ORCID Profile
0000-0001-7350-5489
Current Organisation
University of Southampton
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Publisher: Public Library of Science (PLoS)
Date: 17-10-2014
Publisher: Informa UK Limited
Date: 11-09-2015
Publisher: Elsevier BV
Date: 12-2017
Publisher: The Endocrine Society
Date: 20-02-2019
Abstract: “Accelerated aging,” assessed by adult DNA methylation, predicts cardiovascular disease (CVD). Adolescent accelerated aging might predict CVD earlier. We investigated whether epigenetic age acceleration (assessed age, 17 years) was associated with adiposity/CVD risk measured (ages 17, 20, and 22 years) and projected CVD by middle age. DNA methylation measured in peripheral blood provided two estimates of epigenetic age acceleration: intrinsic (IEAA preserved across cell types) and extrinsic (EEAA dependent on cell admixture and methylation levels within each cell type). Adiposity was assessed by anthropometry, ultrasound, and dual-energy x-ray absorptiometry (ages 17, 20, and 22 years). CVD risk factors [lipids, homeostatic model assessment of insulin resistance (HOMA-IR), blood pressure, inflammatory markers] were assessed at age 17 years. CVD development by age 47 years was calculated by Framingham algorithms. Results are presented as regression coefficients per 5-year epigenetic age acceleration (IEAA/EEAA) for adiposity, CVD risk factors, and CVD development. In 995 participants (49.6% female age, 17.3 ± 0.6 years), EEAA (per 5 years) was associated with increased body mass index (BMI) of 2.4% (95% CI, 1.2% to 3.6%) and 2.4% (0.8% to 3.9%) at 17 and 22 years, respectively. EEAA was associated with increases of 23% (3% to 33%) in high-sensitivity C-reactive protein, 10% (4% to 17%) in interferon-γ–inducible protein of 10 kDa, and 4% (2% to 6%) in soluble TNF receptor 2, adjusted for BMI and HOMA-IR. EEAA (per 5 years) results in a 4% increase in hard endpoints of CVD by 47 years of age and a 3% increase, after adjustment for conventional risk factors. Accelerated epigenetic age in adolescence was associated with inflammation, BMI measured 5 years later, and probability of middle age CVD. Irrespective of whether this is cause or effect, assessing epigenetic age might refine disease prediction.
Publisher: Springer Science and Business Media LLC
Date: 03-02-2023
DOI: 10.1007/S12072-022-10469-7
Abstract: Epigenetic modifications are associated with hepatic fat accumulation and non-alcoholic fatty liver disease (NAFLD). However, few epigenetic modifications directly implicated in such processes have been identified during adolescence, a critical developmental window where physiological changes could influence future disease trajectory. To investigate the association between DNA methylation and NAFLD in adolescence, we undertook discovery and validation of novel methylation marks, alongside replication of previously reported marks. We performed a DNA methylation epigenome-wide association study (EWAS) on DNA from whole blood from 707 Raine Study adolescents phenotyped for steatosis score and NAFLD by ultrasound at age 17. Next, we performed pyrosequencing validation of loci within the most 100 strongly associated differentially methylated CpG sites (dmCpGs) for which ≥ 2 probes per gene remained significant across four statistical models with a nominal p value 0.007. EWAS identified dmCpGs related to three genes ( ANK1, MIR10a , PTPRN2 ) that met our criteria for pyrosequencing. Of the dmCpGs and surrounding loci that were pyrosequenced ( ANK1 n = 6, MIR10a n = 7, PTPRN2 n = 3), three dmCpGs in ANK1 and two in MIR10a were significantly associated with NAFLD in adolescence. After adjustment for waist circumference only dmCpGs in ANK1 remained significant. These ANK1 CpGs were also associated with γ-glutamyl transferase and alanine aminotransferase concentrations. Three of twenty-two differentially methylated dmCpGs previously associated with adult NAFLD were associated with NAFLD in adolescence (all adjusted p 2.3 × 10 –3 ). We identified novel DNA methylation loci associated with NAFLD and serum liver biochemistry markers during adolescence, implicating putative dmCpG/gene regulatory pathways and providing insights for future mechanistic studies.
