scholarly journals Creating and Validating a DNA Methylation-Based Proxy for Interleukin-6

2021 ◽  
Author(s):  
Anna J Stevenson ◽  
Danni A Gadd ◽  
Robert F Hillary ◽  
Daniel L McCartney ◽  
Archie Campbell ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cognitive Functioning ◽  
Chronic Inflammation ◽  
Interleukin 6 ◽  
Inverse Association ◽  
Generation Scotland ◽  
Independent Test ◽  
Lothian Birth Cohort ◽  
Weighted Score ◽  
The Relationship

Abstract Background Studies evaluating the relationship between chronic inflammation and 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. DNA methylation (DNAm) has shown utility in indexing environmental exposures and could be leveraged to provide proxy signatures of chronic inflammation. Method We conducted an elastic net regression of interleukin-6 (IL-6) in a cohort of 875 older adults (Lothian Birth Cohort 1936; mean age: 70 years) to develop a DNAm-based predictor. The predictor was tested in an independent cohort (Generation Scotland; N = 7028 [417 with measured IL-6], mean age: 51 years). Results A weighted score from 35 CpG sites optimally predicted IL-6 in the independent test set (Generation Scotland; R2 = 4.4%, p = 2.1 × 10−5). In the independent test cohort, both measured IL-6 and the DNAm proxy increased with age (serum IL-6: n = 417, β = 0.02, SE = 0.004, p = 1.3 × 10−7; DNAm IL-6 score: N = 7028, β = 0.02, SE = 0.0009, p < 2 × 10−16). Serum IL-6 did not associate with cognitive ability (n = 417, β = −0.06, SE = 0.05, p = .19); however, an inverse association was identified between the DNAm score and cognitive functioning (N = 7028, β = −0.16, SE = 0.02, pFDR < 2 × 10−16). Conclusions These results suggest methylation-based predictors can be used as proxies for inflammatory markers, potentially allowing for further insight into the relationship between inflammation and pertinent health outcomes.

scholarly journals Creating and validating a DNA methylation-based proxy for Interleukin-6

2020 ◽  
Author(s):  
Anna J Stevenson ◽  
Danni A Gadd ◽  
Robert Francis Hillary ◽  
Daniel L. McCartney ◽  
Archie Campbell ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cognitive Functioning ◽  
Cognitive Ability ◽  
Chronic Inflammation ◽  
Interleukin 6 ◽  
Epigenetic Mechanism ◽  
Inverse Association ◽  
Age Related ◽  
Independent Test ◽  
Methylation Score

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.

scholarly journals Characterisation of an inflammation-related epigenetic score and its association with cognitive ability

2019 ◽  
Author(s):  
Anna J. Stevenson ◽  
Daniel L. McCartney ◽  
Robert F. Hillary ◽  
Archie Campbell ◽  
Stewart W. Morris ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cognitive Ability ◽  
Chronic Inflammation ◽  
Birth Cohort ◽  
Large Scale ◽  
Acute Infection ◽  
Plasma Concentrations ◽  
Generation Scotland ◽  
Lothian Birth Cohort ◽  
Serum Crp

ABSTRACTResults from large cohort studies investigating the association between inflammation and cognition have been mixed, possibly due to methodological disparities. However, a key issue in research utilising inflammatory biomarkers is their typically phasic responses. C-reactive protein (CRP) is widely used to investigate the association between chronic inflammation and cognition, but its plasma concentrations can markedly deviate in response to acute infection. Recently a large-scale epigenome-wide association study identified DNA methylation correlates of CRP. DNA methylation is thought to be relatively stable in the short term, marking it as a potentially useful signature of exposure. Here, we generate an epigenetic CRP score and investigate its trajectories with age, and associations with cognitive ability, in comparison to serum CRP in two cohorts: a longitudinal study of older adults (the Lothian Birth Cohort 1936, n=889) and a large, cross-sectional cohort (Generation Scotland, n=7,028).We identified differing trajectories of serum CRP across the cohorts, with no homogeneous trends seen with age. Conversely, the epigenetic score was consistently found to increase with age, and to do so more rapidly in males compared to females. Higher levels of serum CRP were found to associate with poorer cognition in Lothian Birth Cohort 1936, but not in Generation Scotland. However, a consistent negative association was identified between cognition and the epigenetic score in both cohorts. Furthermore, the epigenetic score accounted for a greater proportion of variance in cognitive ability.Our results suggest that epigenetic signatures of acute inflammatory markers may provide an enhanced signature of chronic inflammation, allowing for more reliable stratification of individuals, and thus clearer inference of associations with incident health outcomes.

