Chamberlain Jonviea D, Ackermann Daniel, Bochud Murielle, Booth Tom, Chapatte Laurence, Corley Janie, Cox Simon R, Harris Sarah E, Kinnaer Cassandre, Juster Robert-Paul, Locatelli Isabella, Nanchen David, Ponte Belène, Pruijm Menno, Pradervand Sylvain, Shiels Paul G, Stringhini Silvia, Nusslé Sébastien, Gonseth-Nusslé Semira
Department of Epidemiology and Health Systems (DESS), Unisanté, University Center for Primary Care and Public Health, Lausanne, Switzerland.
Department for Nephrology and Hypertension Inselspital, Inselspital, Bern University Hospital and University of Bern, Bern 3010, Switzerland.
Biosci Rep. 2025 Apr 9;45(4):247-62. doi: 10.1042/BSR20241663.
The allostatic load (AL) concept measures physiological dysregulation in response to internal and external stressors that accumulate across the life course. AL has been consistently linked to chronic disease risk across studies. However, there is considerable variation in its operationalization. In the present study, DNA methylation (DNAm) data (using the Illumina Infinium MethylationEPIC BeadChip array) from the Swiss Kidney Project on Genes in Hypertension (SKIPOGH) cohort, a Swiss-based family cohort study, were used in a discovery epigenome-wide association study to identify cytosine-guanine nucleotide sites associated with phenotypic measures of AL. Elastic net linear regression models were used to estimate an epigenetic signature of AL (methAL), including an Illumina HumanMethylation450K (HM450K) assay-compatible signature (methALT). The methALT signature was validated in the 1936 Lothian Birth Cohort (LBC1936), population-based prospective cohort study. We found that the methAL signature was positively associated with the clinical phenotype of AL in both the SKIPOGH (R2 = 0.59) and LBC1936 (R2 = 0.16) cohorts. In the validation cohort, a one standard deviation increase in methALT signature was associated with 25% higher odds of reported history of cardiovascular disease (CVD) (odd ratio [OR] = 1.25, 95% confidence interval [CI] = 1.05-1.50), and a nearly two-fold increase in all-cause mortality rate at the beginning of follow-up (hazard ratio = 1.68, 95% CI = 1.33-2.13) when adjusting for all potential confounders. In conclusion, the epigenetic signature for AL not only correlated well with phenotype-based AL scores but also exhibited a stronger association with the history of CVD and all-cause mortality compared with AL scores. The methAL signature could help assuage issues of comparison across studies.
累积负荷（AL）概念衡量的是个体在应对贯穿生命历程的内外部应激源时出现的生理失调情况。在各项研究中，AL一直都与慢性病风险相关联。然而，其操作化定义存在相当大的差异。在本研究中，我们使用了瑞士高血压基因肾脏项目（SKIPOGH）队列（一项基于瑞士的家族队列研究）的DNA甲基化（DNAm）数据（采用Illumina Infinium MethylationEPIC BeadChip芯片阵列），进行了一项全表观基因组关联发现研究，以识别与AL表型测量相关的胞嘧啶-鸟嘌呤核苷酸位点。采用弹性网络线性回归模型来估计AL的表观遗传特征（methAL），包括一个与Illumina HumanMethylation450K（HM450K）检测兼容的特征（methALT）。该methALT特征在基于人群的前瞻性队列研究——1936年洛锡安出生队列（LBC1936）中得到了验证。我们发现，在SKIPOGH队列（R2 = 0.59）和LBC1936队列（R2 = 0.16）中，methAL特征均与AL的临床表型呈正相关。在验证队列中，调整所有潜在混杂因素后，methALT特征增加一个标准差与报告的心血管疾病（CVD）病史几率高出25%相关（比值比[OR] = 1.25，95%置信区间[CI] = 1.05 - 1.50），并且在随访开始时全因死亡率增加近两倍（风险比 = 1.68，95% CI = 1.33 - 2.13）。总之，AL的表观遗传特征不仅与基于表型的AL评分密切相关，而且与CVD病史和全因死亡率的关联比AL评分更强。methAL特征有助于缓解不同研究之间的比较问题。
