scholarly journals A PDCD1 Role in the Genetic Predisposition to NAFLD-HCC?

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1412
Author(s):  
Nardeen Eldafashi ◽  
Rebecca Darlay ◽  
Ruchi Shukla ◽  
Misti Vanette McCain ◽  
Robyn Watson ◽  
...  
Keyword(s):  
Animal Studies ◽  
Tolerance Induction ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Genetic Studies ◽  
Alcoholic Fatty Liver ◽  
Immune Tolerance Induction ◽  
Potential Impact ◽  
Alcoholic Fatty Liver Disease

Obesity and non-alcoholic fatty liver disease (NAFLD) are contributing to the global rise in deaths from hepatocellular carcinoma (HCC). The pathogenesis of NAFLD-HCC is not well understood. The severity of hepatic steatosis, steatohepatitis and fibrosis are key pathogenic mechanisms, but animal studies suggest altered immune responses are also involved. Genetic studies have so far highlighted a major role of gene variants promoting fat deposition in the liver (PNPLA3 rs738409; TM6SF2 rs58542926). Here, we have considered single-nucleotide polymorphisms (SNPs) in candidate immunoregulatory genes (MICA rs2596542; CD44 rs187115; PDCD1 rs7421861 and rs10204525), in 594 patients with NAFLD and 391 with NAFLD-HCC, from three European centres. Associations between age, body mass index, diabetes, cirrhosis and SNPs with HCC development were explored. PNPLA3 and TM6SF2 SNPs were associated with both progression to cirrhosis and NAFLD-HCC development, while PDCD1 SNPs were specifically associated with NAFLD-HCC risk, regardless of cirrhosis. PDCD1 rs7421861 was independently associated with NAFLD-HCC development, while PDCD1 rs10204525 acquired significance after adjusting for other risks, being most notable in the smaller numbers of women with NAFLD-HCC. The study highlights the potential impact of inter individual variation in immune tolerance induction in patients with NAFLD, both in the presence and absence of cirrhosis.

scholarly journals Mitochondrial Mutations and Genetic Factors Determining NAFLD Risk

2021 ◽  
Vol 22 (9) ◽  
pp. 4459
Author(s):  
Siarhei A. Dabravolski ◽  
Evgeny E. Bezsonov ◽  
Mirza S. Baig ◽  
Tatyana V. Popkova ◽  
Ludmila V. Nedosugova ◽  
...  
Keyword(s):  
Liver Disease ◽  
Causative Role ◽  
Nucleotide Polymorphisms ◽  
Mitochondrial Mutations ◽  
Single Nucleotide ◽  
Alcoholic Fatty Liver ◽  
Dna Mutations ◽  
Life Threatening ◽  
Mitochondria Dna

NAFLD (non-alcoholic fatty liver disease) is a widespread liver disease that is often linked with other life-threatening ailments (metabolic syndrome, insulin resistance, diabetes, cardiovascular disease, atherosclerosis, obesity, and others) and canprogress to more severe forms, such as NASH (non-alcoholic steatohepatitis), cirrhosis, and HCC (hepatocellular carcinoma). In this review, we summarized and analyzed data about single nucleotide polymorphism sites, identified in genes related to NAFLD development and progression. Additionally, the causative role of mitochondrial mutations and mitophagy malfunctions in NAFLD is discussed. The role of mitochondria-related metabolites of the urea cycle as a new non-invasive NAFLD biomarker is discussed. While mitochondria DNA mutations and SNPs (single nucleotide polymorphisms) canbe used as effective diagnostic markers and target for treatments, age and ethnic specificity should be taken into account.

scholarly journals Antihistamines Increase Body Mass Index Percentiles and Z-Scores in Hispanic Children

Children ◽  
2020 ◽  
Vol 7 (12) ◽  
pp. 305
Author(s):  
Michelle Saad ◽  
Sabeen Syed ◽  
Maheen Ilyas ◽  
Anatoliy A. Gashev
Keyword(s):  
Body Mass Index ◽  
Body Mass ◽  
Animal Studies ◽  
Liver Enzymes ◽  
Comparison Group ◽  
The United States ◽  
Alcoholic Fatty Liver ◽  
Z Scores ◽  
Alcoholic Fatty Liver Disease

