Epigenetic Risk Research Articles

The Role of Genetics, Epigenetics, and the Environment in ASD: A Mini Review.

According to recent findings, variances in autism spectrum disorder (ASD) risk factors might be determined by several factors, including molecular genetic variants. Accumulated evidence has also revealed the important role of biological and chemical pathways in ASD aetiology. In this paper, we assess several reviews with regard to their quality of evidence and provide a brief outline of the presumed mechanisms of the genetic, epigenetic, and environmental risk factors of ASD. We also review some of the critical literature, which supports the basis of each factor in the underlying and specific risk patterns of ASD. Finally, we consider some of the implications of recent research regarding potential molecular targets for future investigations.

Age-Related DNA Methylation in Normal Kidney Tissue Identifies Epigenetic Cancer Risk Susceptibility Loci in the ANKRD34B and ZIC1 Genes.

Both age-dependent and age-independent alteration of DNA methylation in human tissues are functionally associated with the development of many malignant and non-malignant human diseases. TCGA-KIRC data were biometrically analyzed to identify new loci with age-dependent DNA methylation that may contribute to tumor risk in normal kidney tissue. ANKRD34B and ZIC1 were evaluated as candidate genes by pyrosequencing of 539 tissues, including 239 normal autopsy, 157 histopathologically tumor-adjacent normal, and 143 paired tumor kidney samples. All candidate CpG loci demonstrated a strong correlation between relative methylation levels and age (R = 0.70–0.88, p < 2 × 10−16) and seven out of 10 loci were capable of predicting chronological age in normal kidney tissues, explaining 84% of the variance (R = 0.92). Moreover, significantly increased age-independent methylation was found for 9 out of 10 CpG loci in tumor-adjacent tissues, compared to normal autopsy tissues (p = 0.001–0.028). Comparing tumor and paired tumor-adjacent tissues revealed two patient clusters showing hypermethylation, one cluster without significant changes in methylation, and a smaller cluster demonstrating hypomethylation in the tumors (p < 1 × 10−10). Taken together, our results show the presence of additional methylation risk factors besides age for renal cancer in normal kidney tissue. Concurrent tumor-specific hypermethylation suggests a subset of these loci are candidates for epigenetic renal cancer susceptibility.

Programmed epigenetic risk: Can stress exposures in utero predispose infants to obesity and metabolic diseases?

Dr. Kristen Boyle is an Associate Professor in the Department of Pediatrics Nutrition Section studying the regulation of human stem cell metabolism and phenotype in the context of obesity and diabetes. During her early independent career Dr. Boyle began using primary infant mesenchymal stem cells, derived from umbilical cord tissue, to investigate stem cell phenotype and epigenetic signatures as a model for developmental programming in humans. She discovered that cells from infants born to mothers with obesity have epigenetic and metabolic perturbations similar to adults with established obesity and associated with greater child adiposity. Thus, infant stem cell metabolism may elucidate how some children are at increased risk for developing obesity and diabetes later in life, independent of postnatal lifestyle exposures. Dr. Boyle’s current research program focuses on using these infant cells to understand how various maternal stress exposures, from metabolic disease to environmental toxins, may impact offspring metabolic phenotypes through epigenetic mechanisms. Her work is supported by the American Diabetes Association and the NIDDK. The goal of this research is to help identify which maternal factors may most influence metabolic differences in the cells and children, and to determine which children may be most at risk for developing obesity or diabetes in the future so that we may develop better tools for obesity or diabetes prevention strategies.

Update on the Epigenomic Implication of Embryo Cryopreservation Methods Applied in Assisted Reproductive Technologies With Potential Long-Term Health Effects.

