Genetic evidence for the liver-brain axis: lipid metabolism and neurodegenerative disease risk.

IF 3.9 2区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Zeyu Wang, Zixiao Yin, Guangyong Sun, Dong Zhang, Jianguo Zhang
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引用次数: 0

Abstract

Background: The liver‒brain axis is critical in neurodegenerative diseases (NDs), with lipid metabolism influencing neuroinflammation and microglial function. A systematic investigation of the genetic relationship between lipid metabolism abnormalities and ND, namely, Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), is lacking. To assess potential causal links between ND and six lipid parameters, two-sample Mendelian randomization (MR) was used.

Methods: Large-scale European ancestry GWAS data for lipid parameters and ND (AD, ALS, PD, and MS) were used. Genetic variants demonstrating significant correlations (P < 5 × 10-8) with lipid metabolism parameters were identified and employed as instrumental variables (IVs) after proper validation. The research incorporated UK Biobank genomic data to examine associations between genetic variants and lipid metabolism parameters. The analysis included primary MR, sensitivity analyses, and multivariable MR, which considered potential mediators.

Results: MR via the inverse-variance weighted method revealed causal effects of cholesterol (CHOL, OR = 1.10, 95% CI: 1.03-1.18, P = 4.23 × 10⁻3) and low-density lipoprotein cholesterol (LDLC, OR = 1.10, 95% CI: 1.03-1.17, P = 3.28 × 10⁻3) on the risk of ALS, which were validated across multiple methods. Potential correlations were observed between ApoB and ALS and inversely correlated with AD, whereas no significant associations were found for PD or MS. CHOL and LDLC associations with ALS demonstrated no significant heterogeneity or pleiotropy, supporting their reliability.

Conclusions: Higher CHOL and LDLC levels were associated with increased ALS risk, suggesting a potential causal link, and supporting the liver‒brain axis hypothesis in ND. Current genetic evidence does not support a significant role for lipid metabolism in PD and MS etiology, suggesting the relationship between lipid metabolism and other NDs may be more complex and warrants further investigation.

肝脑轴的遗传证据:脂质代谢和神经退行性疾病风险。
背景:肝脑轴在神经退行性疾病(NDs)中至关重要,脂质代谢影响神经炎症和小胶质细胞功能。脂质代谢异常与ND,即阿尔茨海默病(AD)、帕金森病(PD)、多发性硬化症(MS)和肌萎缩侧索硬化症(ALS)之间的遗传关系缺乏系统的研究。为了评估ND与六个脂质参数之间的潜在因果关系,采用了双样本孟德尔随机化(MR)。方法:使用大规模欧洲血统GWAS数据进行脂质参数和ND (AD, ALS, PD和MS)研究。鉴定出与脂质代谢参数具有显著相关性(P -8)的遗传变异,并在适当验证后作为工具变量(IVs)。该研究结合了英国生物银行的基因组数据来检查遗传变异和脂质代谢参数之间的关系。分析包括初级磁共振、敏感性分析和考虑潜在介质的多变量磁共振。结果:MR通过反方差加权法揭示了胆固醇(CHOL, OR = 1.10, 95% CI: 1.03-1.18, P = 4.23 × 10毒血症)和低密度脂蛋白胆固醇(LDLC, OR = 1.10, 95% CI: 1.03-1.17, P = 3.28 × 10毒血症)对ALS风险的因果关系,并通过多种方法验证。ApoB与ALS之间存在潜在的相关性,与AD呈负相关,而与PD或ms没有显著的相关性,CHOL和LDLC与ALS的关联没有显著的异质性或多效性,支持了它们的可靠性。结论:较高的CHOL和ldl水平与ALS风险增加相关,提示存在潜在的因果关系,并支持ND的肝脑轴假说。目前的遗传证据不支持脂质代谢在PD和MS病因学中的重要作用,提示脂质代谢与其他nd之间的关系可能更为复杂,值得进一步研究。
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来源期刊
Lipids in Health and Disease
Lipids in Health and Disease 生物-生化与分子生物学
CiteScore
7.70
自引率
2.20%
发文量
122
审稿时长
3-8 weeks
期刊介绍: Lipids in Health and Disease is an open access, peer-reviewed, journal that publishes articles on all aspects of lipids: their biochemistry, pharmacology, toxicology, role in health and disease, and the synthesis of new lipid compounds. Lipids in Health and Disease is aimed at all scientists, health professionals and physicians interested in the area of lipids. Lipids are defined here in their broadest sense, to include: cholesterol, essential fatty acids, saturated fatty acids, phospholipids, inositol lipids, second messenger lipids, enzymes and synthetic machinery that is involved in the metabolism of various lipids in the cells and tissues, and also various aspects of lipid transport, etc. In addition, the journal also publishes research that investigates and defines the role of lipids in various physiological processes, pathology and disease. In particular, the journal aims to bridge the gap between the bench and the clinic by publishing articles that are particularly relevant to human diseases and the role of lipids in the management of various diseases.
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