Centre of Excellence for Nutrition, North-West University, Potchefstroom, South Africa.
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
Front Immunol. 2020 Jul 31;11:1577. doi: 10.3389/fimmu.2020.01577. eCollection 2020.
DNA methylation data can be used to estimate proportions of leukocyte subsets retrospectively, when directly measured cell counts are unavailable. The methylation-derived neutrophil-to-lymphocyte and lymphocyte-to-monocyte ratios (mdNLRs and mdLMRs) have proven to be particularly useful as indicators of systemic inflammation. As with directly measured NLRs and LMRs, these methylation-derived ratios have been used as prognostic markers for cancer, although little is known about them in relation to other disorders with inflammatory components, such as cardiovascular disease (CVD). Recently, methylation of five genomic cytosine-phosphate-guanine sites (CpGs) was suggested as proxies for mdNLRs, potentially providing a cost-effective alternative when whole-genome methylation data are not available. This study compares seven methylation-derived inflammatory markers (mdNLR, mdLMR, and individual CpG sites) with five conventionally used protein-based inflammatory markers (C-reactive protein, interleukins 6 and 10, tumor-necrosis factor alpha, and interferon-gamma) and a protein-based inflammation score, in their associations with cardiovascular function (CVF) and risk. We found that markers of CVF were more strongly associated with methylation-derived than protein-based markers. In addition, the protein-based and methylation-derived inflammatory markers complemented rather than proxied one another in their contribution to the variance in CVF. There were no strong correlations between the methylation and protein markers either. Therefore, the methylation markers could offer unique information on the inflammatory process and are not just surrogate markers for inflammatory proteins. Although the five CpGs mirrored the mdNLR well in their capacity as proxies, they contributed to CVF above and beyond the mdNLR, suggesting possible added functional relevance. We conclude that methylation-derived indicators of inflammation enable individuals with increased CVD risk to be identified without measurement of protein-based inflammatory markers. In addition, the five CpGs investigated here could be useful surrogates for the NLR when the cost of array data cannot be met. Used in tandem, methylation-derived and protein-based inflammatory markers explain more variance than protein-based inflammatory markers alone.
DNA 甲基化数据可用于在无法直接测量细胞计数时回顾性估计白细胞亚群的比例。衍生自甲基化的中性粒细胞与淋巴细胞比值（mdNLR）和淋巴细胞与单核细胞比值（mdLMR）已被证明是反映全身炎症的特别有用的指标。与直接测量的 NLR 和 LMR 一样，这些衍生自甲基化的比值已被用作癌症的预后标志物，尽管关于它们与其他具有炎症成分的疾病（如心血管疾病 [CVD]）的关系知之甚少。最近，五个基因组胞嘧啶-磷酸-鸟嘌呤位点（CpG）的甲基化被建议作为 mdNLR 的替代物，当无法获得全基因组甲基化数据时，这可能是一种具有成本效益的替代方法。本研究比较了七种衍生自甲基化的炎症标志物（mdNLR、mdLMR 和单个 CpG 位点）与五种常用的基于蛋白质的炎症标志物（C 反应蛋白、白细胞介素 6 和 10、肿瘤坏死因子-α和干扰素-γ）和基于蛋白质的炎症评分，以评估它们与心血管功能（CVF）和风险的相关性。我们发现，与基于蛋白质的标志物相比，CVF 标志物与衍生自甲基化的标志物相关性更强。此外，基于蛋白质和衍生自甲基化的炎症标志物在对 CVF 方差的贡献上相互补充，而不是替代。甲基化和蛋白质标志物之间也没有很强的相关性。因此，甲基化标志物可以提供关于炎症过程的独特信息，而不仅仅是炎症蛋白的替代标志物。尽管这五个 CpG 在作为替代物的能力上很好地反映了 mdNLR，但它们对 CVF 的贡献超出了 mdNLR，表明可能具有额外的功能相关性。我们得出结论，炎症的衍生自甲基化指标可以在不测量基于蛋白质的炎症标志物的情况下识别出 CVD 风险增加的个体。此外，当无法满足阵列数据的成本时，这里研究的五个 CpG 可以作为 NLR 的有用替代物。联合使用衍生自甲基化和基于蛋白质的炎症标志物比单独使用基于蛋白质的炎症标志物可以解释更多的方差。
