Mitochondrial Mutations and Genetic Factors Determining NAFLD Risk.
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ABSTRACT:
SUBMITTER: Dabravolski SA
PROVIDER: S-EPMC8123173 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundHepatic steatosis is a common chronic liver disease that can progress into more severe stages of NAFLD or promote the development of life-threatening secondary diseases for some of those affected. These include the liver itself (nonalcoholic steatohepatitis or NASH; fibrosis and cirrhosis, and hepatocellular carcinoma) or other organs such as the vessels and the heart (cardiovascular disease) or the islets of Langerhans (type 2 diabetes). In addition to elevated caloric intake and a sedentary lifestyle, genetic and epigenetic predisposition contribute to the development of NAFLD and the secondary diseases.Scope of reviewWe present data from genome-wide association studies (GWAS) and functional studies in rodents which describe polymorphisms identified in genes relevant for the disease as well as changes caused by altered DNA methylation and gene regulation via specific miRNAs. The review also provides information on the current status of the use of genetic and epigenetic factors as risk markers.Major conclusionWith our overview we provide an insight into the genetic and epigenetic landscape of NAFLD and argue about the applicability of currently defined risk scores for risk stratification and conclude that further efforts are needed to make the scores more usable and meaningful.
| S-EPMC8324682 | biostudies-literature
Project description:UNLABELLED:Some patients with liver disease progress to cirrhosis, but the risk factors for cirrhosis development are unknown. Dyskeratosis congenita, an inherited bone marrow failure syndrome associated with mucocutaneous anomalies, pulmonary fibrosis, and cirrhosis, is caused by germline mutations of genes in the telomerase complex. We examined whether telomerase mutations also occurred in sporadic cirrhosis. In all, 134 patients with cirrhosis of common etiologies treated at the Liver Research Institute, University of Arizona, between May 2008 and July 2009, and 528 healthy subjects were screened for variation in the TERT and TERC genes by direct sequencing; an additional 1,472 controls were examined for the most common genetic variation observed in patients. Telomere length of leukocytes was measured by quantitative polymerase chain reaction. Functional effects of genetic changes were assessed by transfection of mutation-containing vectors into telomerase-deficient cell lines, and telomerase activity was measured in cell lysates. Nine of the 134 patients with cirrhosis (7%) carried a missense variant in TERT, resulting in a cumulative carrier frequency significantly higher than in controls (P = 0.0009). One patient was homozygous and eight were heterozygous. The allele frequency for the most common missense TERT variant was significantly higher in patients with cirrhosis (2.6%) than in 2,000 controls (0.7%; P = 0.0011). One additional patient carried a TERC mutation. The mean telomere length of leukocytes in patients with cirrhosis, including six mutant cases, was shorter than in age-matched controls (P = 0.0004). CONCLUSION:Most TERT gene variants reduced telomerase enzymatic activity in vitro. Loss-of-function telomerase gene variants associated with short telomeres are risk factors for sporadic cirrhosis.
| S-EPMC3082730 | biostudies-literature
Project description:The distribution of fitness effects (DFE) of new mutations plays a fundamental role in evolutionary genetics. However, the extent to which the DFE differs across species has yet to be systematically investigated. Furthermore, the biological mechanisms determining the DFE in natural populations remain unclear. Here, we show that theoretical models emphasizing different biological factors at determining the DFE, such as protein stability, back-mutations, species complexity, and mutational robustness make distinct predictions about how the DFE will differ between species. Analyzing amino acid-changing variants from natural populations in a comparative population genomic framework, we find that humans have a higher proportion of strongly deleterious mutations than Drosophila melanogaster. Furthermore, when comparing the DFE across yeast, Drosophila, mice, and humans, the average selection coefficient becomes more deleterious with increasing species complexity. Last, pleiotropic genes have a DFE that is less variable than that of nonpleiotropic genes. Comparing four categories of theoretical models, only Fisher's geometrical model (FGM) is consistent with our findings. FGM assumes that multiple phenotypes are under stabilizing selection, with the number of phenotypes defining the complexity of the organism. Our results suggest that long-term population size and cost of complexity drive the evolution of the DFE, with many implications for evolutionary and medical genomics.
