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Hao X, Ma C, Xiang T, Ou L, Zeng Q. Associations Among Methylene Tetrahydrofolate Reductase rs1801133 C677T Gene Variant, Food Groups, and Non-alcoholic Fatty Liver Disease Risk in the Chinese Population. Front Genet 2021; 12:568398. [PMID: 33679874 PMCID: PMC7930608 DOI: 10.3389/fgene.2021.568398] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 01/22/2021] [Indexed: 12/20/2022] Open
Abstract
Objectives To investigate the associations among the methylene tetrahydrofolate reductase rs1801133 C677T gene variant, food groups, and the risk of non-alcoholic fatty liver disease in the Chinese population. Methods A study of gene polymorphism was conducted using the polymerase chain reaction method. A total of 4,049 adults participated in the study, and all underwent physical examination and genotyping. Participants filled out a dietary questionnaire to enable us to assess the frequency and quantity of food consumption. Results The important variables identified as risk factors of non-alcoholic fatty liver disease were age, smoking, sex, body mass index, hyperlipidemia, diabetes, and methylene tetrahydrofolate reductase genotype (T – allele carriers). The homocysteine content was higher in the non-alcoholic fatty liver disease group than in the control group, and was higher in the T- allele than C- allele carriers. The homocysteine content was the highest in the T- allele carriers. Additionally, certain food groups such as milk and beans were associated with a lower risk of non-alcoholic fatty liver disease. Food groups such as meat, were associated with a higher risk of non-alcoholic fatty liver disease. Fresh fruit and vegetables, salted and smoked foods, desserts, cereals, fish, and eggs were not associated with the risk of non-alcoholic fatty liver disease. However, the influence of salted and smoked foods on non-alcoholic fatty liver disease was different in the C-allele and T-allele carriers of methylene tetrahydrofolate reductase (CT + TT vs. CC, OR = 1.196, P = 0.041 for 1–4 times food per week, OR = 1.580, P = 0.004 for 5–7 times per week). Similarly, salted and smoked foods were also a risk factor for the development of non-alcoholic steatohepatitis in patients with non-alcoholic fatty liver disease. Conclusion This study found that the T-allele of the C677T variant of methylene tetrahydrofolate reductase was a risk factor for non-alcoholic fatty liver disease among Chinese people. These results can likely aid the development of novel approaches for managing non-alcoholic fatty liver disease risk.
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Affiliation(s)
- Xiaoyan Hao
- Health Management Institute, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
| | - Cong Ma
- Health Management Institute, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
| | - Tianyuan Xiang
- Health Management Institute, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
| | - Lei Ou
- Health Management Institute, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
| | - Qiang Zeng
- Health Management Institute, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
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2
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Radziejewska A, Muzsik A, Milagro FI, Martínez JA, Chmurzynska A. One-Carbon Metabolism and Nonalcoholic Fatty Liver Disease: The Crosstalk between Nutrients, Microbiota, and Genetics. Lifestyle Genom 2019; 13:53-63. [PMID: 31846961 DOI: 10.1159/000504602] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Accepted: 10/30/2019] [Indexed: 01/02/2023] Open
Abstract
The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. Its etiology includes nutritional, genetic, and lifestyle factors. Several mechanisms may link one-carbon metabolism - the associated metabolic pathways of folate, methionine, and choline - to the onset of NAFLD. In this review, we attempted to assess how choline, folate, methionine, and betaine affect NAFLD development, mainly through their role in the secretion of very low-density lipoproteins (VLDL) from the liver. We also reviewed recent articles that have described the relation between microbiota metabolism and NAFLD progression. Moreover, we describe the effect of single-nucleotide polymorphisms (SNP) in genes related to one-carbon metabolism and disease prevalence. We additionally seek SNP identified by genome-wide associations that may increase the risk of this disease. Even though the evidence available is not entirely consistent, it seems that the concentrations of choline, methionine, folate, and betaine may affect the progression of NAFLD. Since there is no effective therapy for NAFLD, further investigations into the link between nutrition, gut microbiota, genetic factors, and NAFLD are still necessary, with a particular emphasis on methyl donors.