Cryopreservation of embryos has become an efficient method in Assisted Reproductive Technologies (ART) and these methods are currently performed at nearly all fertility centers around the globe. Cryopreservation of supernumerary embryos has contributed to an increase in cumulative pregnancy rates and as a consequence, an increasing number of children are being born through these techniques worldwide. However, long-term follow-up studies of children born through ART are scarce, and concerns about the long-term health effects on individuals conceived through ART have been raised. The relevant genomic transformations that occur at the time cryopreservation is usually applied to embryos may have potential epigenetic risks. With advances in multi-omic single cell technologies, new ways to assess the (epi)genomic status during early embryo development have now become feasible. These novel strategies could provide a revolutionary opportunity to understand the actual impact of ART, but also may help future developments aiming at increase both their efficiency and safety. Here we outline insights in current knowledge and research on the impact of cryopreservation on embryos, the possible consequences at epigenetic level and how emerging new high-throughput technologies can be used for their assessment.

Parkinson's Disease and SARS-CoV-2 Infection: Particularities of Molecular and Cellular Mechanisms Regarding Pathogenesis and Treatment.

Accumulating data suggest that chronic neuroinflammation-mediated neurodegeneration is a significant contributing factor for progressive neuronal and glial cell death in age-related neurodegenerative pathology. Furthermore, it could be encountered as long-term consequences in some viral infections, including post-COVID-19 Parkinsonism-related chronic sequelae. The current systematic review is focused on a recent question aroused during the pandemic’s successive waves: are there post-SARS-CoV-2 immune-mediated reactions responsible for promoting neurodegeneration? Does the host’s dysregulated immune counter-offensive contribute to the pathogenesis of neurodegenerative diseases, emerging as Parkinson’s disease, in a complex interrelation between genetic and epigenetic risk factors? A synthetic and systematic literature review was accomplished based on the ”Preferred Reporting Items for Systematic Principles Reviews and Meta-Analyses” (PRISMA) methodology, including registration on the specific online platform: International prospective register of systematic reviews—PROSPERO, no. 312183. Initially, 1894 articles were detected. After fulfilling the five steps of the selection methodology, 104 papers were selected for this synthetic review. Documentation was enhanced with a supplementary 47 bibliographic resources identified in the literature within a non-standardized search connected to the subject. As a final step of the PRISMA method, we have fulfilled a Population-Intervention-Comparison-Outcome-Time (PICOT)/Population-Intervention-Comparison-Outcome-Study type (PICOS)—based metanalysis of clinical trials identified as connected to our search, targeting the outcomes of rehabilitative kinesitherapeutic interventions compared to clinical approaches lacking such kind of treatment. Accordingly, we identified 10 clinical trials related to our article. The multi/interdisciplinary conventional therapy of Parkinson’s disease and non-conventional multitarget approach to an integrative treatment was briefly analyzed. This article synthesizes the current findings on the pathogenic interference between the dysregulated complex mechanisms involved in aging, neuroinflammation, and neurodegeneration, focusing on Parkinson’s disease and the acute and chronic repercussions of COVID-19. Time will tell whether COVID-19 neuroinflammatory events could trigger long-term neurodegenerative effects and contribute to the worsening and/or explosion of new cases of PD. The extent of the interrelated neuropathogenic phenomenon remains obscure, so further clinical observations and prospective longitudinal cohort studies are needed.

Epigenetic Risks of Medically Assisted Reproduction.

Since the birth of Louise Joy Brown, the first baby conceived via in vitro fertilization, more than 9 million children have been born worldwide using assisted reproductive technologies (ART). In vivo fertilization takes place in the maternal oviduct, where the unique physiological conditions guarantee the healthy development of the embryo. During early embryogenesis, a major wave of epigenetic reprogramming takes place that is crucial for the correct development of the embryo. Epigenetic reprogramming is susceptible to environmental changes and non-physiological conditions such as those applied during in vitro culture, including shift in pH and temperature, oxygen tension, controlled ovarian stimulation, intracytoplasmic sperm injection, as well as preimplantation embryo manipulations for genetic testing. In the last decade, concerns were raised of a possible link between ART and increased incidence of imprinting disorders, as well as epigenetic alterations in the germ cells of infertile parents that are transmitted to the offspring following ART. The aim of this review was to present evidence from the literature regarding epigenetic errors linked to assisted reproduction treatments and their consequences on the conceived children. Furthermore, we provide an overview of disease risk associated with epigenetic or imprinting alterations in children born via ART.

