Within healthy dietary patterns, manipulation of the proportion of macronutrient can reduce CVD risk. However, the biological pathways underlying healthy diet-disease associations are poorly understood. Using an untargeted, large-scale proteomic profiling, we aimed to (1) identify proteins mediating the association between healthy dietary patterns varying in the proportion of macronutrient and lipoproteins, and (2) validate the associations between diet-related proteins and lipoproteins in the Atherosclerosis Risk in Communities (ARIC) Study. In 140 adults from the OmniHeart trial, a randomized, cross-over, controlled feeding study with 3 intervention periods (carbohydrate-rich; protein-rich; unsaturated fat-rich dietary patterns), 4,958 proteins were quantified at the end of each diet intervention period using an aptamer assay (SomaLogic). We assessed differences in log2-transformed proteins in 3 between-diet comparisons using paired t-tests, examined the associations between diet-related proteins and lipoproteins using linear regression, and identified proteins mediating these associations using a causal mediation analysis. Levels of diet-related proteins and lipoprotein associations were validated in the ARIC study (n = 11,201) using multivariable linear regression models, adjusting for important confounders. Three between-diet comparisons identified 497 significantly different proteins (protein-rich vs. carbohydrate-rich = 18; unsaturated fat-rich vs. carbohydrate-rich = 335; protein-rich vs. unsaturated fat-rich dietary patterns = 398). Of these, 9 proteins [apolipoprotein M, afamin, collagen alpha-3(VI) chain, chitinase-3-like protein 1, inhibin beta A chain, palmitoleoyl-protein carboxylesterase NOTUM, cathelicidin antimicrobial peptide, guanylate-binding protein 2, COP9 signalosome complex subunit 7b] were positively associated with lipoproteins [high-density lipoprotein (HDL)-cholesterol (C) = 2; triglyceride = 5; non-HDL-C = 3; total cholesterol to HDL-C ratio = 1]. Another protein, sodium-coupled monocarboxylate transporter 1, was inversely associated with HDL-C and positively associated with total cholesterol to HDL-C ratio. The proportion of the association between diet and lipoproteins mediated by these 10 proteins ranged from 21 to 98%. All of the associations between diet-related proteins and lipoproteins were significant in the ARIC study, except for afamin. We identified proteins that mediate the association between healthy dietary patterns varying in macronutrients and lipoproteins in a randomized feeding study and an observational study. NCT00051350 at clinicaltrials.gov.

中文翻译：

---

循环蛋白与脂蛋白谱的关联：OmniHeart 随机试验和社区动脉粥样硬化风险 (ARIC) 研究的蛋白质组学分析

在健康的饮食模式中，控制大量营养素的比例可以降低心血管疾病的风险。然而，人们对健康饮食与疾病关联的生物学途径知之甚少。使用非针对性的大规模蛋白质组学分析，我们的目的是（1）识别介导不同常量营养素和脂蛋白比例的健康饮食模式之间关联的蛋白质，以及（2）验证饮食相关蛋白质和脂蛋白之间的关联。社区动脉粥样硬化风险 (ARIC) 研究。OmniHeart 试验是一项随机、交叉、控制喂养研究，共有 140 名成年人参加，有 3 个干预期（富含碳水化合物；富含蛋白质；富含不饱和脂肪的饮食模式），在每次饮食干预结束时对 4,958 种蛋白质进行了定量使用适体测定（SomaLogic）的周期。我们使用配对 t 检验评估了 3 个饮食间比较中 log2 转化蛋白质的差异，使用线性回归检查了饮食相关蛋白质和脂蛋白之间的关联，并使用因果中介分析确定了介导这些关联的蛋白质。ARIC 研究（n = 11,201）使用多变量线性回归模型验证了饮食相关蛋白质和脂蛋白关联的水平，并调整了重要的混杂因素。三个饮食之间的比较确定了 497 种显着不同的蛋白质（富含蛋白质与富含碳水化合物= 18；富含不饱和脂肪与富含碳水化合物= 335；富含蛋白质与富含不饱和脂肪的饮食模式= 398）。其中，9 种蛋白质 [载脂蛋白 M、afamin、胶原蛋白 α-3(VI) 链、几丁质酶 3 样蛋白 1、抑制素 β A 链、棕榈酰蛋白羧酸酯酶 NOTUM、cathelicidin 抗菌肽、鸟苷酸结合蛋白 2、COP9 信号体复合体亚基 7b] 与脂蛋白呈正相关[高密度脂蛋白 (HDL)-胆固醇 (C) = 2；甘油三酯=5；非 HDL-C = 3；总胆固醇与 HDL-C 的比率 = 1]。另一种蛋白质，钠偶联单羧酸转运蛋白 1，与 HDL-C 呈负相关，与总胆固醇与 HDL-C 的比率呈正相关。这 10 种蛋白质介导的饮食与脂蛋白之间的关联比例为 21% 至 98%。在 ARIC 研究中，除 afamin 外，饮食相关蛋白质和脂蛋白之间的所有关联都很显着。我们在一项随机喂养研究和一项观察性研究中发现了介导不同宏量营养素和脂蛋白的健康饮食模式之间关联的蛋白质。ClinicalTrials.gov 上的 NCT00051350。