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Affiliation(s)
- Anna Radziejewska
- Institute of Human Nutrition and Dietetics, Poznań University of Life Sciences, Poznań, Poland
| | - Agata Muzsik
- Institute of Human Nutrition and Dietetics, Poznań University of Life Sciences, Poznań, Poland
| | - Fermín I Milagro
- Department of Nutrition, Food Science and Physiology, Centre for Nutrition Research, University of Navarra, Pamplona, Spain.,Navarra's Health Research Institute (IdiSNA), Pamplona, Spain.,Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
| | - J Alfredo Martínez
- Department of Nutrition, Food Science and Physiology, Centre for Nutrition Research, University of Navarra, Pamplona, Spain.,Navarra's Health Research Institute (IdiSNA), Pamplona, Spain.,Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
| | - Agata Chmurzynska
- Institute of Human Nutrition and Dietetics, Poznań University of Life Sciences, Poznań, Poland,
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Wang X, Zhou Y, Zhang M, Wang Y, Qin B. The methylenetetrahydrofolate reductase genotype 677CT and non-alcoholic fatty liver disease have a synergistic effect on the increasing homocysteine levels in subjects from Chongqing, China. Genes Dis 2018; 6:88-95. [PMID: 30906837 PMCID: PMC6411628 DOI: 10.1016/j.gendis.2018.07.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2018] [Accepted: 07/17/2018] [Indexed: 01/13/2023] Open
Abstract
The methylenetetrahydrofolate reductase (MTHFR) genotypes 677CT and 677TT are associated with elevated serum homocysteine (Hcy) levels by means of lowering the activity of MTHFR, and the increase in serum Hcy may be linked to increased susceptibility to non-alcoholic fatty liver disease (NAFLD). However, there are contradictory reports of the relationship among the MTHFR 677CT gene polymorphism, Hcy, and NAFLD. Therefore, the aim of this study was to identify potential associations and interactions of either Hcy levels or the MTHFR 677CT gene polymorphism with the susceptibility to NAFLD in a Chinese population. The association between the MTHFR 677 CT gene polymorphism and Hcy levels was determined in 243 subjects with NAFLD and 388 healthy subjects without NAFLD using polymerase chain reaction-restriction fragment length polymorphism analysis and high-performance liquid chromatography. In subjects with NAFLD, there was no statistical difference in the genotypic and allelic frequencies of the MTHFR 677 CT gene polymorphism, while serum Hcy levels were significantly higher in subjects with NAFLD. Furthermore, these results strongly suggest that the MTHFR 677CT gene polymorphism and NAFLD have a potential synergistic effect on Hcy elevation, although the MTHFR 677CT gene polymorphism was not correlated with NAFLD in a Chinese population.
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Affiliation(s)
- Xiaolin Wang
- Health Management Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yongli Zhou
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Mingjun Zhang
- Health Management Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yonghong Wang
- Health Management Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Bo Qin
- Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Li L, Liu H, Hu X, Huang Y, Wang Y, He Y, Lei Q. Identification of key genes in non‑alcoholic fatty liver disease progression based on bioinformatics analysis. Mol Med Rep 2018; 17:7708-7720. [PMID: 29620197 PMCID: PMC5983972 DOI: 10.3892/mmr.2018.8852] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Accepted: 02/22/2018] [Indexed: 12/18/2022] Open
Abstract
Due to economic development and lifestyle changes, the incidence of non-alcoholic fatty liver disease (NAFLD) has gradually increased in recent years. However, the pathogenesis of NAFLD is not yet fully understood. To identify candidate genes that contribute to the development and progression of NAFLD, two microarray datasets were downloaded from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) were identified and functional enrichment analyses were performed. A protein-protein interaction network was constructed and modules were extracted using the Search Tool for the Retrieval of Interacting Genes and Cytoscape. The enriched functions and pathways of the DEGs included ‘cellular macromolecule biosynthetic process’, ‘cellular response to chemical stimulus’, ‘extracellular matrix organization’, ‘metabolic pathways’, ‘insulin resistance’ and ‘forkhead box protein O1 signaling pathway’. The DEGs, including type-1 angiotensin II receptor, formin-binding protein 1-like, RNA-binding protein with serine-rich domain 1, Ras-related C3 botulinum toxin substrate 1 and polyubiquitin-C, were identified using multiple bioinformatics methods and validated in vitro with reverse transcription-quantitative polymerase chain reaction analysis. In conclusion, five hub genes were identified in the present study, and they may aid in understanding of the molecular mechanisms underlying the development and progression of NAFLD.