Contemporary Use of ICSI and Epigenetic Risks to Future Generations.

Since the birth of Louise Brown in 1978 via IVF, reproductive specialists have acquired enormous knowledge and refined several procedures, which are nowadays applied in assisted reproductive technology (ART). One of the most critical steps in this practice is the fertilization process. In the early days of IVF, a remarkable concern was the unpleasant outcomes of failed fertilization, overtaken by introducing intracytoplasmic sperm injection (ICSI), delineating a real breakthrough in modern ART. ICSI became standard practice and was soon used as the most common method to fertilize oocytes. It has been used for severe male factor infertility and non-male factors, such as unexplained infertility or advanced maternal age, without robust scientific evidence. However, applying ICSI blindly is not free of potential detrimental consequences since novel studies report possible health consequences to offspring. DNA methylation and epigenetic alterations in sperm cells of infertile men might help explain some of the adverse effects reported in ICSI studies on reproductive health in future generations. Collected data concerning the health of ICSI children over the past thirty years seems to support the notion that there might be an increased risk of epigenetic disorders, congenital malformations, chromosomal alterations, and subfertility in babies born following ICSI compared to naturally conceived children. However, it is still to be elucidated to what level these data are associated with the cause of infertility or the ICSI technique. This review provides an overview of epigenetic mechanisms and possible imprinting alterations following the use of ART, in particular ICSI. It also highlights the sperm contribution to embryo epigenetic regulation and the risks of in vitro culture conditions on epigenetic dysregulation. Lastly, it summarizes the literature concerning the possible epigenetic disorders in children born after ART.

Epidemiology-based evaluation of trends in treatment for ruptured intracranial aneurysms in Italy.

In recent years there have been significant advances in the diagnosis, management and treatment of intracranial aneurysms (IAs) in Italy. Changes in prevalence of several epigenetic risk factors in the population as well as in environmental factors may have influenced the epidemiological burden of this disease. No long-term, population-based study about the incidence of treated ruptured IAs (rIAs) in Italy has yet been reported in literature. A long-term (January 2015December 2020), nationwide epidemiology study was performed by using discharge data collected by the Italian National Agency for Regional Healthcare Services with a particular focus on the treatment incidence of rIAs. A sub-analysis per macro-areas (north, center, and south and islands) was also performed, including the data about regional healthcare systems organization. The prevalence of common epigenetic and environmental risk factors has been also assessed. Over 6 years, the mean incidence of rIAs treatment was 2.7x100,000 per year (SD±0.1; range: 2.6-2.9). In 2020, there was a significant north-south decreasing gradient in incidence (north vs. center vs. south and islands: 3.4 vs. 2.4 vs. 1.8x100,000/year; all P<0.001). There were no meaningful differences between macro-areas in terms of access to emergency care and number of neurosurgical wards per population. The rate of unruptured IAs (uIAs) treatment did not show a correlation to that of ruptured ones. Minor regional differences were retrieved for high-risk hypertension as well as for alcohol abuse prevalence. Air pollutants and temperature charts showed a north-south gradient similar to that of the incidence in the treated rIAs. The mean incidence of treated rIAs was stable over the 2015-2020 period in Italy. A north-south decreasing gradient in rIAs treatment incidence was reported. Neither the Regional healthcare organizations nor the rate of uIAs treatment were significant factors explaining the regional differences in the incidence of rIAs treatment. Minor differences in epigenetic and environmental risk factors may be synergistically involved.

