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Sökning: WFRF:(Wang Yunzhang)

  • Resultat 1-8 av 8
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1.
  • Wang, Yunzhang, et al. (författare)
  • Comprehensive longitudinal study of epigenetic mutations in aging
  • 2019
  • Ingår i: ; 11
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The role of DNA methylation in aging has been widely studied. However, epigenetic mutations, here defined as aberrant methylation levels compared to the distribution in a population, are less understood. Hence, we investigated longitudinal accumulation of epigenetic mutations, using 994 blood samples collected at up to five time points from 375 individuals in old ages.Results: We verified earlier cross-sectional evidence on the increase of epigenetic mutations with age, and identified important contributing factors including sex, CD19+ B cells, genetic background, cancer diagnosis, and technical artifacts. We further classified epigenetic mutations into High/Low Methylation Outliers (HMO/LMO) according to their changes in methylation, and specifically studied methylation sites (CpGs) that were prone to mutate (frequently mutated CpGs). We validated four epigenetically mutated CpGs using pyrosequencing in 93 samples. Furthermore, by using twins, we concluded that the age-related accumulation of epigenetic mutations was not related to genetic factors, hence driven by stochastic or environmental effects.Conclusions: Here we conducted a comprehensive study of epigenetic mutation and highlighted its important role in aging process and cancer development. 
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2.
  • Hong, Mun-Gwan, et al. (författare)
  • Profiles of histidine-rich glycoprotein associate with age and risk of all-cause mortality
  • 2020
  • Ingår i: Life Science Alliance. - 2575-1077.
  • Tidskriftsartikel (refereegranskat)abstract
    • Despite recognizing aging as a common risk factor of many human diseases, little is known about its molecular traits. To identify age-associated proteins circulating in human blood, we screened 156 individuals aged 50–92 using exploratory and multiplexed affinity proteomics assays. Profiling eight additional study sets (N = 3,987), performing antibody validation, and conducting a meta-analysis revealed a consistent age association (P = 6.61 × 10−6) for circulating histidine-rich glycoprotein (HRG). Sequence variants of HRG influenced how the protein was recognized in the immunoassays. Indeed, only the HRG profiles affected by rs9898 were associated with age and predicted the risk of mortality (HR = 1.25 per SD; 95% CI = 1.12–1.39; P = 6.45 × 10−5) during a follow-up period of 8.5 yr after blood sampling (IQR = 7.7–9.3 yr). Our affinity proteomics analysis found associations between the particular molecular traits of circulating HRG with age and all-cause mortality. The distinct profiles of this multipurpose protein could serve as an accessible and informative indicator of the physiological processes related to biological aging.
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3.
  • Karlsson, Ida K., et al. (författare)
  • Apolipoprotein E DNA methylation and late-life disease
  • 2018
  • Ingår i: International Journal of Epidemiology. - : Oxford University Press. - 0300-5771 .- 1464-3685. ; 47:3, s. 899-907
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: This study aims to investigate if DNA methylation of the apolipoprotein E (APOE) locus affects the risks of dementia, Alzheimers disease (AD) or cardiovascular disease (CVD).Methods: DNA methylation across the APOE gene has previously been categorized into three distinct regions: a hypermethylated region in the promoter, a hypomethylated region in the first two introns and exons and a hypermethylated region in the 3'exon that also harbours the APOE epsilon 2 and epsilon 4 alleles. DNA methylation levels in leukocytes were measured using the Illumina 450K array in 447 Swedish twins (mean age 78.1 years). We used logistic regression to investigate whether methylation levels in those regions affect the odds of disease.Results: We found that methylation levels in the promoter region were associated with dementia and AD after adjusting for sex, age at blood draw, education, smoking and relatedness among twins [odds ratio (OR) 1.32 per standard deviation increase in methylation levels, 95% confidence interval (CI) 1.08-1.62 for dementia; OR 1.38, 95% CI 1.07-1.78 for AD). We did not detect any difference in methylation levels between CVD cases and controls. Results were similar when comparing within discordant twin pairs, and did not differ as a function of APOE genotype.Conclusions: We found that higher DNA methylation levels in the promoter region of APOE increase the odds of dementia and AD, but not CVD. The effect was independent of APOE genotype, indicating that allelic variation and methylation variation in APOE may act independently to increase the risk of dementia.
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4.
  • Li, Xia, et al. (författare)
  • Longitudinal trajectories, correlations and mortality associations of nine biological ages across 20-years follow-up.
