Non-alcoholic Fatty Liver Disease: What We Learn from Omics Studies

Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver diseases with 10–30% prevalence in western countries. The severity of NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). However, the wide range of clinical staging of the disease prevents the clear understanding of its pathogenesis. Recently, high-throughput genomic, transcriptomic, and proteomic studies focus on enlightening the complex mechanisms responsible for NAFLD and NASH development. All together these Omics studies, in different cohorts once again, proved that NAFLD and NASH are linked with many complex mechanisms such as accumulation and traffic of various lipids in the liver and activation of inflammation responses. Moreover, some of these studies may have identified potential biomarkers and candidate risky or protective alleles that can be a valuable tool for the assessment of susceptibility and histological severity of NAFLD. Nonetheless, confirmation of these potential biomarkers and candidate genes by multiple Omics tools is required for their clinical application in the diagnosis and treatment of NASH and NAFLD

Can Proteomic Profiling Identify Biomarkers and/or Therapeutic Targets for Liver Fibrosis?

Liver fibrosis is a serious disease that affects around 350–400 million people worldwide. The main approach for fibrosis staging is liver biopsy, which is an invasive procedure that is not endured pretty well by patients. Currently, some serum-based biomarker panels are available for diagnosis and staging of liver fibrosis. Recent high-throughput proteomic studies are also very promising for identification of novel biomarkers for diagnosis and/or treatment of liver fibrosis. We hereby review the application of proteomic profiling studies for identification of fibrosis biomarkers with their advantages and drawbacks

Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging

Background Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Results Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. Conclusion This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.Peer reviewe

Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging

Background Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Results Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. Conclusion This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.</p

Community and domestic violence are associated with DNA methylation GrimAge acceleration and heart rate variability in adolescents

Background: Cumulative exposure to violence can change the regulation of epigenetic and physiological markers. Although violence has been associated with accelerated cellular aging, little is known about associations with cardiac autonomic activity. Objective: The current study aimed to investigate the relationship of exposure to community and domestic violence (CDV) with vagal activity and epigenetic aging acceleration. Methods: A total of 86 adolescents (57% female) were evaluated and interviewed at two time-points in São Gonçalo (2014–2019), a Brazilian city with high levels of violence. Exposure to CDV was assessed in both time-points. GrimAge acceleration was calculated from saliva DNA methylation using Infinium HumanMethylation450K (Illumina) collected in the first assessment. Heart rate variability (HRV) was collected during two stress tasks at the second assessment. Results: The exposure to violence witnessed or directly experienced at home and in the community increased significantly (t = 4.87, p < .01) across two-time points, and males had reported higher violence exposure (t = 2.06, p = .043). Violence at 1st assessment was significantly associated with GrimAge acceleration (B = .039, p value = .043). Violence at both assessments were associated with HRV measured during the narration of the worst trauma (traumaHRV) (B = .009, p value = .039, and B = .007, p value = .024, 1st and 2nd assessment respectively). GrimAge acceleration was significantly associated with traumaHRV (B = .043, p value = .049), and HRV measured during a 3D roller coaster video (B = .061, p value = .024). Conclusions: We found relevant evidence that experiencing violence during adolescence is associated with epigenetic aging and stress-related vagal activity. Understanding these factors during this period could contribute to the development of early interventions for health promotion. HIGHLIGHTS Higher exposure to Community and domestic violence is associated with increased GrimAge acceleration. Higher GrimAge acceleration is associated with increased stress-related vagal activity. Exposure to community and domestic violence increased significantly over time

An evaluation of the genome-wide false positive rates of common methods for identifying differentially methylated regions using illumina methylation arrays

