scholarly journals Differential regulation of hepatic physiology and injury by the TAM receptors Axl and Mer

2020 ◽  
Vol 3 (8) ◽  
pp. e202000694
Author(s):  
Anna Zagórska ◽  
Paqui G Través ◽  
Lidia Jiménez-García ◽  
Jenna D Strickland ◽  
Joanne Oh ◽  
...  
Keyword(s):  
Liver Disease ◽  
Apoptotic Cell ◽  
Association Studies ◽  
Acute Injury ◽  
Genome Wide Association Studies ◽  
Chronic Injury ◽  
Tam Receptors ◽  
Cell Accumulation ◽  
Acetaminophen Intoxication ◽  
Injury Models

Genome-wide association studies have implicated the TAM receptor tyrosine kinase (RTK) Mer in liver disease, yet our understanding of the role that Mer and its related RTKs Tyro3 and Axl play in liver homeostasis and the response to acute injury is limited. We find that Mer and Axl are most prominently expressed in hepatic Kupffer and endothelial cells and that as mice lacking these RTKs age, they develop profound liver disease characterized by apoptotic cell accumulation and immune activation. We further find that Mer is critical to the phagocytosis of apoptotic hepatocytes generated in settings of acute hepatic injury, and that Mer and Axl act in concert to inhibit cytokine production in these settings. In contrast, we find that Axl is uniquely important in mitigating liver damage during acetaminophen intoxication. Although Mer and Axl are protective in acute injury models, we find that Axl exacerbates fibrosis in a model of chronic injury. These divergent effects have important implications for the design and implementation of TAM-directed therapeutics that might target these RTKs in the liver.

scholarly journals Genetic and Epigenetic Modifiers of Alcoholic Liver Disease

2018 ◽  
Vol 19 (12) ◽  
pp. 3857 ◽  
Author(s):  
Marica Meroni ◽  
Miriam Longo ◽  
Raffaela Rametta ◽  
Paola Dongiovanni
Keyword(s):  
Liver Disease ◽  
Alcohol Consumption ◽  
Alcoholic Liver Disease ◽  
Complex Disease ◽  
Wide Spectrum ◽  
Association Studies ◽  
Phenotypic Variability ◽  
Genome Wide Association Studies ◽  
Epigenetic Factors ◽  
Excessive Alcohol Consumption

Alcoholic liver disease (ALD), a disorder caused by excessive alcohol consumption is a global health issue. More than two billion people consume alcohol in the world and about 75 million are classified as having alcohol disorders. ALD embraces a wide spectrum of hepatic lesions including steatosis, alcoholic steatohepatitis (ASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). ALD is a complex disease where environmental, genetic, and epigenetic factors contribute to its pathogenesis and progression. The severity of alcohol-induced liver disease depends on the amount, method of usage and duration of alcohol consumption as well as on age, gender, presence of obesity, and genetic susceptibility. Genome-wide association studies and candidate gene studies have identified genetic modifiers of ALD that can be exploited as non-invasive biomarkers, but which do not completely explain the phenotypic variability. Indeed, ALD development and progression is also modulated by epigenetic factors. The premise of this review is to discuss the role of genetic variants and epigenetic modifications, with particular attention being paid to microRNAs, as pathogenic markers, risk predictors, and therapeutic targets in ALD.

scholarly journals Genome-Wide Association Studies and Liver Disease

2015 ◽  
Vol 35 (04) ◽  
pp. 355-360
Author(s):  
Elizabeth Speliotes
Keyword(s):  
Liver Disease ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide

Genetics of connective tissue diseases

2013 ◽  
Author(s):  
Myles Lewis ◽  
Tim Vyse
Keyword(s):  
Systemic Sclerosis ◽  
Connective Tissue ◽  
Large Scale ◽  
Apoptotic Cell ◽  
Association Studies ◽  
Group Analysis ◽  
Connective Tissue Diseases ◽  
Susceptibility Genes ◽  
Type I ◽  
Genome Wide Association Studies