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Affiliation(s)
- Lin Li
- Department of Liver Disease, Chongqing Traditional Chinese Medicine Hospital, Chongqing 400021, P.R. China
| | - Huabao Liu
- Department of Liver Disease, Chongqing Traditional Chinese Medicine Hospital, Chongqing 400021, P.R. China
| | - Xiaoyu Hu
- Department of Infectious Disease, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, P.R. China
| | - Yi Huang
- Department of Liver Disease, Chongqing Traditional Chinese Medicine Hospital, Chongqing 400021, P.R. China
| | - Yanan Wang
- Department of Liver Disease, Chongqing Traditional Chinese Medicine Hospital, Chongqing 400021, P.R. China
| | - Yansha He
- Department of Liver Disease, Chongqing Traditional Chinese Medicine Hospital, Chongqing 400021, P.R. China
| | - Qingsong Lei
- Department of Infectious Disease, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
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Ojeda-Granados C, Panduro A, Gonzalez-Aldaco K, Sepulveda-Villegas M, Rivera-Iñiguez I, Roman S. Tailoring Nutritional Advice for Mexicans Based on Prevalence Profiles of Diet-Related Adaptive Gene Polymorphisms. J Pers Med 2017; 7:16. [PMID: 29125573 PMCID: PMC5748628 DOI: 10.3390/jpm7040016] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Revised: 11/06/2017] [Accepted: 11/08/2017] [Indexed: 12/18/2022] Open
Abstract
Diet-related adaptive gene (DRAG) polymorphisms identified in specific populations are associated with chronic disorders in carriers of the adaptive alleles due to changes in dietary and lifestyle patterns in recent times. Mexico's population is comprised of Amerindians (AM) and Mestizos who have variable AM, European (EUR) and African genetic ancestry and an increased risk of nutrition-related chronic diseases. Nutritional advice based on the Mexican genome and the traditional food culture is needed to develop preventive and therapeutic strategies. Therefore, we aimed to provide a prevalence profile of several DRAG polymorphisms in the Mexican population, including Central West (CW) Mexico subpopulations. Geographic heat maps were built using ArcGIS10 (Esri, Redlands, CA, USA) software, based on the published data of the MTHFR C677T (rs1801133), ABCA1 Arg230Cys (rs9282541), APOE T388C (rs429358)/C526T (rs7412), LCT C-13910T (rs4988235) polymorphisms and AMY1 copy number variation (CNV). Also, new data obtained by allelic discrimination-real-time polymerase chain reaction (RT-PCR) assays for the MTHFR, ABCA1, and APOE polymorphisms as well as the AMY1 CNV in the CW Mexico subpopulations with different proportions of AM and EUR ancestry were included. In the CW region, the highest frequency of the MTHFR 677T, ABCA1 230C and APOE ε4 adaptive alleles was observed in the AM groups, followed by Mestizos with intermediate AM ancestry. The LCT-13910T allele frequency was highest in Mestizos-EUR but extremely low in AM, while the AMY1 diploid copy number was 6.82 ± 3.3 copies. Overall, the heat maps showed a heterogeneous distribution of the DRAG polymorphisms, in which the AM groups revealed the highest frequencies of the adaptive alleles followed by Mestizos. Given these genetic differences, genome-based nutritional advice should be tailored in a regionalized and individualized manner according to the available foods and Mexican traditional food culture that may lead to a healthier dietary pattern.
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Affiliation(s)
- Claudia Ojeda-Granados
- Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara "Fray Antonio Alcalde", Hospital #278, Col. El Retiro, Guadalajara 44280, Jalisco, Mexico.
- Health Sciences Center, University of Guadalajara, Guadalajara 44340, Jalisco, Mexico.
| | - Arturo Panduro
- Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara "Fray Antonio Alcalde", Hospital #278, Col. El Retiro, Guadalajara 44280, Jalisco, Mexico.
- Health Sciences Center, University of Guadalajara, Guadalajara 44340, Jalisco, Mexico.
| | - Karina Gonzalez-Aldaco
- Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara "Fray Antonio Alcalde", Hospital #278, Col. El Retiro, Guadalajara 44280, Jalisco, Mexico.
- Health Sciences Center, University of Guadalajara, Guadalajara 44340, Jalisco, Mexico.
| | - Maricruz Sepulveda-Villegas
- Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara "Fray Antonio Alcalde", Hospital #278, Col. El Retiro, Guadalajara 44280, Jalisco, Mexico.
- Health Sciences Center, University of Guadalajara, Guadalajara 44340, Jalisco, Mexico.
| | - Ingrid Rivera-Iñiguez
- Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara "Fray Antonio Alcalde", Hospital #278, Col. El Retiro, Guadalajara 44280, Jalisco, Mexico.
- Health Sciences Center, University of Guadalajara, Guadalajara 44340, Jalisco, Mexico.
| | - Sonia Roman
- Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara "Fray Antonio Alcalde", Hospital #278, Col. El Retiro, Guadalajara 44280, Jalisco, Mexico.
- Health Sciences Center, University of Guadalajara, Guadalajara 44340, Jalisco, Mexico.
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Umano GR, Martino M, Santoro N. The Association between Pediatric NAFLD and Common Genetic Variants. CHILDREN-BASEL 2017. [PMID: 28629152 PMCID: PMC5483624 DOI: 10.3390/children4060049] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the most common complications of obesity. Several studies have shown that genetic predisposition probably plays an important role in its pathogenesis. In fact, in the last few years a large number of genetic studies have provided compelling evidence that some gene variants, especially those in genes encoding proteins regulating lipid metabolism, are associated with intra-hepatic fat accumulation. Here we provide a comprehensive review of the gene variants that have affected the natural history of the disease.
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Affiliation(s)
- Giuseppina Rosaria Umano
- Department of Pediatrics, Yale University, 06520, New Haven, CT, USA.
- Dipartimento della Donna, del Bambino, di Vhirurgia Generale e Specialistica, Universita' della Campania Luigi Vanvitelli, 80138, Napoli, Italy.
| | - Mariangela Martino
- Department of Pediatrics, Yale University, 06520, New Haven, CT, USA.
- Dipartimento di Medicina V. Tiberio, Universita' del Molise, 86100, Campobasso, Italy.
| | - Nicola Santoro
- Department of Pediatrics, Yale University, 06520, New Haven, CT, USA.