Improving breast cancer risk prediction with epigenetic risk factors

Improving breast cancer risk prediction with epigenetic risk factors

Pro-inflammatory and (Epi-)genetic markers in saliva for disease risk in childhood obesity

Background and aimChildhood obesity is an emerging problem often leading to earlier onset of non-communicable diseases in later life. Biomarkers to identify individual risk scores are insufficient in routine clinical practice, which is related to the need for easily sampled, non-invasive survey methods in children. We aimed to investigate and strengthen possible pro-inflammatory markers and epigenetic risk factors in saliva of obese children compared to lean controls. Methods and results19 overweight/obese (OC, 10.1 ± 1.9 years, BMI 27.7 ± 3.2 kg/m2) and 19 lean control children (CC, 9.7 ± 2.5 years, BMI 16.4 ± 1.8 kg/m2) participated in this explorative pilot study. Anthropometric measures, saliva and cheek swab samples were taken. Saliva profiles were examined for acute phase proteins (CRP and neopterin) and pro-inflammatory cytokines (IL-17a/IL-1β/IL-6). Cheek swabs were analyzed to investigate DNA methylation differences with subsequent hierarchical cluster and principal component analyses (PCA). Saliva analysis showed significant increased CRP concentrations in OC compared to CC (p < 0.001). There were no significant differences, but high intra-individual values in neopterin, IL-17a, IL-1β and IL-6. An unsupervised PCA of CpG loci with high variance (σ/σmax > 0.2) clearly separated OC and CC according to their methylation pattern. Furthermore, a supervised approach revealed 7125 significantly differentially methylated loci, whose corresponding genes were significantly enriched for genes playing roles in e.g., cellular signalling, cytoskeleton organization and cell motility. ConclusionsCRP and methylation status determinations in saliva are suitable as non-invasive methods for early detection of risks for non-communicable diseases in children/adolescents and might be a useful supplementary approach in the routine clinical practice/monitoring.

Stochastic Epigenetic Mutations Influence Parkinson's Disease Risk, Progression, and Mortality.

Stochastic epigenetic mutations (SEM) reflect a deviation from normal site-specific methylation patterns. Epigenetic mutation load (EML) captures the accumulation of SEMs across an individual's genome and may reflect dysfunction of the epigenetic maintenance system in response to epigenetic challenges. We investigate whether EML is associated with PD risk and time to events (i.e., death and motor symptom decline). We employed logistic regression and Cox proportional hazards regression to assess the association between EML and several outcomes. Our analyses are based on 568 PD patients and 238 controls from the Parkinson's disease, Environment and Genes (PEG) study, for whom blood-based methylation data was available. We found an association for PD onset and EML in all genes (OR = 1.90; 95%CI 1.52-2.37) and PD-related genes (OR = 1.87; 95%CI 1.50-2.32). EML was also associated with time to a minimum score of 35 points on the motor UPDRS exam (OR = 1.28; 95%CI 1.06-1.56) and time to death (OR = 1.29, 95%CI 1.11-1.49). An analysis of PD related genes only revealed five intragenic hotspots of high SEM density associated with PD risk. Our findings suggest an enrichment of methylation dysregulation in PD patients in general and specifically in five PD related genes. EML may also be associated with time to death and motor symptom progression in PD patients.

Oxidative Stress in Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is a challenging disease caused by multiple factors, which may partly explain why it still remains an orphan of adequate therapies. This review highlights the interaction between oxidative stress (OS) and disturbed lipid metabolism. Several reactive oxygen species generators, including those produced in the gastrointestinal tract, contribute to the lipotoxic hepatic (and extrahepatic) damage by fatty acids and a great variety of their biologically active metabolites in a “multiple parallel-hit model”. This leads to inflammation and fibrogenesis and contributes to NAFLD progression. The alterations of the oxidant/antioxidant balance affect also metabolism-related organelles, leading to lipid peroxidation, mitochondrial dysfunction, and endoplasmic reticulum stress. This OS-induced damage is at least partially counteracted by the physiological antioxidant response. Therefore, modulation of this defense system emerges as an interesting target to prevent NAFLD development and progression. For instance, probiotics, prebiotics, diet, and fecal microbiota transplantation represent new therapeutic approaches targeting the gut microbiota dysbiosis. The OS and its counter-regulation are under the influence of individual genetic and epigenetic factors as well. In the near future, precision medicine taking into consideration genetic or environmental epigenetic risk factors, coupled with new OS biomarkers, will likely assist in noninvasive diagnosis and monitoring of NAFLD progression and in further personalizing treatments.

