背景:这项研究探讨了血浆蛋白质组指标如何解释不良心血管健康(CVH)与痴呆风险之间的联系。
方法:本研究涉及28,974名年龄在50-74岁(2006-2010年)的英国生物银行参与者,在基线(2006-2010年)时,他们的痴呆发生率≤15岁。CVH使用生命基础8(LE8)总分计算。对分数进行标准化和反向编码以反映较差的CVH(LE8z_rev)。OLINK蛋白质组学可用于该样品(k=1,463血浆蛋白)。该研究主要测试了血浆蛋白质组在LE8z_rev-痴呆效应中的介导作用。总效应被分解为“仅调解”或纯间接效应(PIE),“仅交互”或交互引用(INTREF),“既不是调解也不是互动”或受控直接效应(CDE),和“中介和互动”或中介互动(INTMED)。
结果:研究发现,LE8z_rev评估的较差CVH会使全因痴呆的风险增加11%[每1SD,危险比,(HR)=1.11,95%CI:1.03-1.20,p=0.005)。该研究确定了11种具有强介导作用的血浆蛋白,GDF15与痴呆风险的关联最强(每1个SD,HR=1.24,95%CI:1.16,1.33,当LE8z_rev设置为其平均值时,P<0.001)和最大比例介导的PIE和INTMED(62.6%;TE的48%是PIE),其次是肾上腺髓质素或ADM。具有10个顶级介体的第一主成分(TNFRSF1A,GDF15,FSTL3,COL6A3,PLAUR,ADM,GFRAL,ACVRL1,TNFRSF6B,TGFA)介导了53.6%的LE8z_rev-痴呆效应。使用所有显著的PIE(k=526)蛋白,我们使用OLINKInsight通路分析来确定关键通路,这揭示了免疫系统的参与,信号转导,新陈代谢,疾病,蛋白质代谢,止血,膜贩运,细胞外基质组织,发育生物学,和基因表达等。STRING分析显示,五个最高一致的蛋白质组介体在两个较大的集群中代表,反映了许多相互关联的生物基因本体论途径,最值得注意的是GDF15簇的细胞因子介导的信号通路(GO:0019221)和ADM簇的肽基酪氨酸磷酸化的调节(GO:0050730)。
结论:痴呆与GDF15和ADM介导的不良CVH相关,这些标志物共同解释了总效应的54%。
BACKGROUND: The study examined how plasma proteome indicators may explain the link between poor cardiovascular health (CVH) and dementia risk.
METHODS: The present study involved 28,974 UK Biobank participants aged 50-74y at baseline (2006-2010) who were followed-up for ≤ 15 y for incidence of dementia. CVH was calculated using Life\'s Essential 8 (LE8) total scores. The scores were standardized and reverse coded to reflect poor CVH (LE8z_rev). OLINK proteomics was available on this sample (k = 1,463 plasma proteins). The study primarily tested the mediating effects of the plasma proteome in LE8z_rev-dementia effect. The total effect was decomposed into \"mediation only\" or pure indirect effect (PIE), \"interaction only\" or interaction referent (INTREF), \"neither mediation nor interaction\" or controlled direct effect (CDE), and \"both mediation and interaction\" or mediated interaction (INTMED).
RESULTS: The study found poorer CVH assessed by LE8z_rev increased the risk of all-cause dementia by 11 % [per 1 SD, hazard ratio, (HR) = 1.11, 95 % CI: 1.03-1.20, p = 0.005). The study identified 11 plasma proteins with strong mediating effects, with GDF15 having the strongest association with dementia risk (per 1 SD, HR = 1.24, 95 % CI: 1.16, 1.33, P < 0.001 when LE8z_rev is set at its mean value) and the largest proportion mediated combining PIE and INTMED (62.6 %; 48 % of TE is PIE), followed by adrenomedullin or ADM. A first principal component with 10 top mediators (TNFRSF1A, GDF15, FSTL3, COL6A3, PLAUR, ADM, GFRAL, ACVRL1, TNFRSF6B, TGFA) mediated 53.6 % of the LE8z_rev-dementia effect. Using all the significant PIE (k = 526) proteins, we used OLINK Insight pathway analysis to identify key pathways, which revealed the involvement of the immune system, signal transduction, metabolism, disease, protein metabolism, hemostasis, membrane trafficking, extracellular matrix organization, developmental biology, and gene expression among others. STRING analysis revealed that five top consistent proteomic mediators were represented in two larger clusters reflecting numerous interconnected biological gene ontology pathways, most notably cytokine-mediated signaling pathway for GDF15 cluster (GO:0019221) and regulation of peptidyl-tyrosine phosphorylation for the ADM cluster (GO:0050730).
CONCLUSIONS: Dementia is linked to poor CVH mediated by GDF15 and ADM among several key proteomic markers which collectively explained ∼ 54 % of the total effect.