Würtz Peter, Wang Qin, Kangas Antti J, Richmond Rebecca C, Skarp Joni, Tiainen Mika, Tynkkynen Tuulia, Soininen Pasi, Havulinna Aki S, Kaakinen Marika, Viikari Jorma S, Savolainen Markku J, Kähönen Mika, Lehtimäki Terho, Männistö Satu, Blankenberg Stefan, Zeller Tanja, Laitinen Jaana, Pouta Anneli, Mäntyselkä Pekka, Vanhala Mauno, Elliott Paul, Pietiläinen Kirsi H, Ripatti Samuli, Salomaa Veikko, Raitakari Olli T, Järvelin Marjo-Riitta, Smith George Davey, Ala-Korpela Mika
Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland; NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
PLoS Med. 2014 Dec 9;11(12):e1001765. doi: 10.1371/journal.pmed.1001765. eCollection 2014 Dec.
Increased adiposity is linked with higher risk for cardiometabolic diseases. We aimed to determine to what extent elevated body mass index (BMI) within the normal weight range has causal effects on the detailed systemic metabolite profile in early adulthood.
We used Mendelian randomization to estimate causal effects of BMI on 82 metabolic measures in 12,664 adolescents and young adults from four population-based cohorts in Finland (mean age 26 y, range 16-39 y; 51% women; mean ± standard deviation BMI 24 ± 4 kg/m(2)). Circulating metabolites were quantified by high-throughput nuclear magnetic resonance metabolomics and biochemical assays. In cross-sectional analyses, elevated BMI was adversely associated with cardiometabolic risk markers throughout the systemic metabolite profile, including lipoprotein subclasses, fatty acid composition, amino acids, inflammatory markers, and various hormones (p<0.0005 for 68 measures). Metabolite associations with BMI were generally stronger for men than for women (median 136%, interquartile range 125%-183%). A gene score for predisposition to elevated BMI, composed of 32 established genetic correlates, was used as the instrument to assess causality. Causal effects of elevated BMI closely matched observational estimates (correspondence 87% ± 3%; R(2)= 0.89), suggesting causative influences of adiposity on the levels of numerous metabolites (p<0.0005 for 24 measures), including lipoprotein lipid subclasses and particle size, branched-chain and aromatic amino acids, and inflammation-related glycoprotein acetyls. Causal analyses of certain metabolites and potential sex differences warrant stronger statistical power. Metabolite changes associated with change in BMI during 6 y of follow-up were examined for 1,488 individuals. Change in BMI was accompanied by widespread metabolite changes, which had an association pattern similar to that of the cross-sectional observations, yet with greater metabolic effects (correspondence 160% ± 2%; R(2) = 0.92).
Mendelian randomization indicates causal adverse effects of increased adiposity with multiple cardiometabolic risk markers across the metabolite profile in adolescents and young adults within the non-obese weight range. Consistent with the causal influences of adiposity, weight changes were paralleled by extensive metabolic changes, suggesting a broadly modifiable systemic metabolite profile in early adulthood. Please see later in the article for the Editors' Summary.
肥胖程度增加与心血管代谢疾病的较高风险相关。我们旨在确定在正常体重范围内升高的体重指数（BMI）在多大程度上对成年早期的详细全身代谢物谱具有因果影响。
我们使用孟德尔随机化方法来估计BMI对来自芬兰四个基于人群队列的12664名青少年和年轻人中82种代谢指标的因果影响（平均年龄26岁，范围16 - 39岁；51%为女性；平均±标准差BMI为24±4kg/m²）。通过高通量核磁共振代谢组学和生化分析对循环代谢物进行定量。在横断面分析中，升高的BMI与整个全身代谢物谱中的心血管代谢风险标志物呈负相关，包括脂蛋白亚类、脂肪酸组成、氨基酸、炎症标志物和各种激素（68项指标p<0.0005）。代谢物与BMI的关联通常男性比女性更强（中位数136%，四分位间距125% - 183%）。由32个已确定的遗传相关因素组成的BMI升高易感性基因评分被用作评估因果关系的工具。升高的BMI的因果影响与观察估计值密切匹配（对应度87%±3%；R² = 0.89），表明肥胖对多种代谢物水平有因果影响（24项指标p<0.0005），包括脂蛋白脂质亚类和颗粒大小、支链和芳香族氨基酸以及炎症相关糖蛋白乙酰化物。某些代谢物的因果分析和潜在的性别差异需要更强的统计效力。对1488名个体在6年随访期间与BMI变化相关的代谢物变化进行了检查。BMI的变化伴随着广泛的代谢物变化，其关联模式与横断面观察相似，但具有更大的代谢影响（对应度160%±2%；R² = 0.92）。
孟德尔随机化表明，在非肥胖体重范围内的青少年和年轻人中，肥胖增加对整个代谢物谱中的多种心血管代谢风险标志物具有因果不利影响。与肥胖的因果影响一致，体重变化伴随着广泛的代谢变化，表明成年早期存在广泛可改变的全身代谢物谱。请参阅本文后面的编辑总结。
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