- Dipartimento di Medicina V. Tiberio, Universita' del Molise, 86100, Campobasso, Italy.
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An X, Yang Z, An Z. MiR-149 Compromises the Reactions of Liver Cells to Fatty Acid via its Polymorphism and Increases Non-Alcoholic Fatty Liver Disease (NAFLD) Risk by Targeting Methylene Tetrahydrofolate Reductase (MTHFR). Med Sci Monit 2017; 23:2299-2307. [PMID: 28507283 PMCID: PMC5443364 DOI: 10.12659/msm.901377] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a worldwide health problem, and microRNA (miRNA) has been reported to be involved in NAFLD. The objective of our study was to explore the effect of polymorphism in miR-149 on the pathogenesis of NAFLD. MATERIAL AND METHODS Real-time PCR was performed to explore the effect of long-chain fatty acid (FFA) on the level of miR-149 and methylene tetrahydrofolate reductase (MTHFR). Then in-silicon analysis and luciferase assay were investigated to verify MTHFR was the target gene of miR-149. Finally, Western-blot analysis and real-time PCR were performed to confirm the control of MTHFR by miR-149. RESULTS In this study, we found that miR-149 was apparently upregulated in hepatocytes genotyped as TT treated with FFA; and MTHFR in hepatocytes genotyped as TT treated with FFA was evidently downregulated compared to control. Whereas, FFA had no obvious effect on MTHFR level in hepatocytes genotyped as CC. We searched an online miRNA database and found that miR-149 was a regulator of MTHFR expression, which was confirmed by luciferase assay. In hepatocytes genotyped as TT and treated with or without FFA, miR-149 mimic dose-dependently decreased the level of MTHFR, and miR-149 inhibitor dose-dependently increased the level of MTHFR. And in hepatocytes genotyped as CC treated with or without FFA exhibited a similar inhibition effect of miR-149 on expression of MTHFR. CONCLUSIONS The data suggested that the polymorphism in miR-149 played an important role in the development of NAFLD via altering the expression of miR-149 as well as its target, MTHFR.
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Affiliation(s)
- Xianchao An
- Department of Ultrasound, The Second Affiliated Hospital of Shanxi University of Chinese Medicine, Xianyang, Shaanxi, China (mainland)
| | - Zonglin Yang
- Department of Ultrasound, The Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, China (mainland)
| | - Zhengzhuang An
- Department of Ultrasound, The Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, China (mainland)
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Associations between Methylenetetrahydrofolate Reductase (MTHFR) Polymorphisms and Non-Alcoholic Fatty Liver Disease (NAFLD) Risk: A Meta-Analysis. PLoS One 2016; 11:e0154337. [PMID: 27128842 PMCID: PMC4851382 DOI: 10.1371/journal.pone.0154337] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Accepted: 04/11/2016] [Indexed: 02/07/2023] Open
Abstract
Background C677T and A1298C are the most common allelic variants of Methylenetetrahydrofolate Reductase (MTHFR) gene. The association between MTHFR polymorphisms and the occurrence of non-alcoholic fatty liver disease (NAFLD) remains controversial. This study was thus performed to examine whether MTHFR mutations are associated with the susceptibility to NAFLD. Methods A first meta-analysis on the association between the MTHFR polymorphisms and NAFLD risks was carried out via Review Manager 5.0 and Stata/SE 12.0 software. The on-line databases, such as PubMed, EMBASE, CENTRAL, WOS, Scopus and EBSCOhost (updated to April 1st, 2016), were searched for eligible case-control studies. The odd radio (OR), 95% confidence interval (CI) and P value were calculated through Mantel-Haenszel statistics under random- or fixed-effect model. Results Eight articles (785 cases and 1188 controls) contributed data to the current meta-analysis. For C677T, increased NAFLD risks were observed in case group under homozygote model (T/T vs C/C, OR = 1.49, 95% CI = 1.03~2.15, P = 0.04) and recessive model (T/T vs C/C+C/T, OR = 1.42, 95% CI = 1.07~1.88, P = 0.02), but not the other genetics models, compared with control group. For A1298C, significantly increased NAFLD risks were detected in allele model (C vs A, OR = 1.53, 95% CI = 1.13~2.07, P = 0.006), homozygote model (C/C vs A/A, OR = 2.81, 95% CI = 1.63~4.85, P = 0.0002), dominant model (A/C+C/C vs A/A, OR = 1.60, 95% CI = 1.06~2.41, P = 0.03) and recessive model (C/C vs A/A+A/C, OR = 2.08, 95% CI = 1.45~3.00, P<0.0001), but not heterozygote model. Conclusion T/T genotype of MTHFR C677T polymorphism and C/C genotype of MTHFR A1298C are more likely to be associated with the susceptibility to NAFLD.