The prevalence of childhood obesity has increased over the years in the United States and contributed to a rise in metabolic syndrome and non-alcoholic fatty liver disease (NAFLD). Animal studies suggested the role of histamine blockade on mesenteric lymphatics tone, contributing to weight gain and hepatic steatosis. This study aimed to investigate an association between antihistamines (AH) use in children and obesity. A single-center retrospective cohort study on children with a diagnosis of NAFLD, followed in the gastroenterology clinic, was performed between January 2018 and April 2019. The demographics, medications, and body mass index (BMI) were assessed. Participants were divided into an AH group with documented use and comparison group, antihistamine naïve. Of the 32 participants in the study, 13 used AH, and 19 did not. Antihistamine users had a mean increase in BMI percentile per year of 1.17 compared to a decrease of 0.06 in comparison group (p = 0.0008). AH usage correlated with a mean increase in BMI z-score of 0.23 per year, as opposed to a decrease by 0.012 in comparison group (p = 0.0016). No difference was found in triglycerides (TG), glucose, and liver enzymes. AH use increases BMI percentiles and z-scores over time and is associated with obesity in children.

scholarly journals The interaction of SAMM50-rs738491, PARVB-rs5764455 and PNPLA3-rs738409 increases the susceptibility to nonalcoholic steatohepatitis

2020 ◽  
Author(s):  
Ke Xu ◽  
Kenneth I. Zheng ◽  
Pei-Wu Zhu ◽  
Wen-Yue Liu ◽  
Hong-Lei Ma ◽  
...  
Keyword(s):  
Liver Disease ◽  
Nonalcoholic Steatohepatitis ◽  
Gene Interactions ◽  
Multivariable Logistic Regression Analysis ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Alcoholic Fatty Liver ◽  
Chinese Cohort ◽  
The Mean ◽  
Alcoholic Fatty Liver Disease

Abstract Background: Previous studies have reported that single nucleotide polymorphisms (SNPs) in SAMM50-rs738491, PARVB-rs5764455 and PNPLA3-rs738409 are associated with the development of non-alcoholic fatty liver disease (NAFLD). However, no studies have examined the effect of interactions between these three genotypes to affect liver disease severity. Objective: Our aim was to assess the effect of these three SNPs on nonalcoholic steatohepatitis (NASH) and to investigate gene-gene interactions in a Chinese cohort of patients with biopsy-proven NAFLD.Methods: 415 adult patients with biopsy-proven NAFLD were recruited to the study. Multivariable logistic regression analysis was undertaken to test associations between NASH and SNPs in SAMM50-rs738491, PARVB-rs5764455 and PNPLA3-rs738409. Gene-gene interactions were analyzed by performing a generalized multifactor dimensionality reduction (GMDR) analysis.Results: The mean age of patients was 41.3±12.5 years and 75.9% of them were men. Patients with SAMM50-rs738491 TT, PARVB-rs5764455 AA or PNPLA3-rs738409 GG genotypes had a higher risk of having NASH even after adjustment for age, sex and body mass index. Furthermore, GMDR analysis showed that the combination of all three SNPs was the best model to predict NASH. Additionally, the odds ratio of the haplotype A-G-T for predicting risk of NASH was nearly three times higher than that of the haplotype G-C-C. Conclusions: Patients with NAFLD who have SAMM50-rs738491 TT, PARVB-rs5764455 AA or PNPLA3-rs738409 GG genotypes are at higher risk of NASH. Moreover, these SNPs synergistically interact to increase the susceptibility to NASH.