Does underlying infertility in natural conception modify the epigenetic control of imprinted genes and transposable elements in newborns?

Research questionDoes the epigenetic control of imprinted genes and transposable elements at birth differ according to time to conception in natural conception and after intrauterine insemination (IUI)? DesignA total of 144 singletons were included in four groups: 50 natural pregnancies obtained within 6 months after stopping contraception (group 1); 34 natural pregnancies with infertility period between 6 and 12 months (group 2); 36 pregnancies with an infertility period of more than 12 months (group 3) and 24 pregnancies obtained after IUI (group 4). ResultsThe placental DNA methylation levels of H19/IGF2 and KCNQ1OT1 were lower in groups 2, 3 and 4 than in group 1 (P = 0.025 in the overall comparison). The DNA methylation rate for LINE-1 was higher in placentas from group 2 than in group 1 (P = 0.022). In cord blood, DNA methylation levels were not significantly different between groups except for H19/IGF2 for which the DNA methylation levels were higher in group 2 than in group 1 (H19/IGF2-seq1 and seq2: P = 0.023 and P = 0.002, respectively).In placenta tissue, compared with group 1, relative expression for SNRPN and for LINE-1 was significantly higher in group 2 (P = 0.002 and P < 0.001, respectively). The relative expression of KCNQ1 in placenta was lower in group 4 than in group 1 (P = 0.013). In cord blood, compared with group 1, the relative expression for H19 was significantly higher in group 3 (P = 0.026), and the relative expression of LINE-1 was higher in groups 2 and 3 and in group 4 (P < 0.001). ConclusionsInfertility itself, and not only ART techniques, could contribute to potential epigenetic risks for children.

The Relationship between Epigenetic Age and Myocardial Infarction/Acute Coronary Syndrome in a Population-Based Nested Case-Control Study.

We investigated the relationship between ‘epigenetic age’ (EA) derived from DNA methylation (DNAm) and myocardial infarction (MI)/acute coronary syndrome (ACS). A random population sample was examined in 2003/2005 (n = 9360, 45–69, the HAPIEE project) and followed up for 15 years. From this cohort, incident MI/ACS (cases, n = 129) and age- and sex-stratified controls (n = 177) were selected for a nested case-control study. Baseline EA (Horvath’s, Hannum’s, PhenoAge, Skin and Blood) and the differences between EA and chronological age (CA) were calculated (ΔAHr, ΔAHn, ΔAPh, ΔASB). EAs by Horvath’s, Hannum’s and Skin and Blood were close to CA (median absolute difference, MAD, of 1.08, –1.91 and –2.03 years); PhenoAge had MAD of −9.29 years vs. CA. The adjusted odds ratios (ORs) of MI/ACS per 1–year increments of ΔAHr, ΔAHn, ΔASB and ΔAPh were 1.01 (95% CI 0.95–1.07), 1.01 (95% CI 0.95–1.08), 1.02 (95% CI 0.97–1.06) and 1.01 (0.93–1.09), respectively. When classified into tertiles, only the highest tertile of ΔAPh showed a suggestion of increased risk of MI/ACS with OR 2.09 (1.11–3.94) independent of age and 1.84 (0.99–3.52) in the age- and sex-adjusted model. Metabolic modulation may be the likely mechanism of this association. In conclusion, this case-control study nested in a prospective population-based cohort did not find strong associations between accelerated epigenetic age markers and risk of MI/ACS. Larger cohort studies are needed to re-examine this important research question.

Tumor-Associated Macrophages in Hepatocellular Carcinoma Pathogenesis, Prognosis and Therapy.