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Ramos-Lopez O, Martinez-Lopez E, Roman S, Fierro NA, Panduro A. Genetic, metabolic and environmental factors involved in the development of liver cirrhosis in Mexico. World J Gastroenterol 2015; 21:11552-11566. [PMID: 26556986 PMCID: PMC4631960 DOI: 10.3748/wjg.v21.i41.11552] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 07/29/2015] [Accepted: 09/14/2015] [Indexed: 02/06/2023] Open
Abstract
Liver cirrhosis (LC) is a chronic illness caused by inflammatory responses and progressive fibrosis. Globally, the most common causes of chronic liver disease include persistent alcohol abuse, followed by viral hepatitis infections and nonalcoholic fatty liver disease. However, regardless of the etiological factors, the susceptibility and degree of liver damage may be influenced by genetic polymorphisms that are associated with distinct ethnic and cultural backgrounds. Consequently, metabolic genes are influenced by variable environmental lifestyle factors, such as diet, physical inactivity, and emotional stress, which are associated with regional differences among populations. This Topic Highlight will focus on the genetic and environmental factors that may influence the metabolism of alcohol and nutrients in the setting of distinct etiologies of liver disease. The interaction between genes and environment in the current-day admixed population, Mestizo and Native Mexican, will be described. Additionally, genes involved in immune regulation, insulin sensitivity, oxidative stress and extracellular matrix deposition may modulate the degree of severity. In conclusion, LC is a complex disease. The onset, progression, and clinical outcome of LC among the Mexican population are influenced by specific genetic and environmental factors. Among these are an admixed genome with a heterogenic distribution of European, Amerindian and African ancestry; a high score of alcohol consumption; viral infections; a hepatopathogenic diet; and a high prevalence of obesity. The variance in risk factors among populations suggests that intervention strategies directed towards the prevention and management of LC should be tailored according to such population-based features.
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Macaluso FS, Maida M, Petta S. Genetic background in nonalcoholic fatty liver disease: A comprehensive review. World J Gastroenterol 2015; 21:11088-11111. [PMID: 26494964 PMCID: PMC4607907 DOI: 10.3748/wjg.v21.i39.11088] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Revised: 06/11/2015] [Accepted: 09/02/2015] [Indexed: 02/06/2023] Open
Abstract
In the Western world, nonalcoholic fatty liver disease (NAFLD) is considered as one of the most significant liver diseases of the twenty-first century. Its development is certainly driven by environmental factors, but it is also regulated by genetic background. The role of heritability has been widely demonstrated by several epidemiological, familial, and twin studies and case series, and likely reflects the wide inter-individual and inter-ethnic genetic variability in systemic metabolism and wound healing response processes. Consistent with this idea, genome-wide association studies have clearly identified Patatin-like phosholipase domain-containing 3 gene variant I148M as a major player in the development and progression of NAFLD. More recently, the transmembrane 6 superfamily member 2 E167K variant emerged as a relevant contributor in both NAFLD pathogenesis and cardiovascular outcomes. Furthermore, numerous case-control studies have been performed to elucidate the potential role of candidate genes in the pathogenesis and progression of fatty liver, although findings are sometimes contradictory. Accordingly, we performed a comprehensive literature search and review on the role of genetics in NAFLD. We emphasize the strengths and weaknesses of the available literature and outline the putative role of each genetic variant in influencing susceptibility and/or progression of the disease.
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Kasapoglu B, Turkay C, Yalcin KS, Kosar A, Bozkurt A. MTHFR 677C/T and 1298A/C mutations and non-alcoholic fatty liver disease. Clin Med (Lond) 2015; 15:248-51. [PMID: 26031974 PMCID: PMC4953108 DOI: 10.7861/clinmedicine.15-3-248] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Common genetic mutations encountered in folate metabolism may result in increased homocysteine (Hcy) levels. It has been reported that increased serum Hcy levels may affect the intracellular fat metabolism and may cause enhanced fatty infiltration in the liver resulting in non-alcoholic fatty liver disease (NAFLD). In total, 150 patients diagnosed with FLD by ultrasound examination and 136 healthy control patients that do not have any fatty infiltration in the liver were included in the study. Patients were grouped as mild (n = 88), moderate (n = 38) or severe (n = 24) according to the stage of fatty liver in ultrasound. Serum liver function tests, Hcy, folic acid and vitamin B12 levels of the patients were studied. The genetic MTHFR C677T and A1298C polymorphisms of the patients were also evaluated. Although there was no significant difference in vitamin B12 and folic acid levels, in the severe group, Hcy levels were significantly higher than that of control and mild groups (p<0.001). By contrast, there was no significant difference in heterozygote MTHFR 677C/T and 1298A/C mutations, both MTHFR 677C/T and MTHFR 1298A/C mutations were more common in NAFLD groups compared with the control patients (p<0.001). We have determined increased Hcy levels and increased prevalence of homozygote MTHFR 677C/T and MTHFR 1298A/C mutations in patients with NAFLD compared with healthy controls. Larger studies are warranted to clarify the etiological role of the MTHFR mutations and Hcy levels in FLD.