scholarly journals The association of adiponectin gene polymorphisms with susceptibility and progression of NAFLD in a cohort of Egyptian patients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Eman M. Hasan ◽  
Rasha A. Abd Al Aziz ◽  
Dina Sabry ◽  
Hedy A. Badary ◽  
Yasmine Gaber ◽  
...  
Keyword(s):  
Multivariate Regression ◽  
Multivariate Regression Analysis ◽  
Nucleotide Polymorphisms ◽  
Adiponectin Gene ◽  
Single Nucleotide ◽  
Alcoholic Fatty Liver ◽  
Increased Risk ◽  
Egyptian Patients ◽  
Independent Risk Factors ◽  
Alcoholic Fatty Liver Disease

Abstract Background Several genetic polymorphisms have been proven to play a key role in the progression of non-alcoholic fatty liver disease (NAFLD) from simple steatosis to NASH with fibrosis. Our aim was to study the effect of single nucleotide polymorphisms (SNPs) in the adiponectin gene, namely rs266729 and rs3774261, on susceptibility to NAFLD and disease progression. Results There was a definitive association between polymorphisms of the studied SNPs and NAFLD. Among rs266729, CG was significantly higher among patients than controls showing increased risk for NAFLD (P<0.05). AA genotype of the rs3774261 variant was significantly lower in patients than in controls (P value< 0.001) while AG and GG genotypes were significantly higher in patients than in controls (P value<0.05); A allele was significantly higher among controls (P=0.019) which might have a protective effect. None of the variants correlated significantly with the degree of steatosis. Using multivariate regression analysis, there was no significant correlation with any of the independent risk factors to the degree of steatosis. Conclusions There was an association between polymorphisms of the studied SNPs of rs266729 and rs3774261 of the adiponectin gene and NAFLD.

scholarly journals MOLECULAR GENETIC STUDIES OF COMORBIDITY

2015 ◽  
Vol 14 (6) ◽  
pp. 94-102
Author(s):  
Ye. Yu. Bragina ◽  
M. B. Freidin
Keyword(s):  
Molecular Biology ◽  
Genetic Basis ◽  
Molecular Genetic ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Genetic Studies ◽  
Gene Environment ◽  
Genome Variations ◽  
Genetic Specificity

This review focuses at the problem of the genetic basis of comorbidity. We discuss the concepts and terms relating to combinations of diseases. The guidelines of the study of comorbidity using modern high throughput methods and approaches of genetics, molecular biology and bioinformatics are designated. In this review we present results of studies showing genetic specificity for the combined phenotypes dif-ferent from the isolated disease, we considergene-gene and gene-environment interactions in comorbidity. We also discuss the role of single nucleotide polymorphisms and structural genome variations in the development of comorbidity. Own results of researching shared genes of inversely comorbid diseases like as bronchial asthma and tuberculosis are presented.

Association of genetic polymorphism of cytokines and antioxidant enzymes with the development of asbestosis

2020 ◽  
Vol 60 (12) ◽  
pp. 898-903
Author(s):  
Lyudmila P. Kuzmina ◽  
Anastasiya G. Khotuleva ◽  
Evgeniy V. Kovalevsky ◽  
Nikolay N. Anokhin ◽  
Iraklij M. Tskhomariya
Keyword(s):  
Antioxidant Enzymes ◽  
Genetic Polymorphism ◽  
Genetic Predisposition ◽  
Risk Groups ◽  
Dust Exposure ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Gstp1 Gene ◽  
Polymorphic Variants

