Chronic inflammation is a pervasive feature of ageing and may be linked to age-related cognitive decline. However, population studies evaluating its relationship with cognitive functioning have produced heterogeneous results. A potential reason for this is the variability of inflammatory mediators which could lead to misclassifications of individuals' persisting levels of inflammation. The epigenetic mechanism DNA methylation has shown utility in indexing environmental exposures and could potentially be leveraged to provide proxy signatures of chronic inflammation. We conducted an elastic net regression of interleukin-6 (IL-6) in a cohort of 895 older adults (mean age: 69 years) to develop a DNA methylation-based predictor. The predictor was tested in an independent cohort (n=7,028 [417 with measured IL-6], mean age: 51 years).We examined the association between the DNA methylation IL-6 score and serum IL-6, its association with age and established correlates of circulating IL-6, and with cognitive ability. A weighted score from 12 DNA methylation sites optimally predicted IL-6 (independent test set R2=5.1%). In the independent test cohort, both measured IL-6, and the DNA methylation proxy, increased as a function of age (serum IL-6: n=417, β=0.02, SE=0.004 p=1.3x10-7; DNAm IL-6 score: n=7,028, β=0.02, SE=0.0009, p<2x10-16). Serum IL-6 was not found to associate with cognitive ability (n=417, β=-0.06, SE=0.05, p=0.19); however, an inverse association was identified between the DNA methylation score and cognitive functioning (n=7,028, β=-0.14, SE=0.02, pFDR=1.5x10-14). These results suggest DNA methylation-based predictors can be used as proxies for inflammatory markers, potentially allowing for reliable insights into the relationship between chronic inflammation and pertinent health outcomes.

中文翻译：

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创建并验证基于DNA甲基化的Interleukin-6代理

慢性炎症是衰老的普遍现象，可能与年龄相关的认知能力下降有关。然而，评估其与认知功能关系的人群研究产生了不同的结果。造成这种情况的一个潜在原因是炎症介质的变异性，可能导致个体持续炎症水平的错误分类。DNA甲基化的表观遗传机制已显示出可用于对环境暴露进行索引的功能，并有可能被利用来提供慢性炎症的代理特征。我们在895名年龄较大的成年人（平均年龄：69岁）中进行了白细胞介素6（IL-6）的弹性净回归，以开发基于DNA甲基化的预测因子。在独立队列中对预测变量进行了测试（n = 7,028 [417，测定的IL-6]，平均年龄：51岁）。我们检查了DNA甲基化IL-6得分与血清IL-6之间的关联，其与年龄的关联以及已建立的循环IL-6的关联以及与认知能力的关联。来自12个DNA甲基化位点的加权评分可最佳预测IL-6（独立测试集R2 = 5.1％）。在独立的测试队列中，测得的IL-6和DNA甲基化代理均随年龄增加而增加（血清IL-6：n = 417，β= 0.02，SE = 0.004 p = 1.3x10-7； DNAm IL -6分：n = 7,028，β= 0.02，SE = 0.0009，p <2x10-16）。血清IL-6未发现与认知能力相关（n = 417，β= -0.06，SE = 0.05，p = 0.19）；然而，在DNA甲基化评分与认知功能之间发现了负相关关系（n = 7,028，β= -0.14，SE = 0.02，pFDR = 1.5x10-14）。