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Affiliation(s)
- Benan Kasapoglu
- Turgut Ozal University Medical School, Division of Gastroenterology, Ankara, Turkey
| | - Cansel Turkay
- Turgut Ozal University Medical School, Division of Gastroenterology, Ankara, Turkey
| | - Kadir Serkan Yalcin
- Turgut Ozal University Medical School, Department of Internal Medicine, Ankara, Turkey
| | - Ali Kosar
- Turgut Ozal University Medical School, Division of Hematology, Ankara, Turkey
| | - Alper Bozkurt
- Turgut Ozal University Medical School, Division of Radiology, Ankara, Turkey
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12
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Wood KL, Miller MH, Dillon JF. Systematic review of genetic association studies involving histologically confirmed non-alcoholic fatty liver disease. BMJ Open Gastroenterol 2015; 2:e000019. [PMID: 26462272 PMCID: PMC4599155 DOI: 10.1136/bmjgast-2014-000019] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Revised: 01/21/2015] [Accepted: 01/23/2015] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease has an increasing prevalence in Western countries, affecting up to 20% of the population.
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Affiliation(s)
| | - Michael H Miller
- Medical Research Institute, University of Dundee, Ninewells Hospital , Dundee , UK
| | - John F Dillon
- Medical Research Institute, University of Dundee, Ninewells Hospital , Dundee , UK
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Islek EE, Sazci A, Ozel MD, Aygun C. Genetic variants in the PNPLA3 gene are associated with nonalcoholic steatohepatitis. Genet Test Mol Biomarkers 2014; 18:489-96. [PMID: 24831885 DOI: 10.1089/gtmb.2014.0019] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
In this study, we report the association of the rs738407, rs738409, and rs2896019 variants of the patatin-like phospholipase domain-containing protein 3 (PNPLA3) (adiponutrin) gene with nonalcoholic steatohepatitis (NASH) (χ(2)=14.528, p=0.001; χ(2)=18.882, p=0.000; χ(2)=7.449, p=0.024, respectively) in 80 patients with NASH and 303 healthy controls. We genotyped the subjects using three polymerase chain reaction-restriction fragment length polymorphism methods developed in our laboratory. Our findings confirm the findings of the recent case-control and genome-wide association studies carried out in different populations around the world. Thus, the three variants in PNPLA3 gene may be a genetic risk factor for NASH.
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Affiliation(s)
- Eylul Ece Islek
- 1 Department of Medical Biology and Genetics, University of Kocaeli , Kocaeli, Turkey
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Radwan MM, Radwan BM, Nandipati KC, Hunter WJ, Agrawal DK. Immunological and molecular basis of nonalcoholic steatohepatitis and nonalcoholic fatty liver disease. Expert Rev Clin Immunol 2014; 9:727-38. [PMID: 23971751 DOI: 10.1586/1744666x.2013.816484] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The prevalence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is rising worldwide with the increasing incidence of obesity, Type 2 diabetes mellitus and metabolic syndrome. NASH is currently one of the most common indications of liver transplantation in the United States. The immune system plays a major role in the pathogenesis of NAFLD/NASH. The metabolic changes, associated with obesity and metabolic syndrome, induce immunological responses resulting in NAFLD and further aggravation of the metabolic derangement in a feed-forward loop. Genetic and endocrine factors modulate the immunological and metabolic responses and determine the pathophysiological features of NAFLD. Histologically, NAFLD is a spectrum that ranges from simple hepatic steatosis to severe steatohepatitis, liver cirrhosis and/or hepatocellular carcinoma. Liver cirrhosis and hepatocellular carcinoma are responsible for the morbidity and mortality of the disease. This article is a critical evaluation of our current knowledge of the immunological and molecular basis of the disease.
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Affiliation(s)
- Mohamed M Radwan
- Center for Clinical & Translational Science, Creighton University School of Medicine, Omaha, NE 68178, USA
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Mehta R, Birerdinc A, Younossi ZM. Host genetic variants in obesity-related nonalcoholic fatty liver disease. Clin Liver Dis 2014; 18:249-67. [PMID: 24274878 DOI: 10.1016/j.cld.2013.09.017] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a complex disease. The considerable variability in the natural history of the disease suggests an important role for genetic variants in the disease development and progression. There is evidence based on genome-wide association studies and/or candidate gene studies that genetic polymorphisms underlying insulin signaling, lipid metabolism, oxidative stress, fibrogenesis, and inflammation can predispose individuals to NAFLD. This review highlights some of the genetic variants in NAFLD.
