英国生物银行中总体和中心性肥胖对循环脂蛋白、脂质和代谢物水平的影响：一项多变量孟德尔随机化研究
Effects of general and central adiposity on circulating lipoprotein, lipid, and metabolite levels in UK Biobank: A multivariable Mendelian randomization study.
作者信息
Bell Joshua A, Richardson Tom G, Wang Qin, Sanderson Eleanor, Palmer Tom, Walker Venexia, O'Keeffe Linda M, Timpson Nicholas J, Cichonska Anna, Julkunen Heli, Würtz Peter, Holmes Michael V, Davey Smith George
机构信息
MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.
Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
出版信息
Lancet Reg Health Eur. 2022 Jul 6;21:100457. doi: 10.1016/j.lanepe.2022.100457. eCollection 2022 Oct.
BACKGROUND
The direct effects of general adiposity (body mass index (BMI)) and central adiposity (waist-to-hip-ratio (WHR)) on circulating lipoproteins, lipids, and metabolites are unknown.
METHODS
We used new metabolic data from UK Biobank (=109,532, a five-fold higher N over previous studies). EDTA-plasma was used to quantify 249 traits with nuclear-magnetic-resonance spectroscopy including subclass-specific lipoprotein concentrations and lipid content, plus pre-glycemic and inflammatory metabolites. We used univariable and multivariable two-stage least-squares regression models with genetic risk scores for BMI and WHR as instruments to estimate total (unadjusted) and direct (mutually-adjusted) effects of BMI and WHR on metabolic traits; plus effects on statin use and interaction by sex, statin use, and age (proxy for medication use).
FINDINGS
Higher BMI decreased apolipoprotein B and low-density lipoprotein cholesterol (LDL-C) before and after WHR-adjustment, whilst BMI increased triglycerides only before WHR-adjustment. These effects of WHR were larger and BMI-independent. Direct effects differed markedly by sex, e.g., triglycerides increased only with BMI among men, and only with WHR among women. Adiposity measures increased statin use and showed metabolic effects which differed by statin use and age. Among the youngest (38-53y, statins-5%), BMI and WHR (per-SD) increased LDL-C (total effects: 0.04-SD, 95%CI=-0.01,0.08 and 0.10-SD, 95%CI=0.02,0.17 respectively), but only WHR directly. Among the oldest (63-73y, statins-29%), BMI and WHR directly lowered LDL-C (-0.19-SD, 95%CI=-0.27,-0.11 and -0.05-SD, 95%CI=-0.16,0.06 respectively).
INTERPRETATION
Excess adiposity likely raises atherogenic lipid and metabolite levels exclusively via adiposity stored centrally, particularly among women. Apparent effects of adiposity on lowering LDL-C are likely explained by an effect of adiposity on statin use.
FUNDING
UK Medical Research Council; British Heart Foundation; Novo Nordisk; National Institute for Health Research; Wellcome Trust; Cancer Research UK.
背景
总体肥胖（体重指数（BMI））和中心性肥胖（腰臀比（WHR））对循环脂蛋白、脂质和代谢物的直接影响尚不清楚。
方法
我们使用了英国生物银行的新代谢数据（=109532例，样本量是之前研究的五倍）。采用乙二胺四乙酸血浆，通过核磁共振波谱法定量249种性状，包括亚类特异性脂蛋白浓度和脂质含量，以及血糖前期和炎症性代谢物。我们使用单变量和多变量两阶段最小二乘回归模型，以BMI和WHR的遗传风险评分作为工具，来估计BMI和WHR对代谢性状的总体（未调整）和直接（相互调整）影响；以及对他汀类药物使用的影响，以及性别、他汀类药物使用和年龄（药物使用的替代指标）之间的相互作用。
研究结果
在调整WHR前后，较高的BMI均降低了载脂蛋白B和低密度脂蛋白胆固醇（LDL-C），而BMI仅在调整WHR前增加了甘油三酯。WHR的这些影响更大且独立于BMI。直接影响在性别上有显著差异，例如，甘油三酯仅在男性中随BMI升高，而在女性中仅随WHR升高。肥胖指标增加了他汀类药物的使用，并显示出因他汀类药物使用和年龄而异的代谢影响。在最年轻的人群（38 - 53岁，他汀类药物使用率5%）中，BMI和WHR（每标准差）增加了LDL-C（总体影响：0.04标准差，95%置信区间=-0.01,0.08和0.10标准差，95%置信区间=0.02,0.17），但只有WHR有直接影响。在最年长的人群（63 - 73岁，他汀类药物使用率29%）中，BMI和WHR直接降低了LDL-C（-0.19标准差，95%置信区间=-0.27,-0.11和-0.05标准差，95%置信区间=-0.16,0.06）。
解读
肥胖可能仅通过中心储存的脂肪增加致动脉粥样硬化的脂质和代谢物水平，尤其是在女性中。肥胖对降低LDL-C的明显影响可能是由肥胖对他汀类药物使用的影响所解释的。
资助
英国医学研究理事会；英国心脏基金会；诺和诺德公司；英国国家卫生研究院；惠康信托基金会；英国癌症研究基金会。
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