| S-EPMC5410820 | biostudies-other
Project description:Background: Venothromboembolism (VTE) including deep venous thrombosis (DVT) and pulmonary embolism (PE) are significant health care problems. A highly specific DVT risk stratification model requires a combination of genetic, environmental, clinical, laboratory and radiographic measurements. Genetic factors associated with DVT in post-hospitalized medical and surgical patients are incompletely understood. Aim: Using the Personalized Medicine Research Project (PMRP) population and a limited number of disease associated polymorphisms were used to determine whether these markers were associated with DVT in the post-hospitlalization period. Methods: Marshfield Clinic patients who have experienced a DVT between 1999 and 2007 enrolled in the PMRP were genotyped for 52 disease associated polymorphisms (N=1124). From these individuals we identified 451 who experienced a DVT after post-hospitalization for a medical (N=164) or surgical (N=136) procedure or both (N=151). This cohort was compared to the PMRP population that had a recorded hospitalization without a post-hospitalization DVT during the same time period (N=1662). Results: Polymorphisms in APOB (rs1042031), PLAU (rs2227564), HTR2A (rs6313) and the Vitamin D receptor haplotype (rs731236 and rs7975232) were associated with post hospitalization DVT. When the population that incurred a DVT was stratified by DVT category (post medical, post surgical or both), the PLAU polymorphism was most strongly associated with individuals experiencing a DVT post-surgically. Vitamin D receptor haplotype was significantly associated with individuals experiencing both post medical and post surgical DVTs, and polymorphisms associated with cholesterol and lipid levels were most likely to be associated with post-medical DVTs. Conclusions: This hypothesis generating study demonstrates that there are many polymorphisms that are associated with DVT that have yet to be characterized. Categorization of associated DVT polymorphisms will involve careful interrogation of both the environmental conditions as well as genetic alleles of individuals. Genes such as PLAU, HTR2A, and Vitamin D are just now being investigated for thrombogenic effects and in future may lead to a better understanding of indentifying the individuals at risk for a DVT post hospitilization.
| S-EPMC3006593 | biostudies-literature
Project description:Background & aimsWe developed comprehensive models to determine risk of Barrett's esophagus (BE) or esophageal adenocarcinoma (EAC) based on genetic and non-genetic factors.MethodsWe used pooled data from 3288 patients with BE, 2511 patients with EAC, and 2177 individuals without either (controls) from participants in the international Barrett's and EAC consortium as well as the United Kingdom's BE gene study and stomach and esophageal cancer study. We collected data on 23 genetic variants associated with risk for BE or EAC, and constructed a polygenic risk score (PRS) for cases and controls by summing the risk allele counts for the variants weighted by their natural log-transformed effect estimates (odds ratios) extracted from genome-wide association studies. We also collected data on demographic and lifestyle factors (age, sex, smoking, body mass index, use of nonsteroidal anti-inflammatory drugs) and symptoms of gastroesophageal reflux disease (GERD). Risk models with various combinations of non-genetic factors and the PRS were compared for their accuracy in identifying patients with BE or EAC using the area under the receiver operating characteristic curve (AUC) analysis.ResultsIndividuals in the highest quartile of risk, based on genetic factors (PRS), had a 2-fold higher risk of BE (odds ratio, 2.22; 95% confidence interval, 1.89-2.60) or EAC (odds ratio, 2.46; 95% confidence interval, 2.07-2.92) than individual in the lowest quartile of risk based on PRS. Risk models developed based on only demographic or lifestyle factors or GERD symptoms identified patients with BE or EAC with AUC values ranging from 0.637 to 0.667. Combining data on demographic or lifestyle factors with data on GERD symptoms identified patients with BE with an AUC of 0.793 and patients with EAC with an AUC of 0.745. Including PRSs with these data only minimally increased the AUC values for BE (to 0.799) and EAC (to 0.754). Including the PRSs in the model developed based on non-genetic factors resulted in a net reclassification improvement for BE of 3.0% and for EAC of 5.6%.ConclusionsWe used data from 3 large databases of patients from studies of BE or EAC to develop a risk prediction model based on genetic, clinical, and demographic/lifestyle factors. We identified a PRS that increases discrimination and net reclassification of individuals with vs without BE and EAC. However, the absolute magnitude of improvement is not sufficient to justify its clinical use.