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Affiliation(s)
- Rohini Mehta
- Betty and Guy Beatty Center for Integrated Research, Center for Liver Disease, Inova Health System, Claude Moore Building, 3300 Gallows Road, Falls Church, VA 22042, USA
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Franco Brochado MJ, Domenici FA, Candolo Martinelli ADL, Zucoloto S, de Carvalho da Cunha SF, Vannucchi H. Methylenetetrahydrofolate reductase gene polymorphism and serum homocysteine levels in nonalcoholic fatty liver disease. ANNALS OF NUTRITION AND METABOLISM 2013; 63:193-9. [PMID: 24051448 DOI: 10.1159/000353139] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/08/2013] [Accepted: 05/15/2013] [Indexed: 01/12/2023]
Abstract
BACKGROUND/AIMS Nonalcoholic fatty liver disease (NAFLD) is a metabolic disorder characterized by hepatic fat accumulation in the absence of alcohol consumption. Hyperhomocysteinemia is considered an independent risk factor for liver diseases, and the genetic polymorphisms C677T and A1298C in the MTHFR gene have been linked to hyperhomocysteinemia. The purpose of this study was to investigate serum homocysteine (Hcy) concentrations and the MTHFR C677T and A1298C polymorphisms as risk factors for the development of NAFLD. METHODS One hundred and thirty-four Brazilian patients with biopsy-proven NAFLD and 134 healthy controls were recruited. The MTHFR C677T and A1298C polymorphisms were detected through polymerase chain reaction restriction fragment length polymorphism. Serum Hcy levels were determined by chemiluminescence. RESULTS Serum Hcy levels were higher in NAFLD patients as compared to control subjects, but there were no differences between patients with steatosis and nonalcoholic steatohepatitis. The NAFLD and control groups did not differ in genotypic and allelic frequencies of the MTHFR C677T and A1298C polymorphisms, either. Elevated plasma Hcy levels were positively correlated with age in the NAFLD subjects. CONCLUSION The MTHFR C677T and A1298C polymorphisms are not genetic risk factors for the development of NAFLD. Higher Hcy levels exist in NAFLD subjects, but they are not associated with liver disease severity.
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Sazci A, Ozel MD, Ergul E, Aygun C. Association of nicotinamide-N-methyltransferase gene rs694539 variant with patients with nonalcoholic steatohepatitis. Genet Test Mol Biomarkers 2013; 17:849-53. [PMID: 23964925 DOI: 10.1089/gtmb.2013.0309] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of abnormal hepatic steatosis in the absence of a history of alcohol use and with a prevalence of 15%-45% in developed nations. Nonalcoholic steatohepatitis (NASH) is an advanced stage of NAFLD with a pronounced major inflammatory component. The aim of this study was to investigate the possible role of nicotinamide-N-methyltransferase (NNMT) gene rs694539 variant in the development of NASH. Therefore, we analyzed 80 NASH patients and 183 healthy controls using a polymerase chain reaction-restriction fragment length polymorphism method developed in our laboratory. The NNMT rs694539 variant was found to be significantly associated with NASH (χ(2)=9.349, p=0.009). The individuals with the GG genotype had protection against NASH (χ(2)=3.793, p=0.051, odds ratio [OR]=0.580, 95% confidence interval [CI]=0.334-1.006), whereas the individuals with the AA genotype showed statistically significant increased risk for NASH (χ(2)=7.748, p=0.005, OR=7.338, 95% CI=1.448-37.190). Moreover, the G allele was protective against NASH (χ(2)=7.748, p=0.005, OR=0.136, and 95% CI=0.027-0.691). On the other hand, the A allele was a risk factor for NASH (χ(2)=3.793, p=0.051, OR=1.725, and 95% CI=0.994-2.996). Consequently, the rs694539 variant of NNMT gene is a genetic risk factor for developing NASH.
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Affiliation(s)
- Ali Sazci
- 1 Department of Medical Biology and Genetics, Faculty of Medicine, University of Kocaeli , Kocaeli, Turkey
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Anstee QM, Targher G, Day CP. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol 2013; 10:330-44. [PMID: 23507799 DOI: 10.1038/nrgastro.2013.41] [Citation(s) in RCA: 1305] [Impact Index Per Article: 108.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
NAFLD is a spectrum of progressive liver disease that encompasses simple steatosis, NASH, fibrosis and, ultimately, cirrhosis. NAFLD is recognized as the hepatic component of the metabolic syndrome, as these conditions have insulin resistance as a common pathophysiological mechanism. Therefore, NAFLD is strongly associated with type 2 diabetes mellitus and abdominal obesity. As lifestyles have become increasingly sedentary and dietary patterns have changed, the worldwide prevalence of NAFLD has increased dramatically and is projected to be the principal aetiology for liver transplantation within the next decade. Importantly, a growing body of clinical and epidemiological evidence suggests that NAFLD is associated not only with liver-related morbidity and mortality, but also with an increased risk of developing both cardiovascular disease and type 2 diabetes mellitus. This article reviews the evidence that suggests NAFLD is a multisystem disease and the factors that might determine interindividual variation in the development and progression of its major hepatic and extrahepatic manifestations (principally type 2 diabetes mellitus and cardiovascular disease).
