Search for common genetic variants to allow reliable Mendelian randomization investigations into ketone metabolism.

IF 5.9 1区 医学 Q1 PUBLIC, ENVIRONMENTAL & OCCUPATIONAL HEALTH
European Journal of Epidemiology Pub Date : 2025-06-01 Epub Date: 2025-06-09 DOI:10.1007/s10654-025-01246-5
Zhu Liduzi Jiesisibieke, Héléne Toinét Cronjé, C Mary Schooling, Stephen Burgess
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引用次数: 0

Abstract

Ketogenic diets are popular among people aiming for weight management. Ketone supplementation has been linked to improved cognitive performance and increased risk of insulin resistance. We aim to identify common genetic variants that allow Mendelian randomization investigations into further potential effects of ketone metabolism. We set four premises that we believe any valid instrument for ketone metabolism should satisfy. These are: (1) location in a gene region relevant to ketone metabolism, (2) association with all three primary ketone bodies (acetone, acetoacetate, and beta-hydroxybutyrate), (3) no pleiotropic associations, (4) associations with positive control variables (cognitive performance, two-hour glucose, and insulin fold change). We considered gene regions containing variants previously associated with acetone. Four of these regions had biological relevance to ketone metabolism. Lead variants for three of these four regions (SLC2A4, HMGCS2, OXCT1) were associated with all three primary ketone bodies. One region (SLC2A4) was associated with two-hour glucose and insulin fold change; however, this region had strong pleiotropic associations with blood pressure. One region (OXCT1) showed an association with cognitive performance, and thus satisfied all our premises to be a valid instrument for ketone metabolism. In a complementary agnostic approach considering all genome-wide significant predictors of the three primary ketone bodies in turn, genetically predicted acetoacetate based on seven variants was associated with improved cognitive performance. However, several variants selected in this approach were not located in biologically relevant gene regions and were pleiotropic. Causal claims from Mendelian randomization will be most reliable when the instrumental variable assumptions are plausibly satisfied. We illustrate a framework to identify candidate instruments based on biological considerations.

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寻找常见的遗传变异,允许可靠的孟德尔随机调查酮代谢。
生酮饮食在旨在控制体重的人群中很受欢迎。补充酮类与改善认知能力和增加胰岛素抵抗的风险有关。我们的目标是确定常见的遗传变异,允许孟德尔随机化调查酮代谢的进一步潜在影响。我们设定了四个前提,我们认为任何有效的酮代谢仪器都应该满足这些前提。它们是:(1)位于与酮代谢相关的基因区域,(2)与所有三种主要酮体(丙酮、乙酰乙酸酯和β -羟基丁酸酯)相关,(3)无多效性关联,(4)与阳性控制变量(认知能力、两小时葡萄糖和胰岛素折叠变化)相关。我们考虑了包含先前与丙酮相关的变异的基因区域。其中四个区域与酮代谢具有生物学相关性。这四个区域中的三个(SLC2A4, HMGCS2, OXCT1)的铅变异体与所有三个主要酮体相关。其中一个区域(SLC2A4)与2小时葡萄糖和胰岛素折叠变化相关;然而,这个区域与血压有很强的多效性联系。其中一个区域(OXCT1)显示与认知表现相关,因此满足了我们作为酮代谢有效工具的所有前提。在一种互补的不可知论方法中,考虑到三个主要酮体的所有全基因组显著预测因子,基于七个变体的遗传预测乙酰乙酸酯与改善的认知能力相关。然而,在这种方法中选择的一些变异并不位于生物学相关的基因区域,并且是多效性的。当工具变量假设被合理地满足时,孟德尔随机化的因果断言将是最可靠的。我们举例说明了一个框架,以确定基于生物学考虑的候选仪器。
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来源期刊
European Journal of Epidemiology
European Journal of Epidemiology 医学-公共卫生、环境卫生与职业卫生
CiteScore
21.40
自引率
1.50%
发文量
109
审稿时长
6-12 weeks
期刊介绍: The European Journal of Epidemiology, established in 1985, is a peer-reviewed publication that provides a platform for discussions on epidemiology in its broadest sense. It covers various aspects of epidemiologic research and statistical methods. The journal facilitates communication between researchers, educators, and practitioners in epidemiology, including those in clinical and community medicine. Contributions from diverse fields such as public health, preventive medicine, clinical medicine, health economics, and computational biology and data science, in relation to health and disease, are encouraged. While accepting submissions from all over the world, the journal particularly emphasizes European topics relevant to epidemiology. The published articles consist of empirical research findings, developments in methodology, and opinion pieces.
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