The advent of genome-wide association studies (GWAS) has been an exciting breakthrough in our understanding of the genetic aetiology of autoimmune diseases. Substantial overlap has been found in susceptibility genes across multiple diseases, from connective tissue diseases and rheumatoid arthritis (RA) to inflammatory bowel disease, coeliac disease, and psoriasis. Major technological advances now permit genotyping of millions of single nucleotide polymorphisms (SNPs). Group analysis of SNPs by haplotypes, aided by completion of the Hapmap project, has improved our ability to pinpoint causal genetic variants. International collaboration to pool large-scale cohorts of patients has enabled GWAS in systemic lupus erythematosus (SLE), systemic sclerosis and Behçet's disease, with studies in progress for ANCA-associated vasculitis. These 'hypothesis-free' studies have revealed many novel disease-associated genes. In both SLE and systemic sclerosis, identified genes map to known pathways including antigen presentation (MHC, TNFSF4), autoreactivity of B and T lymphocytes (BLK, BANK1), type I interferon production (STAT4, IRF5) and the NFκ‎B pathway (TNIP1). In SLE alone, additional genes appear to be involved in dysregulated apoptotic cell clearance (ITGAM, TREX1, C1q, C4) and recognition of immune complexes (FCGR2A, FCGR3B). Future developments include whole-genome sequencing to identify rare variants, and efforts to understand functional consequences of susceptibility genes. Putative environmental triggers for connective tissue diseases include infectious agents, especially Epstein-Barr virus; cigarette smoking; occupational exposure to toxins including silica; and low vitamin D, due to its immunomodulatory effects. Despite numerous studies looking at toxin exposure and connective tissue diseases, conclusive evidence is lacking, due to either rarity of exposure or rarity of disease.

scholarly journals Genomics of Human Fibrotic Diseases: Disordered Wound Healing Response

2020 ◽  
Vol 21 (22) ◽  
pp. 8590
Author(s):  
Rivka C. Stone ◽  
Vivien Chen ◽  
Jamie Burgess ◽  
Sukhmani Pannu ◽  
Marjana Tomic-Canic
Keyword(s):  
Wound Healing ◽  
Association Studies ◽  
Acute Injury ◽  
Transcriptional Networks ◽  
Genome Wide Association Studies ◽  
Matrix Deposition ◽  
Healing Response ◽  
Wound Healing Response ◽  
Genomic Studies ◽  
Fibrotic Diseases

Fibrotic disease, which is implicated in almost half of all deaths worldwide, is the result of an uncontrolled wound healing response to injury in which tissue is replaced by deposition of excess extracellular matrix, leading to fibrosis and loss of organ function. A plethora of genome-wide association studies, microarrays, exome sequencing studies, DNA methylation arrays, next-generation sequencing, and profiling of noncoding RNAs have been performed in patient-derived fibrotic tissue, with the shared goal of utilizing genomics to identify the transcriptional networks and biological pathways underlying the development of fibrotic diseases. In this review, we discuss fibrosing disorders of the skin, liver, kidney, lung, and heart, systematically (1) characterizing the initial acute injury that drives unresolved inflammation, (2) identifying genomic studies that have defined the pathologic gene changes leading to excess matrix deposition and fibrogenesis, and (3) summarizing therapies targeting pro-fibrotic genes and networks identified in the genomic studies. Ultimately, successful bench-to-bedside translation of observations from genomic studies will result in the development of novel anti-fibrotic therapeutics that improve functional quality of life for patients and decrease mortality from fibrotic diseases.

scholarly journals Genetic Factors in the Pathogenesis of Nonalcoholic Fatty Liver and Steatohepatitis

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Paola Dongiovanni ◽  
Stefano Romeo ◽  
Luca Valenti
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Association Studies ◽  
Liver Steatosis ◽  
Liver Fat ◽  
Genome Wide Association Studies ◽  
Very Low Density Lipoproteins ◽  
Fat Accumulation ◽  
Nonalcoholic Fatty Liver ◽  
Hepatic Fat