Simple SummaryHepatocellular carcinoma (HCC) constitutes a major health burden, accounting for >80% of primary liver cancers globally. Inflammation has come into the spotlight as a hallmark of cancer, and it is evident that tumor-associated inflammation drives the involvement of monocytes in tumor growth and metastasis. Tumor-associated macrophages (TAMs) actively participate in tumor-related inflammation, representing the main type of inflammatory cells in the tumor microenvironment, setting the crosstalk between tumor and stromal cells. Infiltrating TAMs exert either anti-tumorigenic (M1) or pro-tumorigenic (M2) functions. In most solid human tumors, increased TAM infiltration has been associated with enhanced tumor growth and metastasis, while other studies showcase that under certain conditions, TAMs exhibit cytotoxic and tumoricidal activity, inhibiting the progression of cancer. In this review, we summarize the current evidence on the role of macrophages in the pathogenesis and progression of HCC and we highlight their potential utilization in HCC prognosis and therapy.Hepatocellular carcinoma (HCC) constitutes a major health burden globally, and it is caused by intrinsic genetic mutations acting in concert with a multitude of epigenetic and extrinsic risk factors. Cancer induces myelopoiesis in the bone marrow, as well as the mobilization of hematopoietic stem and progenitor cells, which reside in the spleen. Monocytes produced in the bone marrow and the spleen further infiltrate tumors, where they differentiate into tumor-associated macrophages (TAMs). The relationship between chronic inflammation and hepatocarcinogenesis has been thoroughly investigated over the past decade; however, several aspects of the role of TAMs in HCC development are yet to be determined. In response to certain stimuli and signaling, monocytes differentiate into macrophages with antitumor properties, which are classified as M1-like. On the other hand, under different stimuli and signaling, the polarization of macrophages shifts towards an M2-like phenotype with a tumor promoting capacity. M2-like macrophages drive tumor growth both directly and indirectly, via the suppression of cytotoxic cell populations, including CD8+ T cells and NK cells. The tumor microenvironment affects the response to immunotherapies. Therefore, an enhanced understanding of its immunobiology is essential for the development of next-generation immunotherapies. The utilization of various monocyte-centered anticancer treatment modalities has been under clinical investigation, selectively targeting and modulating the processes of monocyte recruitment, activation and migration. This review summarizes the current evidence on the role of TAMs in HCC pathogenesis and progression, as well as in their potential involvement in tumor therapy, shedding light on emerging anticancer treatment methods targeting monocytes.

Maternal dietary fatty acid composition and newborn epigenetic aging—a geometric framework approach

Maternal nutrition is associated with epigenetic and cardiometabolic risk factors in offspring. Research in humans has primarily focused on assessing the impact of individual nutrients. We sought to assess the collective impact of maternal dietary MUFAs, PUFAs, and SFAs on epigenetic aging and cardiometabolic risk markers in healthy newborn infants using a geometric framework approach. Body fatness (n=162), aortic intima-media thickness (aIMT; n=131), heart rate variability (n=118), and epigenetic age acceleration (n=124) were assessed in newborn infants. Maternal dietary intake was cross-sectionally assessed in the immediate postpartum period via a validated 80-item self-administered FFQ. Generalized additive models were used to explore interactive associations of nutrient intake, with results visualized as response surfaces. After adjustment for total energy intake, maternal age, gestational age, and sex there was a 3-way interactive association of MUFAs, PUFAs, and SFAs (P=0.001) with newborn epigenetic aging. This suggests that the nature of each fat class association depends upon one another. Response surfaces revealed MUFAs were positively associated with newborn epigenetic age acceleration only at proportionately lower intakes of SFAs or PUFAs. We also demonstrate a potential beneficial association of omega-3 (n-3) PUFAs with newborn epigenetic age acceleration (P=0.008). There was no significant association of fat class with newborn aIMT, heart rate variability, or body fatness. In this study, we demonstrated an association between maternal dietary fat class composition and epigenetic aging in newborns. Future research should consider other characteristics such as the source of maternal dietary fatty acids.

