Desine Stacy, Gabriel Curtis L, Smith Holly M, Antonetti Olivia R, Wang Chuan, Calcutt M Wade, Doran Amanda C, Silver Heidi J, Nair Sangeeta, Terry James G, Carr J Jeffrey, Linton MacRae F, Brown Jonathan D, Koethe John R, Ferguson Jane F
Division of Cardiovascular Medicine, Vanderbilt University Medical Center.
Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center.
medRxiv. 2023 Jun 6:2023.06.05.23290990. doi: 10.1101/2023.06.05.23290990.
Plasma levels of the metabolite alpha-aminoadipic acid (2-AAA) have been associated with risk of type 2 diabetes (T2D) and atherosclerosis. However, little is known about the relationship of 2-AAA to other cardiometabolic risk markers in pre-disease states, or in the setting of comorbid disease. We measured circulating 2-AAA using two methods in 1) a sample of 261 healthy individuals (2-AAA Study), and 2) in a sample of 134 persons comprising 110 individuals with treated HIV, with or without T2D, a population at high risk of metabolic disease and cardiovascular events despite suppression of circulating virus, and 24 individuals with T2D without HIV (HATIM Study). We examined associations between plasma 2-AAA and markers of cardiometabolic health within each cohort. We observed differences in 2-AAA by sex and race in both cohorts, with higher levels observed in men compared with women, and in Asian compared with Black or white individuals (P<0.05). There was no significant difference in 2-AAA by HIV status within individuals with T2D in the HATIM Study. We confirmed associations between 2-AAA and dyslipidemia in both cohorts where high 2-AAA associated with low HDL cholesterol (P<0.001) and high triglycerides (P<0.05). As expected, within the cohort of people with HIV, 2-AAA was higher in the setting of T2D compared to pre-diabetes or normoglycemia (P<0.001). 2-AAA was positively associated with body mass index (BMI) in the 2-AAA Study, and with waist circumference and measures of visceral fat volume in HATIM (all P<0.05). Further, 2-AAA associated with increased liver fat in persons with HIV (P<0.001). Our study confirms 2-AAA as a marker of cardiometabolic risk in both healthy individuals and those at high cardiometabolic risk, reveals relationships with adiposity and hepatic steatosis, and highlights important differences by sex and race. Further studies are warranted to establish molecular mechanisms linking 2-AAA to disease in other high-risk populations.
代谢物α-氨基己二酸(2-AAA)的血浆水平与2型糖尿病(T2D)和动脉粥样硬化风险相关。然而,对于疾病前期状态或合并疾病情况下2-AAA与其他心脏代谢风险标志物之间的关系,我们知之甚少。我们采用两种方法测量了循环中的2-AAA:1)在261名健康个体的样本中(2-AAA研究);2)在134人的样本中,其中包括110名接受治疗的HIV感染者(无论是否患有T2D),这是一个尽管循环病毒得到抑制但仍有代谢疾病和心血管事件高风险的人群,以及24名无HIV的T2D患者(HATIM研究)。我们在每个队列中研究了血浆2-AAA与心脏代谢健康标志物之间的关联。我们在两个队列中均观察到2-AAA在性别和种族上存在差异,男性的水平高于女性,亚洲人的水平高于黑人或白人个体(P<0.05)。在HATIM研究中,患有T2D的个体中,2-AAA水平在HIV状态方面无显著差异。我们在两个队列中均证实了2-AAA与血脂异常之间的关联,高2-AAA与低高密度脂蛋白胆固醇相关(P<0.001),与高甘油三酯相关(P<0.05)。正如预期的那样,在HIV感染者队列中,与糖尿病前期或血糖正常相比,T2D患者的2-AAA水平更高(P<0.001)。在2-AAA研究中,2-AAA与体重指数(BMI)呈正相关,在HATIM研究中与腰围和内脏脂肪体积测量值呈正相关(均P<0.05)。此外,2-AAA与HIV感染者肝脏脂肪增加相关(P<0.001)。我们的研究证实2-AAA是健康个体和心脏代谢高风险个体心脏代谢风险的标志物,揭示了其与肥胖和肝脂肪变性的关系,并突出了性别和种族方面的重要差异。有必要进行进一步研究以确定将2-AAA与其他高风险人群疾病联系起来的分子机制。