Publisher: Future Medicine Ltd
Date: 08-2017
Abstract: Excitement about DNA methylation biomarkers has been tempered by a growing appreciation of the complex causal relations with cell fate. Inters le differences in DNA methylation can be partitioned into those that are independent of cellular heterogeneity and those that are caused by differential mixtures of cell types. Generally, the field has assumed that the former are more likely to be causative of disease. The latter has been considered a likely consequence of disease and a confounder to be removed. We argue that the conceptual separation of these signals is artificial and not necessarily informative about causation. DNA methylation is a very sensitive measure of cell fate mix and therefore reveals much about underlying disease etiology including aspects of causation.
Publisher: Elsevier BV
Date: 05-2017
Publisher: Frontiers Media SA
Date: 05-09-2019
Publisher: Frontiers Media SA
Date: 10-09-2019
Publisher: Informa UK Limited
Date: 08-02-2021
Publisher: Public Library of Science (PLoS)
Date: 06-03-2014
Publisher: Springer Science and Business Media LLC
Date: 08-01-2019
Publisher: Wiley
Date: 15-06-2021
DOI: 10.1002/RCO2.44
Abstract: Despite increasing knowledge of the pathogenesis of muscle ageing, the molecular mechanisms are poorly understood. Based on an expression analysis of muscle biopsies from older Caucasian men, we undertook an in‐depth analysis of the expression of the long non‐coding RNA, H19 , to identify molecular mechanisms that may contribute to the loss of muscle mass with age. We carried out transcriptome analysis of vastus lateralis muscle biopsies from 40 healthy Caucasian men aged 68–76 years from the Hertfordshire Sarcopenia Study (HSS) with respect to appendicular lean mass adjusted for height (ALMi). Validation and replication was carried out using qRT‐PCR in 130 independent male and female participants aged 73–83 years recruited into an extension of the HSS (HSSe). DNA methylation was assessed using pyrosequencing. Lower ALMi was associated with higher muscle H19 expression ( r 2 = 0.177, P 0.001). The microRNAs, miR‐675‐5p/3p encoded by exon 1 of H19 , were positively correlated with H19 expression (Pearson r = 0.192 and 0.182, respectively, P 0.03), and miR‐675‐5p expression negatively associated with ALMi ( r 2 = 0.629, P = 0.005). The methylation of CpGs within the H19 imprinting control region (ICR) were negatively correlated with H19 expression (Pearson r = −0.211 to −0.245, P ≤ 0.05). Moreover, RNA and protein levels of SMAD1 and 5 , targets of miR‐675‐3p , were negatively associated with miR‐675‐3p ( r 2 = 0.792 and 0.760, respectively) and miR‐675‐5p ( r 2 = 0.584 and 0.723, respectively) expression, and SMAD1 and 5 RNA levels positively associated with greater type II fibre size ( r 2 = 0.184 and 0.246, respectively, P 0.05). Increased expression profiles of H19/miR‐675‐5p/3p and lower expression of the anabolic SMAD1/5 effectors of bone morphogenetic protein (BMP) signalling are associated with low muscle mass in older in iduals.
Publisher: Springer Science and Business Media LLC
Date: 20-12-2019
DOI: 10.1038/S41467-019-13694-1
Abstract: The causes of impaired skeletal muscle mass and strength during aging are well-studied in healthy populations. Less is known on pathological age-related muscle wasting and weakness termed sarcopenia, which directly impacts physical autonomy and survival. Here, we compare genome-wide transcriptional changes of sarcopenia versus age-matched controls in muscle biopsies from 119 older men from Singapore, Hertfordshire UK and Jamaica. In iduals with sarcopenia reproducibly demonstrate a prominent transcriptional signature of mitochondrial bioenergetic dysfunction in skeletal muscle, with low PGC-1α/ERRα signalling, and downregulation of oxidative phosphorylation and mitochondrial proteostasis genes. These changes translate functionally into fewer mitochondria, reduced mitochondrial respiratory complex expression and activity, and low NAD + levels through perturbed NAD + biosynthesis and salvage in sarcopenic muscle. We provide an integrated molecular profile of human sarcopenia across ethnicities, demonstrating a fundamental role of altered mitochondrial metabolism in the pathological loss of skeletal muscle mass and function in older people.
Publisher: Cambridge University Press (CUP)
Date: 11-2009
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Karen Lillycrop.