Methylation-based markers of aging and lifestyle-related factors and risk of breast cancer: a pooled analysis of four prospective studies

BackgroundDNA methylation in blood may reflect adverse exposures accumulated over the lifetime and could therefore provide potential improvements in the prediction of cancer risk. A substantial body of research has shown associations between epigenetic aging and risk of disease, including cancer. Here we aimed to study epigenetic measures of aging and lifestyle-related factors in association with risk of breast cancer.MethodsUsing data from four prospective case–control studies nested in three cohorts of European ancestry participants, including a total of 1,655 breast cancer cases, we calculated three methylation-based measures of lifestyle factors (body mass index [BMI], tobacco smoking and alcohol consumption) and seven measures of epigenetic aging (Horvath-based, Hannum-based, PhenoAge and GrimAge). All measures were regression-adjusted for their respective risk factors and expressed per standard deviation (SD). Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional or unconditional logistic regression and pooled using fixed-effects meta-analysis. Subgroup analyses were conducted by age at blood draw, time from blood sample to diagnosis, oestrogen receptor-positivity status and tumour stage.ResultsNone of the measures of epigenetic aging were associated with risk of breast cancer in the pooled analysis: Horvath ‘age acceleration’ (AA): OR per SD = 1.02, 95%CI: 0.95–1.10; AA-Hannum: OR = 1.03, 95%CI:0.95–1.12; PhenoAge: OR = 1.01, 95%CI: 0.94–1.09 and GrimAge: OR = 1.03, 95%CI: 0.94–1.12, in models adjusting for white blood cell proportions, body mass index, smoking and alcohol consumption. The BMI-adjusted predictor of BMI was associated with breast cancer risk, OR per SD = 1.09, 95%CI: 1.01–1.17. The results for the alcohol and smoking methylation-based predictors were consistent with a null association. Risk did not appear to substantially vary by age at blood draw, time to diagnosis or tumour characteristics.ConclusionWe found no evidence that methylation-based measures of aging, smoking or alcohol consumption were associated with risk of breast cancer. A methylation-based marker of BMI was associated with risk and may provide insights into the underlying associations between BMI and breast cancer.

Analyzing TCGA Data to Identify Gene Mutations Linked to Hepatocellular Carcinoma in Asians

Introduction: Liver cancer is the sixth most common and second most fatal type of cancer worldwide. Few treatment options are available as patients with liver cancer are often diagnosed in an advanced stage due to a lack of clinical symptoms. Effectively preventing and treating liver cancer relies heavily on early diagnosis; early diagnosis results from identifying and monitoring high-risk patients. Epigenetic risk factors, such as hepatitis B, hepatitis C, cirrhosis, nonalcoholic fatty liver disease, and alcohol/tobacco abuse, are highly prevalent in Asia and likely cause Asians to have a higher incidence and mortality rate of liver cancer. While these acquired risk factors are relatively well understood, the underlying genetic background of liver cancer in Asians has not been well established or correlated with clinical outcomes. Methods: In this study, we accessed The Cancer Genome Atlas (TCGA) hepatocellular carcinoma clinical and mutation data through TCGAbiolinksGUI. Results: We found that mutations in five genes (TP53, TTN, OBSCN, MUC5B, CSMD1) were statistically linked with increased mortality in Asians compared to non-Asians, four of which (TTN, OBSCN, MUC5B, CSMD1) were also more prevalent in the Asian population. Within the Asian cohort, two gene mutations (TTN, HMCN1) were statistically linked with worse outcomes. We also found that the TP53 mutation predicts worse outcomes within the non-Asian cohort but not within the Asian cohort. Discussion/Conclusion: Our findings can improve cancer care in the Asian population through better disease prognostication, evaluations for potential targeted therapy, and a deeper understanding of liver cancer pathogenesis.

