had a significantly reduced risk of developing metabolic dysfunction-associated SLD (MASLD, adjusted odds ratio [aOR] = 0.92, 95% confidence interval [CI], 0.88-0.96). The protective effect of this variant was enhanced in patients with alcoholic liver disease. Our results were replicated in PMBB and the All of Us cohort. Strikingly, the protective effects of ERLIN1 p.Ile291Val were not apparent in individuals carrying the TM6SF2 p.Glu167Lys variant associated with increased risk of SLD. We analyzed the effects of predicted loss-of-function ERLIN1 variants and found that they had opposite effects, namely reduced plasma lipids, suggesting that ERLIN1 p.Ile291Val may be a gain-of-function variant.

Conclusion: Our study contributes to a better understanding of ERLIN1 by investigating a coding variant that has emerged as a potential gain-of-function mutation with protective effects against MASLD development.

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来源期刊
Med
Med MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
17.70
自引率
0.60%
发文量
102
期刊介绍: Med is a flagship medical journal published monthly by Cell Press, the global publisher of trusted and authoritative science journals including Cell, Cancer Cell, and Cell Reports Medicine. Our mission is to advance clinical research and practice by providing a communication forum for the publication of clinical trial results, innovative observations from longitudinal cohorts, and pioneering discoveries about disease mechanisms. The journal also encourages thought-leadership discussions among biomedical researchers, physicians, and other health scientists and stakeholders. Our goal is to improve health worldwide sustainably and ethically. Med publishes rigorously vetted original research and cutting-edge review and perspective articles on critical health issues globally and regionally. Our research section covers clinical case reports, first-in-human studies, large-scale clinical trials, population-based studies, as well as translational research work with the potential to change the course of medical research and improve clinical practice.
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