Huang Xin, Zhao Jie V
School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
Am J Clin Nutr. 2023 Nov;118(5):1020-1028. doi: 10.1016/j.ajcnut.2023.08.011. Epub 2023 Aug 26.
Alanine is an amino acid commonly used as a nutritional supplement and plays a key role in the glucose-alanine cycle. Plasma alanine has been associated in observational studies with a higher risk of coronary artery disease (CAD) and unhealthier lipid profiles. However, evidence from large randomized controlled trials is lacking.
Using Mendelian randomization (MR), we assessed the unconfounded associations of plasma alanine with CAD and CAD risk factors.
We applied single nucleotide polymorphisms that were strongly (P < 5 ×10) associated with plasma alanine as genetic instruments to large genome-wide association studies of CAD (63,108 cases; 296,901 controls), diabetes (90,612 cases; 583,493 controls), glucose (515,538 participants), lipids (low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, triglycerides, total cholesterol, and apolipoprotein B) (>1.1 million participants), blood pressure (BP) (757,601 participants), and body mass index (682,137 participants). Given the potential sex disparity, we also conducted sex-specific analyses. MR estimates per standard deviation increase in alanine concentrations were obtained using inverse variance weighting followed by sensitivity analyses using weighted median, MR-Egger, MR-Pleiotropy RESidual Sum and Outlier, and MR-Robust Adjusted Profile Score.
Genetically predicted plasma alanine was not associated with CAD but with a higher risk of diabetes (odds ratio [OR]: 1.35; 95% confidence interval [CI]: 1.06, 1.72), higher glucose (β: 0.11; 95% CI: 0.02, 0.19), LDL cholesterol (β: 0.08; 95% CI: 0.04, 0.12), triglycerides (β: 0.25; 95% CI: 0.13, 0.38), total cholesterol (β: 0.14; 95% CI: 0.08, 0.20), apolipoprotein B (β: 0.12; 95% CI: 0.03, 0.21), and BP (β: 1.17; 95% CI: 0.31, 2.04 for systolic BP: β: 0.97; 95% CI: 0.49, 1.45 for diastolic BP) overall. The positive associations of serum alanine with LDL cholesterol and triglycerides were more notable in women than in men.
Alanine or factors affecting alanine may have causal effects on diabetes, blood glucose, lipid profiles, and BP but not on CAD. Further studies are needed to clarify possible mechanisms.
丙氨酸是一种常用作营养补充剂的氨基酸，在葡萄糖-丙氨酸循环中起关键作用。在观察性研究中，血浆丙氨酸与冠状动脉疾病（CAD）风险较高和脂质谱不健康有关。然而，缺乏大型随机对照试验的证据。
使用孟德尔随机化（MR）方法，我们评估了血浆丙氨酸与CAD及CAD风险因素之间无混杂因素的关联。
我们将与血浆丙氨酸强烈相关（P < 5×10）的单核苷酸多态性作为基因工具，应用于CAD（63108例；296901例对照）、糖尿病（90612例；583493例对照）、血糖（515538名参与者）、脂质（低密度脂蛋白[LDL]胆固醇、高密度脂蛋白[HDL]胆固醇、甘油三酯、总胆固醇和载脂蛋白B）（超过110万名参与者）、血压（BP）（757601名参与者）和体重指数（682137名参与者）的大型全基因组关联研究。鉴于潜在的性别差异，我们还进行了性别特异性分析。使用逆方差加权法获得丙氨酸浓度每增加一个标准差的MR估计值，随后使用加权中位数、MR-Egger、MR-多效性残差和异常值以及MR-稳健调整轮廓得分进行敏感性分析。
基因预测的血浆丙氨酸与CAD无关，但与糖尿病风险较高（比值比[OR]：1.35；95%置信区间[CI]：1.06，1.72）、血糖较高（β：0.11；95%CI：0.02，0.19）、LDL胆固醇（β：0.08；95%CI：0.04，0.12）、甘油三酯（β：0.25；95%CI：0.13，0.38）、总胆固醇（β：0.14；95%CI：0.08，0.20）、载脂蛋白B（β：0.12；95%CI：0.03，0.21）和BP（收缩压β：1.17；95%CI：0.31，2.04；舒张压β：0.97；95%CI：0.49，1.45）总体相关。血清丙氨酸与LDL胆固醇和甘油三酯的正相关在女性中比在男性中更显著。
丙氨酸或影响丙氨酸的因素可能对糖尿病、血糖、脂质谱和BP有因果影响，但对CAD没有影响。需要进一步研究以阐明可能的机制。
