Background:Circulating biomarkers have been previously associated with atherosclerosis-related risk factors, but the nature of these associations is incompletely understood.Methods:We performed multivariable-adjusted regressions and 2-sample Mendelian randomization analyses to assess observational and causal associations of 27 circulating biomarkers with 7 cardiovascular traits in up to 451 933 participants of the UK Biobank.Results:After multiple-testing correction (alpha=1.3×10⁻⁴), we found a total of 15, 9, 21, 22, 26, 24, and 26 biomarkers strongly associated with coronary artery disease, ischemic stroke, atrial fibrillation, type 2 diabetes, systolic blood pressure, body mass index, and waist-to-hip ratio; respectively. The Mendelian randomization analyses confirmed strong evidence of previously suggested causal associations for several glucose- and lipid-related biomarkers with type 2 diabetes and coronary artery disease. Particularly interesting findings included a protective role of IGF-1 (insulin-like growth factor 1) in systolic blood pressure, and the strong causal association of lipoprotein(a) in coronary artery disease development (β, −0.13; per SD change in exposure and outcome and odds ratio, 1.28; P=2.6×10⁻⁴ and P=7.4×10⁻³⁵, respectively). In addition, our results indicated a causal role of increased ALT (alanine aminotransferase) in the development of type 2 diabetes and hypertension (odds ratio, 1.59 and β, 0.06, per SD change in exposure and outcome; P=4.8×10⁻¹¹ and P=6.0×10⁻⁵). Our results suggest that it is unlikely that CRP (C-reactive protein) and vitamin D play causal roles of any meaningful magnitude in development of cardiometabolic disease.Conclusions:We confirmed and extended known associations and reported several novel causal associations providing important insights about the cause of these diseases, which can help accelerate new prevention strategies.

中文翻译：

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循环生物标志物及其在动脉粥样硬化相关危险因素和临床事件中的因果作用的综合调查

背景：循环生物标志物以前与动脉粥样硬化相关危险因素相关，但这些关联的性质尚不完全清楚。方法：我们进行了多变量调整回归和 2 样本孟德尔随机分析，以评估 27 种循环生物标志物的观察性和因果关系在英国生物银行多达 451 933 名参与者中具有 7 项心血管特征。结果：经过多次测试校正（alpha=1.3×10 ^-4)，我们总共发现了 15、9、21、22、26、24 和 26 个与冠状动脉疾病、缺血性中风、心房颤动、2 型糖尿病、收缩压、体重指数和腰围密切相关的生物标志物。臀围比；分别。孟德尔随机化分析证实了先前提出的几种葡萄糖和脂质相关生物标志物与 2 型糖尿病和冠状动脉疾病的因果关系的有力证据。特别有趣的发现包括 IGF-1（胰岛素样生长因子 1）在收缩压中的保护作用，以及脂蛋白 (a) 在冠状动脉疾病发展中的强因果关系（β，-0.13；每个 SD 暴露变化结果和优势比，1.28；P =2.6×10 ^-4和P=7.4×10 ^-35，分别）。此外，我们的结果表明 ALT（丙氨酸转氨酶）增加在 2 型糖尿病和高血压的发展中的因果作用（比值比，1.59 和 β，0.06，暴露和结果的每个 SD 变化；P =4.8×10 ^-11并且P =6.0×10 ^-5）。我们的研究结果表明，CRP（C 反应蛋白）和维生素 D 不太可能在心脏代谢疾病的发展中发挥任何有意义的因果作用。这些疾病的原因，这有助于加快新的预防策略。