Liver fat accumulation generally related to systemic insulin resistance characterizes nonalcoholic fatty liver disease (NAFLD), which in the presence of nonalcoholic steatohepatitis (NASH) can progress towards cirrhosis and hepatocellular carcinoma. Due to the epidemic of obesity, NAFLD is now the most frequent liver disease in Western countries. Epidemiological, familial, and twin studies provide evidence for a strong genetic component of NAFLD susceptibility. Recently, genome-wide association studies led to the identification of the major inherited determinants of hepatic fat accumulation:patatin-like phospholipase domain-containing 3 (PNPLA3)I148M gene andtransmembrane 6 superfamily member 2 (TM6SF2)E167K gene variants, involved in lipid droplets remodelling and very low-density lipoproteins secretion, are the major determinants of interindividual differences in liver steatosis, and susceptibility to progressive NASH. In this review, we aimed to provide an overview of recent insights into the genetics of hepatic fat accumulation and steatohepatitis.

scholarly journals Is HSD17B13 Genetic Variant a Protector for Liver Dysfunction? Future Perspective as a Potential Therapeutic Target

2021 ◽  
Vol 11 (7) ◽  
pp. 619
Author(s):  
Takashi Motomura ◽  
Sriram Amirneni ◽  
Ricardo Diaz-Aragon ◽  
Lanuza A. P. Faccioli ◽  
Michelle R. Malizio ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Therapeutic Target ◽  
Fatty Liver Disease ◽  
Genetic Variant ◽  
Association Studies ◽  
Future Perspective ◽  
Genome Wide Association Studies ◽  
Potential Therapeutic Target ◽  
Alcoholic Fatty Liver

As diet and lifestyle have changed, fatty liver disease (FLD) has become more and more prevalent. Many genetic risk factors, such as variants of PNPLA3, TM6SF2, GCKR, and MBOAT7, have previously been uncovered via genome wide association studies (GWAS) to be associated with FLD. In 2018, a genetic variant (rs72613567, T > TA) of hydroxysteroid 17-β dehydrogenase family 13 (HSD17B13) was first associated with a lower risk of developing alcoholic liver disease and non-alcoholic fatty liver disease (NAFLD) in minor allele carriers. Other HSD17B13 variants were also later linked with either lower inflammation scores among NAFLD patients or protection against NAFLD (rs6834314, A > G and rs9992651, G > A) respectively. HSD17B13 is a lipid droplet-associated protein, but its function is still ambiguous. Compared to the other genetic variants that increase risk for FLD, HSD17B13 variants serve a protective role, making this gene a potential therapeutic target. However, the mechanism by which these variants reduce the risk of developing FLD is still unclear. Because studies in cell lines and mouse models have produced conflicting results, human liver tissue modeling using induced pluripotent stem cells may be the best way to move forward and solve this mystery.

scholarly journals Causal effect of adiposity on the risk of 19 gastrointestinal diseases: a Mendelian randomization study

2021 ◽  
Author(s):  
Min Seo Kim ◽  
Minku Song ◽  
Soyeon Kim ◽  
Beomsu Kim ◽  
Wonseok Kang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Liver Disease ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Association Studies ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Alcoholic Fatty Liver ◽  
Increased Risk