Introduction. Various industries widely use chrysotile asbestos, which determines the relevance of research aimed at the prevention of asbestos-related diseases. It is promising to assess the role of specific genes, which products are potentially involved in the development and regulation of certain links in the pathogenesis of asbestosis, forming a genetic predisposition to the disease. The study aims to analyze the presence of associations of genetic polymorphism of cytokines and antioxidant enzymes with asbestosis development. Materials and methods. Groups were formed for examination among employees of OJSC "Uralasbest" with an established diagnosis of asbestosis and without lung diseases. For each person included in the study, dust exposure doses were calculated considering the percentage of time spent at the workplace during the shift for the entire work time. Genotyping of single nucleotide polymorphisms of cytokines IL1b (rs16944), IL4 (rs2243250), IL6 (rs1800795), TNFα (rs1800629) and antioxidant enzymes SOD2 (rs4880), GSTP1 (rs1610011), CAT (rs1001179) was carried out. Results. The authors revealed the associations of polymorphic variants A511G IL1b gene (OR=2.457, 95% CI=1.232-4.899) and C47T SOD2 gene (OR=1.705, 95% CI=1.055-2.756) with the development of asbestosis. There was an increase in the T allele IL4 gene (C589T) frequency in persons with asbestosis at lower values of dust exposure doses (OR=2.185, 95% CI=1.057-4.514). The study showed the associations of polymorphism C589T IL4 gene and C174G IL6 gene with more severe asbestosis, polymorphism A313G GSTP1 gene with pleural lesions in asbestosis. Conclusion. Polymorphic variants of the genes of cytokines and antioxidant enzymes, the protein products directly involved in the pathogenetic mechanisms of the formation of asbestosis, contribute to forming a genetic predisposition to the development and severe course of asbestosis. Using the identified genetic markers to identify risk groups for the development and intense period of asbestos-related pathology will optimize treatment and preventive measures, considering the organism's characteristics.

scholarly journals The Role of the Transsulfuration Pathway in Non-Alcoholic Fatty Liver Disease

2021 ◽  
Vol 10 (5) ◽  
pp. 1081
Author(s):  
Mikkel Parsberg Werge ◽  
Adrian McCann ◽  
Elisabeth Douglas Galsgaard ◽  
Dorte Holst ◽  
Anne Bugge ◽  
...  
Keyword(s):  
Liver Disease ◽  
Animal Models ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Alcoholic Fatty Liver ◽  
Precise Control ◽  
Transsulfuration Pathway ◽  
Global Population ◽  
Alcoholic Fatty Liver Disease

The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing and approximately 25% of the global population may have NAFLD. NAFLD is associated with obesity and metabolic syndrome, but its pathophysiology is complex and only partly understood. The transsulfuration pathway (TSP) is a metabolic pathway regulating homocysteine and cysteine metabolism and is vital in controlling sulfur balance in the organism. Precise control of this pathway is critical for maintenance of optimal cellular function. The TSP is closely linked to other pathways such as the folate and methionine cycles, hydrogen sulfide (H2S) and glutathione (GSH) production. Impaired activity of the TSP will cause an increase in homocysteine and a decrease in cysteine levels. Homocysteine will also be increased due to impairment of the folate and methionine cycles. The key enzymes of the TSP, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE), are highly expressed in the liver and deficient CBS and CSE expression causes hepatic steatosis, inflammation, and fibrosis in animal models. A causative link between the TSP and NAFLD has not been established. However, dysfunctions in the TSP and related pathways, in terms of enzyme expression and the plasma levels of the metabolites (e.g., homocysteine, cystathionine, and cysteine), have been reported in NAFLD and liver cirrhosis in both animal models and humans. Further investigation of the TSP in relation to NAFLD may reveal mechanisms involved in the development and progression of NAFLD.

scholarly journals Target Therapies for NASH/NAFLD: From the Molecular Aspect to the Pharmacological and Surgical Alternatives

2021 ◽  
Vol 11 (6) ◽  
pp. 499
Author(s):  
Michele Finotti ◽  
Maurizio Romano ◽  
Pasquale Auricchio ◽  
Michele Scopelliti ◽  
Marco Brizzolari ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Fatty Liver Disease ◽  
Hepatic Disease ◽  
Lifestyle Modifications ◽  
Alcoholic Fatty Liver ◽  
Target Therapies ◽  
Chronic Hepatic Disease ◽  
The Impact ◽  
Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease represents an increasing cause of chronic hepatic disease in recent years. This condition usually arises in patients with multiple comorbidities, the so-called metabolic syndrome. The therapeutic options are multiple, ranging from lifestyle modifications, pharmacological options, to liver transplantation in selected cases. The choice of the most beneficial one and their interactions can be challenging. It is mandatory to stratify the patients according to the severity of their disease to tailor the available treatments. In our contribution, we review the most recent pharmacological target therapies, the role of bariatric surgery, and the impact of liver transplantation on the NAFLD outcome.

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