scholarly journals DNA methylation and cognitive functioning in healthy older adults

2011 ◽  
Vol 107 (5) ◽  
pp. 744-748 ◽  
Author(s):  
Olga J. G. Schiepers ◽  
Martin P. J. van Boxtel ◽  
Renate H. M. de Groot ◽  
Jelle Jolles ◽  
Frans J. Kok ◽  
...  
Keyword(s):  
Older Adults ◽  
Dna Methylation ◽  
Folic Acid ◽  
Cognitive Functioning ◽  
Cognitive Performance ◽  
Global Dna Methylation ◽  
Older Individuals ◽  
Healthy Older Adults ◽  
Study Results ◽  
The Relationship

Long-term supplementation with folic acid may improve cognitive performance in older individuals. The relationship between folate status and cognitive performance might be mediated by changes in methylation capacity, as methylation reactions are important for normal functioning of the brain. Although aberrant DNA methylation has been implicated in neurodevelopmental disorders, the relationship between DNA methylation status and non-pathological cognitive functioning in human subjects has not yet been investigated. The present study investigated the associations between global DNA methylation and key domains of cognitive functioning in healthy older adults. Global DNA methylation, defined as the percentage of methylated cytosine to total cytosine, was measured in leucocytes by liquid chromatography–MS/MS, in 215 men and women, aged 50–70 years, who participated in the Folic Acid and Carotid Intima-Media Thickness (FACIT) study (clinical trial registration number NCT00110604). Cognitive performance was assessed by means of the Visual Verbal Word Learning Task, the Stroop Colour-Word Interference Test, the Concept Shifting Test, the Letter–Digit Substitution Test and the Verbal Fluency Test. Using hierarchical linear regression analyses adjusted for age, sex, level of education, alcohol consumption, smoking status, physical activity, erythrocyte folate concentration and 5,10-methylenetetrahydrofolate reductase 677 C → T genotype, we found that global DNA methylation was not related to cognitive performance on any of the domains measured. The present study results do not support the hypothesis that global DNA methylation, as measured in leucocytes, might be associated with cognitive functioning in healthy older individuals.

scholarly journals DNA methylation proxies for 16 plasma proteins predict the incidence of 7 leading causes of morbidity

2020 ◽  
Author(s):  
Danni A Gadd ◽  
Robert F Hillary ◽  
Daniel L McCartney ◽  
Anna J Stevenson ◽  
Cliff Nangle ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Plasma Proteins ◽  
Multiple Testing ◽  
Disease Risk ◽  
Common Disease ◽  
Protein Biomarkers ◽  
Inflammatory Protein ◽  
Generation Scotland ◽  
Lothian Birth Cohort

AbstractChronic morbidities place longstanding burdens on our health as we age. Although protein biomarkers are critical for the early detection of such diseases, current studies are limited by low sample sizes, variability in proteomics methods and fluctuations in inflammatory protein expression. Here, we present a novel framework for protein-by-proxy analysis of incident disease. We show that DNA methylation proxies for nine inflammatory and seven neurology plasma proteins (generated in up to 875 individuals in the Lothian Birth Cohort 1936) predict the incidence of seven leading causes of morbidity in the Generation Scotland cohort (n=9,537), ascertained via electronic health data linkage over a follow-up period of up to 14 years. After correction for multiple testing and adjustment for common disease risk factors, these included proxy associations between CCL11 and depression (Hazard Ratio: HR = 1.45, P = 1.8 x 10-4), VEGFA and ischaemic heart disease (HR = 1.16, P = 0.02) and associations between incident diabetes and FGF-21 (HR = 1.39, P = 9.7 x 10-7), NEP (HR = 1.32, P = 2.8 x 10-6) and N-CDase (HR = 1.16, P = 0.02). Several of the protein-proxy associations with disease pinpoint proteins that are already therapeutic targets for the diseases in question. These results provide new opportunities to identify circulating biomarkers for disease detection and candidate pathways for drug targeting.

