全球范围内,肥胖和相关非酒精性脂肪性肝病(NAFLD)的负担正在上升,但对循环代谢组学生物标志物在介导其关联中的作用知之甚少。
我们旨在研究肥胖与代谢组学生物标志物的观察性和遗传学关联,以及代谢组学生物标志物与NAFLD的观察性关联。
前瞻性中国嘉道理生物库的病例-亚组研究包括176例NAFLD病例和180个亚组个体,并使用代谢测定法测量了储存的基线血浆中的1208种代谢物。在子队列中,使用线性回归评估BMI与生物标志物的观察性和遗传相关性,与多个测试调整。Cox回归用于估计与生物标志物相关的NAFLD的校正HR。
在观察性分析中,BMI(kg/m2;亚组中的平均值:23.9)与199种代谢物相关,错误发现率为5%。遗传升高的BMI与特定代谢物的影响与观察性关联在方向上一致。总的来说,35种代谢物与NAFLD风险相关,其中15个也与BMI相关,包括谷氨酸(每1-SD较高代谢物的HR:1.95;95%CI:1.48,2.56),半胱氨酸-谷胱甘肽二硫化物(0.44;0.31,0.62),甘油二酯(C32:1)(1.71;1.24,2.35),二十二酰基二氢鞘磷脂(C40:0)(1.92;1.42,2.59),丁酰肉碱(C4)(1.91;1.38,2.35),2-羟基二十二烷酸酯(1.81;1.34,2.45),和4-cholesten-3-one(1.79;1.27,2.54)。当模型中同时考虑28种代谢物时,已知危险因素的判别性能增加(加权C统计量:0.84至0.90;P<0.001)。
在相对瘦的中国成年人中,一系列代谢组学生物标志物与NAFLD风险相关,这些生物标志物可能位于肥胖和NAFLD之间的通路上.
Globally, the burden of obesity and associated nonalcoholic fatty liver disease (NAFLD) are rising, but little is known about the role that circulating metabolomic biomarkers play in mediating their association.
We aimed to examine the observational and genetic associations of
adiposity with metabolomic biomarkers and the observational associations of metabolomic biomarkers with incident NAFLD.
A
case-subcohort study within the prospective China Kadoorie Biobank included 176 NAFLD cases and 180 subcohort individuals and measured 1208 metabolites in stored baseline plasma using a Metabolon assay. In the subcohort the observational and genetic associations of BMI with biomarkers were assessed using linear regression, with adjustment for multiple testing. Cox regression was used to estimate adjusted HRs for NAFLD associated with biomarkers.
In observational analyses, BMI (kg/m2; mean: 23.9 in the subcohort) was associated with 199 metabolites at a 5% false discovery rate. The effects of genetically elevated BMI with specific metabolites were directionally consistent with the observational associations. Overall, 35 metabolites were associated with NAFLD risk, of which 15 were also associated with BMI, including glutamate (HR per 1-SD higher metabolite: 1.95; 95% CI: 1.48, 2.56), cysteine-glutathione disulfide (0.44; 0.31, 0.62), diaclyglycerol (C32:1) (1.71; 1.24, 2.35), behenoyl dihydrosphingomyelin (C40:0) (1.92; 1.42, 2.59), butyrylcarnitine (C4) (1.91; 1.38, 2.35), 2-hydroxybehenate (1.81; 1.34, 2.45), and 4-cholesten-3-one (1.79; 1.27, 2.54). The discriminatory performance of known risk factors was increased when 28 metabolites were also considered simultaneously in the model (weighted C-statistic: 0.84 to 0.90; P < 0.001).
Among relatively lean Chinese adults, a range of metabolomic biomarkers are associated with NAFLD risk and these biomarkers may lie on the pathway between
adiposity and NAFLD.