| S-EPMC5880715 | biostudies-literature
Project description:The presented study performed an mtDNA genome-wide association analysis to screen the peripheral blood of breast cancer patients for high-risk germline mutations. Unlike previous studies, which have used breast tissue in analyzing somatic mutations, we looked for germline mutations in our study, since they are better predictors of breast cancer in high-risk groups, facilitate early, non-invasive diagnoses of breast cancer and may provide a broader spectrum of therapeutic options. The data comprised 22 samples of healthy group and 83 samples from breast cancer patients. The sequencing data showed 170 mtDNA mutations in the healthy group and 393 mtDNA mutations in the disease group. Of these, 283 mtDNA mutations (88 in the healthy group and 232 in the disease group) had never been reported in the literature. Moreover, correlation analysis indicated there was a significant difference in 32 mtDNA mutations. According to our relative risk analysis of these 32 mtDNA mutations, 27 of the total had odds ratio values (ORs) of less than 1, meaning that these mutations have a potentially protective role to play in breast cancer. The remaining 5 mtDNA mutations, RNR2-2463 indelA, COX1-6296 C>A, COX1-6298 indelT, ATP6-8860 A>G, and ND5-13327 indelA, whose ORs were 8.050, 4.464, 4.464, 5.254 and 4.853, respectively, were regarded as risk factors of increased breast cancer. The five mutations identified here may serve as novel indicators of breast cancer and may have future therapeutic applications. In addition, the use of peripheral blood samples was procedurally simple and could be applied as a non-invasive diagnostic technique.
| S-EPMC5058755 | biostudies-literature
Project description:Non-alcoholic fatty liver disease (NAFLD) is becoming the predominant liver disease worldwide, and vitamin E has been clinically shown to improve histological parameters in a subset of patients. In this narrative review, we investigate whether genetic factors may help to explain why some patients show histological improvements upon high-dose alpha-tocopherol (αT) treatment while others do not. In summary, we identified two factors that are associated with treatment response, including genetic variations in haptoglobin as well as fatty acid desaturase 1/2 (FADS1/FADS2). Other genetic variants such as in alpha-tocopherol transfer protein (αTTP), tocopherol associated protein (TAP), transmembrane 6 superfamily 2 (TM6SF2), cluster of differentiation 36 (CD36), and proteins involved in lipoprotein metabolism may also play a role, but have not yet been investigated in a clinical context. We propose to further validate these associations in larger populations, to then use them as a clinical tool to identify the subset of patients that will benefit the most from vitamin E supplementation.
| S-EPMC9311784 | biostudies-literature
Project description:Grain weight is one of the major factors determining single plant yield production of rice and other cereal crops. Research has begun to reveal the regulatory mechanisms underlying grain weight as well as grain size, highlighting the importance of this research for plant molecular biology. The developmental trait of grain weight is affected by multiple molecular and genetic aspects that lead to dynamic changes in cell division, expansion and differentiation. Additionally, several important biological pathways contribute to grain weight, such as ubiquitination, phytohormones, G-proteins, photosynthesis, epigenetic modifications and microRNAs. Our review integrates early and more recent findings, and provides future perspectives for how a more complete understanding of grain weight can optimize strategies for improving yield production. It is surprising that the acquired wealth of knowledge has not revealed more insights into the underlying molecular mechanisms. To accelerating molecular breeding of rice and other cereals is becoming an emergent and critical task for agronomists. Lastly, we highlighted the importance of leveraging gene editing technologies as well as structural studies for future rice breeding applications.
| S-EPMC8313227 | biostudies-literature
Project description:The COVID-19 pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) poses an unprecedented challenge to humanity. SARS-CoV-2 infections range from asymptomatic to severe courses of COVID-19 with acute respiratory distress syndrome (ARDS), multiorgan involvement and death. Risk factors for disease severity include older age, male sex, increased BMI and pre-existing comorbidities. Ethnicity is also relevant to COVID-19 susceptibility and severity. Host genetic predisposition to COVID-19 is now increasingly recognized and whole genome and candidate gene association studies regarding COVID-19 susceptibility have been performed. Several common and rare variants in genes related to inflammation or immune responses have been identified. We summarize research on COVID-19 host genetics and compile genetic variants associated with susceptibility to COVID-19 and disease severity. We discuss candidate genes that should be investigated further to understand such associations and provide insights relevant to pathogenesis, risk classification, therapy response, precision medicine, and drug repurposing.
| S-EPMC8512556 | biostudies-literature
Project description:Transcriptional Profiling of Insulin Sensitive and Insulin Resistant Samples Sixty two participants at the tail ends of the distribution of insulin sensitivity adjusted for age, gender and natural logarithm of BMI for each ethnic group separately. Individuals at tail ends were well matched for age, gender, BMI, and percent fat, but were different for insulin sensitivity. Participants were of age 20 years to 55 years, body mass index (BMI) between 19 kg/m2 and 42 kg/m2, and had all biopsies obtained in the fasting state.
2013-04-16 | E-GEOD-40234 | biostudies-arrayexpress