scholarly journals Socially stratified epigenetic profiles are associated with cognitive functioning in children and adolescents

2021 ◽  
Author(s):  
Laurel Amber Sjodin Raffington ◽  
Peter Tanksley ◽  
Aditi Sabhlok ◽  
Liza Vinnik ◽  
Travis Triplett Mallard ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cognitive Functioning ◽  
Social Inequality ◽  
Chronic Inflammation ◽  
Social Inequalities ◽  
Surrogate Endpoint ◽  
Biological Aging ◽  
Negative Effects ◽  
Reading And Math ◽  
Perceptual Reasoning

Children's cognitive functioning and educational performance are socially stratified. Social inequality, including classism and racism, may operate partly via epigenetic mechanisms that modulate neurocognitive development. Following preregistered analyses of data from 1,183 8- to 19-year-olds from the Texas Twin Project, we examined whether salivary DNA-methylation measures of inflammation (DNAm-CRP), cognitive functioning (Epigenetic-g), and pace of biological aging (DunedinPoAm) are socially stratified and associated with performance on tests of cognitive functions. We find that children growing up in more disadvantaged families and neighborhoods and children from marginalized racial/ethnic groups exhibit DNA-methylation profiles associated with higher chronic inflammation, lower cognitive functioning, and faster pace of biological aging. These salivary DNA-methylation profiles were associated with processing speed, general executive function, perceptual reasoning, verbal comprehension, reading, and math. Given that the DNA-methylation measures we examined were originally developed in adults, our results suggest that social inequalities may produce in children molecular signatures that, when observed in adults, are associated with chronic inflammation, advanced aging, and reduced cognitive function. Salivary DNA-methylation profiles might be useful as a surrogate endpoint in assessing the effectiveness of psychological and economic interventions that aim to reduce negative effects of childhood social inequality on lifespan development.

scholarly journals DNA methylation in the APOE gene: its link with Alzheimer’s and cardiovascular health

2019 ◽  
Author(s):  
Jure Mur ◽  
Daniel L. McCartney ◽  
Rosie M. Walker ◽  
Archie Campbell ◽  
Mairead L. Bermingham ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cardiovascular Disease ◽  
Dna Methylation ◽  
Genetic Variation ◽  
Linear Regression ◽  
Cardiovascular Health ◽  
Hdl Cholesterol ◽  
Blood Cholesterol ◽  
Generation Scotland ◽  
The Relationship

AbstractGenetic variation in the apolipoprotein E (APOE) gene is associated with Alzheimer’s disease (AD) and risk factors for cardiovascular disease (CVD). DNA methylation at APOE has been linked to altered cognition and AD. It is unclear if epigenetic marks could be used for predicting future disease. We assessed blood-based DNA methylation at 13 CpGs in the APOE gene in 5828 participants from the Generation Scotland (GS) cohort. Using linear regression, we examined the relationship between APOE methylation, cognition, cholesterol, and the risks for AD and CVD. DNA methylation at two CpGs was associated with the ratio of total-to-HDL cholesterol, but not with cognition, or the risks of AD or CVD. APOE methylation could be involved in the levels of blood cholesterol, but there is no evidence for the utility of APOE methylation as a biomarker for predicting AD or CVD.

scholarly journals The Relationship Between Chronic Inflammation and Glucidic-Lipidic Profile Disorders in Kidney Transplant Recipients

