Development and validation of an epigenetic signature of allostatic load

Abstract

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.

Keywords: Allostatic load; Chronic Stress; Chronic diseases; DNA methylation; Epigenetic signature; Prevention.

Figure 1. Plot of the correlation between phenotypic allostatic load and the epigenetic signature in the SKIPOGH cohort.

(A). The correlation between AL-GP (the phenotype-based score) and the methAL signature. (B). The correlation between AL-GP and the HM-450K compatible methALT signature, stratified by sex. Plots were created using data from the SKIPOGH cohort.SKIPOGH, Swiss Kidney Project on Genes in Hypertension.

Figure 2. Plot of odds ratios and 95% confidence intervals for probability of history of cardiovascular disease corresponding to different measures of allostatic load.

Odds ratios and 95% confidence intervals for the association between measures of AL and a history of cardiovascular disease. Presented odds ratios correspond to standardized signatures.

Figure 3. Association between methALT and the risk of mortality in the LBC1936 cohort over time.

The solid black line represents the hazard ratio (HR) of the association between the methALT signature and risk of mortality with increasing time since study entry. HRs correspond to the standardized methALT signature. The gray area represents the 95% confidence interval. LBC1936, Lothian Birth Cohort 1936.

Figure 4. Risk of mortality according to the method used to measure allostatic load in the LBC1936 cohort.

Filled-in circles represent the point estimate, while the solid lines correspond to the 95% confidence interval. All presented hazard ratios correspond to the standardized signature/score. LBC1936, Lothian Birth Cohort 1936.