Objectives: We applied Mendelian randomization (MR) to investigate the causal associations of body mass index (BMI) and waist circumference (WC) with 19 gastrointestinal (GI) disorders. Design: MR study. Setting: The UK Biobank, Genetic Investigation of Anthropometric Traits (GIANT) Consortium, FinnGen consortium, and genome-wide association studies. Participants: Overall, >400,000 UK Biobank participants, >170,000 participants of Finnish descent, and numerous consortia participants with predominantly European ancestry. Interventions: Single-nucleotide polymorphisms associated with BMI and WC were used as instrumental variables to estimate the causal associations with the GI conditions. Main outcome measures: Risk of developing 19 GI diseases Results: After correction for multiple testing (Bonferroni-corrected threshold of P<0.05/19) and testing for consistencies using several MR methods with varying assumptions (inverse variance weighted, weighted median, MR-Egger, and MR-PRESSO), genetically predicted BMI was associated with increased risks of non-alcoholic fatty liver disease (NAFLD), cholecystitis, cholelithiasis, and primary biliary cholangitis. The odds ratio (OR) per one standard deviation (SD) increased in genetically predicted BMI (4.77 kg/m2) from 1.22 (95% confidence interval [CI] 1.12 to 1.34; P<0.0001) for NAFLD to 1.65 (95% CI 1.31 to 2.06; P<0.0001) for cholecystitis. Genetically predicted WC was associated with increased risks of NAFLD, alcoholic liver disease (ALD), cholecystitis, cholelithiasis, colon cancer, and gastric cancer. ALD was associated with WC even after adjustment for alcohol consumption in multivariable MR analysis. The OR per 1 SD increased in genetically predicted WC (12.52 cm) from 1.41 (95% CI 1.17 to 1.70; P=0.0015) for gastric cancer to 1.74 (95% CI 1.21 to 1.78; P<0.0001) for cholelithiasis. Conclusions: Higher BMI and WC are causally associated with an increased risk of GI abnormalities, particularly of hepatobiliary organs (liver, biliary tract, and gallbladder) that are functionally related to fat metabolism. Abdominal obesity measured by WC might be more influential and relevant with a diverse span of GI diseases than BMI, highlighting a possible pathophysiological role of visceral abdominal fats in the development of GI disorders and cancers.

scholarly journals Association of Common Variant Rs2281135 of PNPLA3 with Alcohol-Related Cirrhosis in Chinese Han Males

2021 ◽  
Vol 8 (2) ◽  
Author(s):  
Chen H ◽  
◽  
Zhang Y ◽  
Huang J ◽  
Yang F ◽  
...  
Keyword(s):  
Liver Disease ◽  
Genetic Model ◽  
Association Studies ◽  
Common Variant ◽  
Genome Wide Association Studies ◽  
Chinese Han ◽  
Chi Square ◽  
Nonalcoholic Fatty Liver ◽  
Han Population ◽  
Increased Risk

Background and Aim: Alcoholic Liver Disease (ALD), caused by longterm heavy alcohol consumption, is influenced by genetic factors. Studies have illustrated the overlapping genetic mechanism in Nonalcoholic Fatty Liver Disease (NAFLD) and ALD. Recently, a number of Genome-Wide Association Studies (GWAS) have demonstrated several SNPs were strongly associated with NAFLD. The aim of present study is to evaluate the association between these NAFLD-associated SNPs and ALD in Chinese Han population. Methods: Nine SNPs were selected and genotyped in a cohort of 507 patients with ALD and 645 healthy controls by using MassARRAY iPLEX system. Alleles and genotypes analysis of SNPs were performed in logistic regression. The association between SNP and the level of liver serum biomarkers was tested in chi-square test and linear regression model. Results: Our data confirmed that rs2281135 A-allele in PNPLA3 and rs3761472 G-allele in SAMM50 were significantly associated with increased risk of ALD (P = 1.93×10-12, OR [95% CI] = 1.82 [1.54-2.15]; P = 2.08×10-16, OR [95% CI] = 1.06 [1.04-1.08], respectively). The genotypes of rs2281135 were associated with ALD in additive, dominant and recessive genetic model (P = 1.24×10-11, P = 1.46×10-7, P = 2.07×10-9, respectively). In addition, rs2281135 was found to be associated with serum elevated levels of ALT (P = 5.0×10-3), AST (P = 0.03), ALP (P = 0.02), GGT (P = 0.03) in patients with ALD. Conclusions: The present study confirmed that PNPLA3 common variant rs2281135 was significantly associated with ALD in Chinese male Han population.

scholarly journals OR22-07 Novel Variants in Protein Kinase a Signaling-Related Genes Identified in Obese Children with and Without NAFLD

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Michelle Bloyd ◽  
Steven Coon ◽  
James Iben ◽  
Ninet Sinaii ◽  
Fabio Rueda Faucz ◽  
...  
Keyword(s):  
Liver Disease ◽  
Allele Frequency ◽  
Plasma Lipids ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Gene Variants ◽  
Nucleotide Polymorphisms ◽  
Clinical Markers ◽  
Nonalcoholic Fatty Liver ◽  
Triglyceride Accumulation