2016 ◽  
Vol 62 (1) ◽  
pp. 60-63
Author(s):  
I.D. Tarța ◽  
Carmen Denise Căldăraru ◽  
Mirela Gliga ◽  
Adina Huțanu ◽  
Z. Bajko ◽  
...  
Keyword(s):  
Lipid Profile ◽  
Chronic Inflammation ◽  
Kidney Transplant ◽  
Interleukin 6 ◽  
Transplant Recipients ◽  
Kidney Transplant Recipients ◽  
Diabetic Kidney ◽  
Group A ◽  
Group B ◽  
The Relationship

AbstractIntroduction: Chronic inflammation has a proven role in atherogenesis, lipid profile parameters being related to cytokine production. In kidney transplant recipients, interleukin 6 (IL-6) is significantly associated with graft-related outcomes and also alterations of cholesterol and triglyceride metabolism. The aim of this study was to investigate the relationship between chronic inflammation and glucidic-lipidic metabolism disorders in a group of patients with kidney transplantation as renal replacement therapy. Methods: A prospective observational study which enrolled thirtysix non-diabetic kidney transplant recipients was conducted in the Nephrology and Peritoneal Dialysis Department, County Clinic Hospital of Tirgu Mures. The study group was divided as following: recipients with serum IL-6 concentration higher than 3.8 pg/ml (group A) and IL-6 within the normal range (group B). Results: Allograft recipients with higher serum IL-6 had significant higher erytrocyte sedimentation rate(ESR, p=0.0067). Patients with over-the-range levels of IL-6 had significant higher levels of serum cholesterol and LDL-cholesterol respectively (p=0.0242 and p=0.0081). Serum Apo-B was also significant higher in Group A than Group B. Protein excretion was significant higher in patients from group A (p=0.0013). No statistical significant relationship could be proven between elevated levels of IL-6 and hbA1c, insulin and glycosuria disturbances in the two groups. Also, we found no statistical significant association between resistivity and pulsatility indices (both hilum and intragraft) or carotid intima media thickness. Conclusion: Serum interleukin 6 is related to lipid profile disorders and less to glucidic metabolism anomalies in non-diabetic kidney transplant recipients.

scholarly journals An epigenetic proxy of chronic inflammation outperforms serum levels as a biomarker of brain ageing

2020 ◽  
Author(s):  
Eleanor L.S. Conole ◽  
Anna J. Stevenson ◽  
Claire Green ◽  
Sarah E. Harris ◽  
Susana Muñoz Maniega ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Chronic Inflammation ◽  
Later Life ◽  
Serum Levels ◽  
Inverse Association ◽  
Domain Specific ◽  
Reactive Protein ◽  
Inflammatory Status ◽  
Brain Ageing ◽  
Serum Crp

AbstractLow-level chronic inflammation increases with age and is associated with cognitive decline. DNA methylation (DNAm) levels may provide more stable reflections of cumulative inflammatory burden than traditional serum approaches. Using structural and diffusion MRI data from 521 individuals aged 73, we demonstrate that a DNAm proxy of C-Reactive Protein (CRP) shows significantly (on average 6.4-fold) stronger associations with brain structural outcomes than serum CRP. We additionally find that DNAm CRP has an inverse association with global and domain-specific (speed, visuospatial and memory) cognitive functioning, and that brain structure partially mediates this CRP-cognitive association (up to 29.4%), dependent on lifestyle and health factors. These data support the hypothesis that chronic systemic inflammation may contribute to neurodegenerative brain changes which underlie differences in cognitive ability in later life. DNA methylation-based predictors could be used as proxies for chronic inflammatory status.

scholarly journals Yogurt Consumption Is Associated with Lower Levels of Chronic Inflammation in the Framingham Offspring Study

Nutrients ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 506
Author(s):  
Mengjie Yuan ◽  
Martha R. Singer ◽  
Lynn L. Moore
Keyword(s):  
Chronic Inflammation ◽  
Interleukin 6 ◽  
Normal Weight ◽  
Community Dwelling ◽  
Inflammatory Biomarkers ◽  
Inverse Association ◽  
Dairy Foods ◽  
Diet Records ◽  
Different Types