Differentially methylated regions (DMRs) are genomic regions with specific methylation patterns across multiple loci that are associated with a phenotype. We examined the genome-wide false positive (GFP) rates of five widely used DMR methods: comb-p, Bumphunter, DMRcate, mCSEA and coMethDMR using both Illumina HumanMethylation450 (450 K) and MethylationEPIC (EPIC) data and simulated continuous and dichotomous null phenotypes (i.e., generated independently of methylation data). coMethDMR provided well-controlled GFP rates (~5%) except when analysing skewed continuous phenotypes. DMRcate generally had well-controlled GFP rates when applied to 450 K data except for the skewed continuous phenotype and EPIC data only for the normally distributed continuous phenotype. GFP rates for mCSEA were at least 0.096 and comb-p yielded GFP rates above 0.34. Bumphunter had high GFP rates of at least 0.35 across conditions, reaching as high as 0.95. Analysis of the performance of these methods in specific regions of the genome found that regions with higher correlation across loci had higher regional false positive rates on average across methods. Based on the false positive rates, coMethDMR is the most recommended analysis method, and DMRcate had acceptable performance when analysing 450 K data. However, as both could display higher levels of FPs for skewed continuous distributions, a normalizing transformation of skewed continuous phenotypes is suggested. This study highlights the importance of genome-wide simulations when evaluating the performance of DMR-analysis methods

Proteomic profiling of HBV infected liver biopsies with different fibrotic stages

Abstract Background Hepatitis B virus (HBV) is a global health problem, and infected patients if left untreated may develop cirrhosis and eventually hepatocellular carcinoma. This study aims to enlighten pathways associated with HBV related liver fibrosis for delineation of potential new therapeutic targets and biomarkers. Methods Tissue samples from 47 HBV infected patients with different fibrotic stages (F1 to F6) were enrolled for 2D-DIGE proteomic screening. Differentially expressed proteins were identified by mass spectrometry and verified by western blotting. Functional proteomic associations were analyzed by EnrichNet application. Results Fibrotic stage variations were observed for apolipoprotein A1 (APOA1), pyruvate kinase PKM (KPYM), glyceraldehyde 3-phospahate dehydrogenase (GAPDH), glutamate dehydrogenase (DHE3), aldehyde dehydrogenase (ALDH2), alcohol dehydrogenase (ALDH1A1), transferrin (TRFE), peroxiredoxin 3 (PRDX3), phenazine biosynthesis-like domain-containing protein (PBLD), immuglobulin kappa chain C region (IGKC), annexin A4 (ANXA4), keratin 5 (KRT5). Enrichment analysis with Reactome and Kegg databases highlighted the possible involvement of platelet release, glycolysis and HDL mediated lipid transport pathways. Moreover, string analysis revealed that HIF-1α (Hypoxia-inducible factor 1-alpha), one of the interacting partners of HBx (Hepatitis B X protein), may play a role in the altered glycolytic response and oxidative stress observed in liver fibrosis. Conclusions To our knowledge, this is the first protomic research that studies HBV infected fibrotic human liver tissues to investigate alterations in protein levels and affected pathways among different fibrotic stages. Observed changes in the glycolytic pathway caused by HBx presence and therefore its interactions with HIF-1α can be a target pathway for novel therapeutic purposes

Cumulative stress, PTSD, and emotion dysregulation during pregnancy and epigenetic age acceleration in Hispanic mothers and their newborn infants

Pregnancy can exacerbate or prompt the onset of stress-related disorders, such as post-traumatic stress disorder (PTSD). PTSD is associated with heightened stress responsivity and emotional dysregulation, as well as increased risk of chronic disorders and mortality. Further, maternal PTSD is associated with gestational epigenetic age acceleration in newborns, implicating the prenatal period as a developmental time period for the transmission of effects across generations. Here, we evaluated the associations between PTSD symptoms, maternal epigenetic age acceleration, and infant gestational epigenetic age acceleration in 89 maternal-neonatal dyads. Trauma-related experiences and PTSD symptoms in mothers were assessed during the third trimester of pregnancy. The MethylationEPIC array was used to generate DNA methylation data from maternal and neonatal saliva samples collected within 24 h of infant birth. Maternal epigenetic age acceleration was calculated using Horvath’s multi-tissue clock, PhenoAge and GrimAge. Gestational epigenetic age was estimated using the Haftorn clock. Maternal cumulative past-year stress (GrimAge: p = 3.23e-04, PhenoAge: p = 9.92e-03), PTSD symptoms (GrimAge: p = 0.019), and difficulties in emotion regulation (GrimAge: p = 0.028) were associated with accelerated epigenetic age in mothers. Maternal PTSD symptoms were associated with lower gestational epigenetic age acceleration in neonates (p = 0.032). Overall, our results suggest that maternal cumulative past-year stress exposure and trauma-related symptoms may increase the risk for age-related problems in mothers and developmental problems in their newborns