Genome-wide Studies of knee Osteoarthritis: Review

Background. Knee osteoarthritis (OA) is a multifactorial disease resulting from the interaction of many environmental, epigenetic and genetic risk factors, and the latter account for 40% to 65%. Genetic bases of the knee OA based on genome-wide association study (GWAS) are being actively studied by many scientific teams around the world. At the same time, the results obtained are often contradictory and ambiguous, as for the conducted replicative studies of knee OA. This dictates the need for additional replicative studies in various populations, including populations of Russia. The aim of the study was to analyze genome-wide studies of knee OA and to establish GWAS-significant polymorphic loci associated with OA. Materials and Methods. The search for publications was carried out in the electronic databases PubMed, PubMedCentral, eLIBRARY, in the GWAS catalog for the period from 2008 to the present by the keywords: knee osteoarthritis, GWAS studies, candidate genes. Results. Firstly, for the period from 2008 to 2021, 15 genome-wide studies of knee OA were performed (8 GWAS, 6 meta-analyzes of GWAS data, 1 study a combination of GWAS and meta-analysis of GWAS data), as a result of which 78 polymorphic loci were found associated with the risk of developing osteoarthritis of the knee joint at p510-08. Second ly, the vast majority of these loci (62 out of 78 SNPs, 79%) showed GWAS-significant associations with OA in meta-analyzes of GWAS data and only 16 loci (21%) in GWAS studies. Third ly, almost 95% of GWAS-significant loci for knee OA (74 SNPs) were found in samples of Caucasian origin. Fourthly, 21 out of 78 GWAS-significant SNPs are associated with isolated knee OA, and 57 SNPs are associated with knee, hip and hand OA (mixed sample). Fifth, all genome-wide studies of knee OA and meta-analyzes of GWAS data were carried out abroad on samples from various foreign populations, and samples from the Russian Federation were not included in these studies. Sixth, only two GWAS-significant polymorphic loci for OA (rs143384 of the GDF5 gene for knee OA isolated localization and rs3771501 of the TGFA gene for OA of any localization) were replicated at the whole genome level of significance (p510-08) in two different studies. Conclusion. The main genome-wide studies of knee OA were reviewed and GWAS-significant polymorphisms associated with OA were identified. The obtained materials on GWAS-significant loci can be used both in the selection of polymorphisms in replicative studies of OA in various populations of Russia, and for expanding the understanding of the molecular genetic mechanisms of the disease development.

Abstract 10666: Epigenetic Risk Score Capturing Alcohol Consumption is Not Associated with Cardiac Structure and Function: The Framingham Heart Study

Habitual, heavy alcohol consumption increases the risk of detrimental outcomes such alcoholic dilated cardiomyopathy; however, alcohol’s complex effects on cardiac structure and function are incompletely understood. We previously identified 144 differentially methylated CpGs associated with alcohol consumption and sought to create an epigenetic risk score (ERS) derived from these CpGs to examine 1) the cross-sectional association of the ERS with cardiac structure and function, and 2) longitudinal association of the ERS with incident heart failure and atrial fibrillation in Framingham Heart Study (FHS) participants (n=1,843). We first conducted analyses examining the cross-sectional association between each of the 144 alcohol-associated CpGs and the outcomes listed above. After application of Bonferroni correction (p=3.47E-04), two CpGs (cg07504977, cg16246545) were significantly associated with left ventricular posterior wall thickness (p=2.69E-05 and p=1.75E-04, respectively) and one CpG (cg11682350) was significantly associated with left ventricular global longitudinal strain (p=2.15E-04). cg07504977 annotates to the promoter of a lcRNA LINC00623, while cg16246545 maps to the PHGDH , a protein-coding gene implicated in serine synthesis. cg11682350 is not annotated to a gene. Cross-sectional analyses examining the association between the ERS and left ventricular mass (BSA-indexed; p=0.15) systolic diameter (p=0.92), diastolic diameter (p=0.87), fractional shortening (p=0.95), and global longitudinal strain (p=0.28), were not statistically significant, while ERS association with LV posterior wall thickness was nominally significant (p=0.03). Longitudinal associations for HF (p=0.18) and AF (p=0.65) were not significant. Though most of our results are not statistically significant, we plan to explore other means of generating alcohol ERS including by LASSO penalty coefficient thresholds, Gene Ontology biological pathways, and weighted gene expression network analyses. In conclusion, such alcohol-related ERS may be examined in relation to other phenotypes and serve as a predictive or diagnostic tool to monitor and elucidate the epigenetic pathways connecting environmental exposures and disease.