Lower Merion High School, Ardmore, PA, USA; Department of Genetics, Franklin College of Arts and Sciences, University of Georgia, Athens, GA, USA.
Department of Genetics, Franklin College of Arts and Sciences, University of Georgia, Athens, GA, USA.
J Neuroimmunol. 2023 Jun 15;379:578105. doi: 10.1016/j.jneuroim.2023.578105. Epub 2023 May 11.
To prioritize circulating metabolites that likely play causal roles in the pathogenesis of multiple sclerosis (MS). Two-sample Mendelian randomization analysis was performed to estimate the causal effects of 571 circulating metabolites on the risk of MS. Genetic instruments for circulating metabolites were obtained from three previous genome-wide association studies (GWAS) of the blood metabolome (N = 7824; 24,925; and 115,078; respectively), while genetic associations with MS were from a large GWAS by the International Multiple Sclerosis Genetics Consortium (14,802 cases and 26,703 control). The primary analysis was performed with the multiplicative random-effect inverse variance-weighted method, while multiple sensitivity analyses were conducted with the weighted median, weighted mode, MR-Egger, and MR-PRESSO. A total of 29 metabolites had suggestive evidence of causal associations with MS. Genetically instrumented levels of serine (OR = 1.56, 95% CI = 1.25-1.95), lysine (OR = 1.18, 95% CI = 1.01-1.38), acetone (OR = 2.45, 95% CI = 1.02-5.90), and acetoacetate (OR = 2.47, 95% CI = 1.14-5.34) were associated with a higher MS risk. Total cholesterol and phospholipids in large very-low-density lipoprotein were associated with a lower MS risk (OR = 0.83, 95% CI = 0.69-1.00; OR = 0.80, 95% CI = 0.68-0.95), but risk-increasing associations (OR = 1.20, 95% CI = 1.04-1.40; OR = 1.13, 95% CI = 1.00-1.28) were observed for the same two lipids in very large high-density lipoprotein. Our metabolome-wide Mendelian randomization study prioritized a list of circulating metabolites, such as serine, lysine, acetone, acetoacetate, and lipids, that likely have causal associations with MS.
为了确定在多发性硬化症（MS）发病机制中可能起因果作用的循环代谢物。进行了两样本孟德尔随机化分析，以估计 571 种循环代谢物对 MS 风险的因果影响。循环代谢物的遗传工具来自三项先前的血液代谢组全基因组关联研究（GWAS）（分别为 7824 人；24925 人；和 115078 人），而与 MS 的遗传关联来自国际多发性硬化症遗传学联合会（14802 例病例和 26703 例对照）的一项大型 GWAS。主要分析采用乘法随机效应倒数方差加权法进行，同时还采用加权中位数、加权模式、MR-Egger 和 MR-PRESSO 进行了多种敏感性分析。共有 29 种代谢物具有与 MS 因果关联的提示性证据。遗传上仪器化的丝氨酸（OR=1.56，95%CI=1.25-1.95）、赖氨酸（OR=1.18，95%CI=1.01-1.38）、丙酮（OR=2.45，95%CI=1.02-5.90）和乙酰乙酸（OR=2.47，95%CI=1.14-5.34）水平与较高的 MS 风险相关。大极低密度脂蛋白中的总胆固醇和磷脂与较低的 MS 风险相关（OR=0.83，95%CI=0.69-1.00；OR=0.80，95%CI=0.68-0.95），但同一两种脂质在非常大的高密度脂蛋白中观察到与风险增加相关的关联（OR=1.20，95%CI=1.04-1.40；OR=1.13，95%CI=1.00-1.28）。我们的代谢组学全基因组孟德尔随机化研究确定了一系列循环代谢物，如丝氨酸、赖氨酸、丙酮、乙酰乙酸和脂质等，这些代谢物可能与 MS 有因果关系。