Some studies suggest that dairy foods may be linked with less chronic inflammation. However, few studies have investigated the separate effects of different types of dairy on inflammation. Therefore, the current study aims to examine the separate prospective impacts of milk, yogurt and cheese on biomarkers of chronic inflammation in 1753 community-dwelling participants of the Framingham Offspring Study (FOS). Mean intakes of dairy foods were derived from two sets of three-day diet records. Six inflammatory biomarkers were assessed approximately seven years later at exam 7. Results showed that those who consumed yogurt (vs. those who did not) had statistically significantly lower levels of interleukin-6 (IL-6) (mean log-transformed levels of 1.31 and 1.26 in consumers/non-consumers, respectively, p = 0.02) and fibrin (mean log-transformed levels of 5.91 and 5.89 in consumers/non-consumers, respectively, p = 0.03). The inverse association between IL-6 and yogurt consumption was similar in participants who were of normal weight and those who were overweight. For fibrin, the effects were stronger in overweight individuals. No statistically significant associations were observed between any of these inflammation biomarkers and milk or cheese intakes. Overall, our study compared the separate impacts of three types of dairy foods on chronic inflammation and found that only yogurt intake was linked with lower levels of chronic inflammation.

scholarly journals DNA Methylation and Protein Markers of Chronic Inflammation and Their Associations With Brain and Cognitive Aging

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012997
Author(s):  
Eleanor L.S. Conole ◽  
Anna J. Stevenson ◽  
Susana Muñoz Maniega ◽  
Sarah E. Harris ◽  
Claire Green ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Health Outcomes ◽  
Cognitive Functioning ◽  
Chronic Inflammation ◽  
Brain Health ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Matter Volume ◽  
Inflammatory Status ◽  
Serum Crp

Objective:To investigate chronic inflammation in relation cognitive ageing by comparison of an epigenetic and serum biomarker of C-Reactive Protein and their associations with neuroimaging and cognitive outcomes.Methods:At baseline, participants (N = 521) were cognitively normal, around 73 years of age (M = 72.4, SD = 0.716), and had inflammation, vascular risk (cardiovascular disease history, hypertension, diabetes, smoking, alcohol consumption and BMI) and neuroimaging (structural and diffusion MRI) data available. Baseline inflammatory status was quantified by a traditional measure of peripheral inflammation – serum C-Reactive Protein (serum CRP) – and an epigenetic measure (DNA methylation signature of CRP; DNAm CRP). Linear models were used to examine the inflammation-brain health associations; mediation analyses were performed to interrogate the relationship between chronic inflammation, brain structure and cognitive functioning.Results:We demonstrate that DNAm CRP shows significantly (on average 6.4-fold) stronger associations with brain health outcomes than serum CRP. DNAm CRP is associated with total brain volume (β = -0.197, 95% CI [-0.28, -0.12], pFDR = 8.42 x 10-6), grey matter volume (β = -0.200, 95% CI [-0.28, -0.12], pFDR = 1.66 x 10-5) and white matter volume (β = -0.150, 95% CI [-0.23, -0.07], pFDR = 0.001) and regional brain atrophy. We additionally find that DNAm CRP has an inverse association with global and domain-specific (speed, visuospatial and memory) cognitive functioning, and that brain structure partially mediates this CRP-cognitive association (up to 29.7%), dependent on lifestyle and health factors.Conclusions:These results support the hypothesis that chronic inflammation may contribute to neurodegenerative brain changes which underlie differences in cognitive ability in later life and highlight the potential of DNA methylation proxies for indexing chronic inflammatory status.Classification of Evidence:This study provides Class II evidence that a DNA methylation signature of CRP levels is more strongly associated with brain health outcomes than serum CRP levels.

Sign in / Sign up

Export Citation Format

Share Document