  • 2020
  • Ingår i: eLIFE. - : eLife Sciences Publications. - 2050-084X. ; 9
  • Tidskriftsartikel (refereegranskat)abstract
    • Biological age measurements (BAs) assess aging-related physiological change and predict health risks among individuals of the same chronological age (CA). Multiple BAs have been proposed and are well studied individually but not jointly. We included 845 individuals and 3973 repeated measurements from a Swedish population-based cohort and examined longitudinal trajectories, correlations, and mortality associations of nine BAs across 20 years follow-up. We found the longitudinal growth of functional BAs accelerated around age 70; average levels of BA curves differed by sex across the age span (50-90 years). All BAs were correlated to varying degrees; correlations were mostly explained by CA. Individually, all BAs except for telomere length were associated with mortality risk independently of CA. The largest effects were seen for methylation age estimators (GrimAge) and the frailty index (FI). In joint models, two methylation age estimators (Horvath and GrimAge) and FI remained predictive, suggesting they are complementary in predicting mortality.
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5.
  • Wang, Yunzhang, et al. (författare)
  • Epigenetic influences on aging : a longitudinal genome-wide methylation study in old Swedish twins
  • 2018
  • Ingår i: ; 13:9, s. 975-987
  • Tidskriftsartikel (refereegranskat)abstract
    • Age-related changes in DNA methylation were observed in cross-sectional studies, but longitudinal evidence is still limited. Here, we aimed to characterize longitudinal age-related methylation patterns using 1011 blood samples collected from 385 Swedish twins (age at entry: mean 69 and standard deviation 9.7, 73 monozygotic and 96 dizygotic pairs) up to five times (mean 2.6) over 20 years (mean 8.7). We identified 1316 age-associated methylation sites (P<1.3x10(-7)) using a longitudinal epigenome-wide association study design. We measured how estimated cellular compositions changed with age and how much they confounded the age effect. We validated the results in two independent longitudinal cohorts, where 118 CpGs were replicated in Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS, 390 samples) (P<3.9x10(-5)), 594 in Lothian Birth Cohort (LBC, 3018 samples) (P<5.1x10(-5)) and 63 in both. Functional annotation of age-associated CpGs showed enrichment in CCCTC-binding factor (CTCF) and other transcription factor binding sites. We further investigated genetic influences on methylation and found no interaction between age and genetic effects in the 1316 age-associated CpGs. Moreover, in the same CpGs, methylation differences within twin pairs increased with 6.4% over 10 years, where monozygotic twins had smaller intra-pair differences than dizygotic twins. In conclusion, we show that age-related methylation changes persist in a longitudinal perspective, and are fairly stable across cohorts. The changes are under genetic influence, although this effect is independent of age. Moreover, methylation variability increase over time, especially in age-associated CpGs, indicating the increase of environmental contributions on DNA methylation with age.
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8.
  • Wang, Yunzhang (författare)
  • DNA methylation and aging : a longitudinal study of old Swedish twins
  • 2020
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • DNA methylation is a well-known biomarker of aging. Many previous studies have reported the change of DNA methylation patterns with age, and analyzed DNA methylation in association with aging outcomes. However, most publications were based on cross-sectional data while longitudinal evidence was largely missing. Hence, in this thesis, we used longitudinal measures of DNA methylation from the Swedish Adoption/Twin Study of Aging (SATSA) to comprehensively study the role of DNA methylation in aging. The first three studies in this thesis focus on different mechanisms of DNA methylation related to aging, including methylation level, methylation variability and epigenetic mutation. In Study I, we investigated the longitudinal change of methylation level with age from an epigenome-wide association study (EWAS) using a mixed effect model. We identified 1316 age-related CpGs and successfully validated them in two external cohorts. Further, we analyzed the methylation difference between paired twins at the same time-point, and found it increased with age. We also identified genetic effect on age-associated CpGs, but the effect was independent on age. In Study II, we first developed a method that could properly model the longitudinal change of methylation variability with age in simulated data. The method included a linear model to regress methylation on age, followed by a random intercept model to regress the absolute residuals on age. Next, we applied the method in an EWAS and identified 570 age-varying CpGs. The inter-individual variance of most CpGs increased with age longitudinally. In Study III, we comprehensively studied epigenetic mutations, which are extreme outliers in the distribution of methylation level. The number of epigenetic mutations significantly increased with age in our longitudinal data. We also identified other factors associated with epigenetic mutations, including sex, B cell, sample quality, cancer diagnosis and first genetic principal component. Further, we classified CpGs into frequent mutated CpGs, highly methylated outliers (HMO) and lowly methylated outliers (LMO), and found frequent HMOs were more related to biological factors. In the end, we validated epigenetic mutations using bisulfite pyrosequencing and proved that epigenetic mutations were persist and could accumulate in aging. In Study IV, we performed an EWAS to analyze methylation levels, methylation variability and epigenetic mutations in association with mortality. We observed age-varying effect of methylation level on all-cause mortality which may explain the poor replication in previous studies. We also identified CpGs of cancer genes related to death from cancer. In the end, we provided evidence that methylation variability could predict all-cause mortality.
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