Abstract Context: Nonalcoholic fatty liver disease (NAFLD) is estimated to affect nearly 10% of Americans age 2-19 and about 38% of those affected are obesei. NAFLD is characterized by triglyceride accumulation in hepatocytes and can progress to nonalcoholic steatohepatitis, end stage liver disease and hepatocellular carcinoma. The underlying causes of NAFLD in youth are unclear although obesity, insulin resistance, type 2 diabetes mellitus and metabolic syndrome are risk factors. Genome-wide association studies and candidate gene studies have found several single nucleotide polymorphisms that affect susceptibility to and progression of NAFLD, but clinical translation for some of these genetics is lackingii. Study design: Because mouse models of dysregulated PKA signaling demonstrate the centrality of this pathway in hepatic lipid metabolism and glucose homeostasis, we hypothesized that defects in hepatic PKA signaling genes could affect susceptibility to or severity of NAFLD in children. We asked whether identified variants might be associated with differences in clinical markers in a cohort of obese pediatric patients (non-NAFLD, n=295; NAFLD, n=165) followed at Yale Medical School, where clinical data and genomic DNA were collected. Exon sequencing of 54 PKA-related candidate genes included those coding for PKA subunits, PDEs and other proteins integral to the hepatic PKA system. Variants were ranked by allele frequency and potential pathogenicity. Ongoing analyses aim to identify associations between single variants and potential additive effects with clinical parameters (anthropometric, liver function, glucose metabolism, plasma lipids). Results: Gene variants were identified in ABCA1, ADCY4, ADCY5, AKAP7, CREB3L1, CREB3L4, CREM, CYP27A1, DHCR7, ERN1, GYS2, IL6, IL10RB, MC2R, PDE1B, PDE2A, PDE3B, PDE4A, PDE7B, PDE10A, PDE11A, PPARGC1B, PRKAR2A, and PRKAR1B. Reported variants met criteria of high to moderate impact based on 9 in silico scores that predict pathogenicity. Allele frequency ranged from 2.5 to over 50 times higher in our cohort than the general population. One or more variant was identified in 34.9% of non-NAFLD and 19.4% of NAFLD patients (p=.0004). Conclusion: We report PKA-related gene variants among a cohort of pediatric obese patients that might serve as useful predictors of risk of NAFLD or obesity. Further analyses will help determine whether any of these variants may play a functional role in NAFLD. Endnotes i Schwimmer JB, Deutsch R, Kahen T, Lavine JE, Stanley C, Behling C. Pediatrics. 2006;118(4):1388. ii Vespasiani-Gentilucci U, Gallo P, Dell’Unto C et al. World J Gastroenterol. 2018;24(43):4835-4845.

Genetics in Common Liver Diseases: From Pathophysiology to Precise Treatment

2016 ◽  
Vol 34 (4) ◽  
pp. 391-395 ◽  
Author(s):  
Frank Lammert
Keyword(s):  
Liver Disease ◽  
Liver Diseases ◽  
Association Studies ◽  
Clinical Care ◽  
Genome Wide Association Studies ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
The Past ◽  
Genomic Technologies ◽  
Genome Wide

In the past 2 decades, advances in genetics have improved our understanding of liver disease and physiology. Firstly, developments in genomic technologies drove the identification of genes responsible for monogenic (Mendelian) liver diseases. Over the last decade, genome-wide association studies allowed for the dissection of the genetic susceptibility to complex liver diseases such as fatty liver disease and drug-induced liver injury, in which environmental co-factors play critical roles. The findings have allowed the identification and elaboration of pathophysiological processes, have indicated the need for reclassification of liver diseases and risk factors and have already pointed to new disease treatments. This is illustrated by the interaction of alcohol, overnutrition and the PNPLA3 gene, which represents an ‘infernal triangle' for the liver. In the future, genetics will allow further stratification of liver diseases and contribute to personalized (precision) medicine, offering novel opportunities for translational research and clinical care of our patients.

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