Methylation of FKBP5 is associated with accelerated DNA methylation ageing and cardiometabolic risk: replication in young-adult and middle-aged Black Americans

Abstract

Methylation of FKBP5 is involved in the regulation of the stress response and is influenced by early stress exposure. Two CpG sites, cg20813374 and cg00130530, have been identified as potential reporters of early stress. We examined whether FKBP5 methylation was associated with accelerated DNA methylation ageing and indirectly predicted poorer cardiovascular health among both young adult and middle-aged Black Americans. Four hundred and forty-nine young adults, with a mean age of 28.67 and N = 469 middle-age parents and their current partners with a mean age of 57.21, provided self-reports, biometric assessments, and blood draws. Methylation values were obtained using the Illumina Epic Array. Cardiometabolic risk was calculated by summing the standardized log-transformed scores for the body mass index, mean arterial blood pressure, and HbA1c. We also used a more standard index of risk, the Framingham 10-year cardiometabolic risk index, as an alternative measure of cardiometabolic risk. To measure accelerated ageing, four widely used indices of accelerated, DNA methylation-based ageing were used controlling sex, age, other variation in FKBP5, and cell-type. Exposure to community danger was associated with demethylation of FKBP5. FKBP5 methylation was significantly associated with accelerated ageing for both young-adult and middle-aged samples, with significant indirect effects from FKBP5 methylation to cardiometabolic risk through accelerated ageing for both. Early exposure to danger may influence FKBP5 methylation. In turn, FKBP5 methylation may help explain intrinsic accelerated ageing and elevated cardiometabolic risk in adulthood for Black Americans.

Do Loneliness and Per Capita Income Combine to Increase the Pace of Biological Aging for Black Adults across Late Middle Age?

“…For example, although only 8% of Framingham Health Study (FHS) participants with both self-report and genome-wide DNA methylation profiling self-reported current smoking at their Wave 8 assessment, over 50% of them had probe-based assessment of cg05575921 methylation, a generally accepted biomarker of smoking, in the range suggestive of current and/or past smoking [ 43 ]. Combined with prior studies, which show high rates of unreliable self-reports of smoking [ 17 , 44 , 45 , 46 , 47 , 48 ], we believe that there is considerable reason to be concerned that underreporting could affect conclusions regarding the relationship of smoking to accelerated EA, contributing to apparent inconsistencies in the literature. Accordingly, in the current investigation we use level of methylation at cg05575921 as our index of cumulative exposure to cigarette smoke.…”

Refining epigenetic prediction of chronological and biological age

“…Hypomethylation at probes nearby these genes has been previously linked to increased mortality risk, be that all-cause or disease specific (e.g., cancer or, cardiovascularrelated mortality) 20,[68][69][70] . Other, non-smoking related, lead probes mapped to genes whose methylation has been linked to various forms of cancer, increased cardiometabolic risk, and age-related macular degeneration [25][26][27][28][29][30][31][32][33][34] . There was moderate agreement (correlation of 0.58 between Z scores) between our findings and the significant results from a previous EWAS meta-analysis of survival.…”

“…Of the non-smoking-related CpGs amongst the top 50 associations, seven mapped to genes whose methylation has been linked to various forms of cancer, including ZMIZ1 25 , SOCS3 [26][27][28] , ZMYND8 29 and CHD5 [30][31][32] . Another probe mapped to FKBP5, a gene whose methylation is involved in the regulation of the stress response, and which has been linked to increased cardiometabolic risk through accelerated ageing 33 . Finally, one top probe mapped to SKI, whose methylation has been linked to age-related macular degeneration 34 .…”

Sex differences in saliva-based DNA methylation changes and environmental stressor in young African American adults

“…This study sought to explore whether social/environmental stressors such as exposure to interpersonal and community violence as measured by immune, neurotransmitter, and stress biomarkers cause detectable changes in saliva DNA methylation in young African American adults. In this study, we evaluated the promoter-specific DNA methylation of several genes that are key regulators of the HPA axis such as FKBP 5 [ 49 ] and NR3C 1, a glucocorticoid receptor gene, that plays a role in adaptation to stress [ 50 ]. The dopaminergic system, of which dopamine D2 receptor ( DRD 2) is closely associated with locomotion, reward, and memory [ 51 ] was analyzed as stress directly influences several fundamental behaviors and phenomena including locomotor activity, sexual activity, appetite, drugs or abuse via the dopaminergic system [ 52 ].…”