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Affiliation(s)
- Quentin M Anstee
- Liver Research Group, Institute of Cellular Medicine, The Medical School, Newcastle University, Framlington Place, Newcastle-upon-Tyne NE2 4HH, UK
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de Carvalho SCR, Muniz MTC, Siqueira MDV, Siqueira ERF, Gomes AV, Silva KA, Bezerra LCL, D’Almeida V, de Oliveira CPMS, Pereira LMMB. Plasmatic higher levels of homocysteine in non-alcoholic fatty liver disease (NAFLD). Nutr J 2013; 12:37. [PMID: 23547829 PMCID: PMC3626579 DOI: 10.1186/1475-2891-12-37] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2012] [Accepted: 03/08/2013] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease, which includes a spectrum of hepatic pathology such as simple steatosis, steatohepatitis, fibrosis and cirrhosis. The increased serum levels of homocysteine (Hcy) may be associated with hepatic fat accumulation. Genetic mutations in the folate route may only mildly impair Hcy metabolism. The aim of this study was to investigate the relation between liver steatosis with plasma homocysteine level and MTHFR C677T and A1298C polymorphisms in Brazilian patients with NAFLD. METHODS Thirty-five patients diagnosed with NAFLD by liver biopsy and forty-five healthy controls neither age nor sex matched were genotyped for C677T and A1298C MTHFR polymorphisms using PCR-RFLP and PCR-ASA, respectively, and Hcy was determined by HPLC. All patients were negative for markers of Wilson's, hemochromatosis and autoimmune diseases. Their daily alcohol intake was less than 100 g/week. A set of metabolic and serum lipid markers were also measured at the time of liver biopsies. RESULTS The plasma Hcy level was higher in NAFLD patients compared to the control group (p = 0.0341). No statistical difference for genotypes 677C/T (p = 0.110) and 1298A/C (p = 0.343) in patients with NAFLD and control subjects was observed. The genotypes distribution was in Hardy-Weinberg equilibrium (677C/T p = 0.694 and 1298 A/C p = 0.188). The group of patients and controls showed a statistically significant difference (p < 0.001) for BMI and HOMA_IR, similarly to HDL cholesterol levels (p < 0,006), AST, ALT, γGT, AP and triglycerides levels (p < 0.001). A negative correlation was observed between levels of vitamin B12 and Hcy concentration (p = 0.005). CONCLUSION Our results indicate that plasma Hcy was higher in NAFLD than controls. The MTHFR C677T and A1298C polymorphisms did not differ significantly between groups, despite the 677TT homozygous frequency was higher in patients (17.14%) than in controls (677TT = 4.44%) (p > 0.05). The suggested genetic susceptibility to the MTHFR C677T and A1298C should be confirmed in large population based studies.
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Affiliation(s)
| | - Maria Tereza Cartaxo Muniz
- School of Medicine, Universityof Pernambuco, Pernambuco, Brazil
- Pediatrics Hematology and Oncology Center, University of Pernambuco, Pernambuco, Brazil
- Biological Science Institute, University of Pernambuco, Pernambuco, Brazil
- Instituto do Fígado de Pernambuco, Arnóbio Marques Street, 310, Santo Amaro- Recife, PE, Zip Code: 50.100-130, Brazil
| | - Maria Deozete Vieira Siqueira
- School of Medicine, Universityof Pernambuco, Pernambuco, Brazil
- Pediatrics Hematology and Oncology Center, University of Pernambuco, Pernambuco, Brazil
- Biological Science Institute, University of Pernambuco, Pernambuco, Brazil
| | - Erika Rabelo Forte Siqueira
- Liver Institute of Pernambuco, Pernambuco, Brazil
- School of Medicine, University of São Paulo, São Paulo, Brazil
| | - Adriana Vieira Gomes
- School of Medicine, Universityof Pernambuco, Pernambuco, Brazil
- Pediatrics Hematology and Oncology Center, University of Pernambuco, Pernambuco, Brazil
- Biological Science Institute, University of Pernambuco, Pernambuco, Brazil
| | - Karina Alves Silva
- Pediatrics Hematology and Oncology Center, University of Pernambuco, Pernambuco, Brazil
| | | | - Vânia D’Almeida
- Department of Pediatrics, Federal University of São Paulo, São Paulo, Brazil
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Hernaez R. Genetic factors associated with the presence and progression of nonalcoholic fatty liver disease: a narrative review. GASTROENTEROLOGIA Y HEPATOLOGIA 2011; 35:32-41. [PMID: 22093607 DOI: 10.1016/j.gastrohep.2011.08.002] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/28/2011] [Accepted: 08/04/2011] [Indexed: 12/25/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world. Whereas insulin resistance and obesity are considered major risk factors for the development and progression of NAFLD, the genetic underpinnings are unclear. Before 2008, candidate gene studies based on prior knowledge of pathophysiology of fatty liver yielded conflicting results. In 2008, Romeo et al. published the first genome wide association study and reported the strongest genetic signal for the presence of fatty liver (PNPLA3, patatin-like phospholipase domain containing 3; rs738409). Since then, two additional genome wide scans were published and identified 9 additional genetic variants. Whereas these results shed light into the understanding of the genetics of NAFLD, most of associations have not been replicated in independent samples and, therefore, remain undetermined the significance of these findings. This review aims to summarize the understanding of genetic epidemiology of NAFLD and highlights the gaps in knowledge.
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Affiliation(s)
- Ruben Hernaez
- Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
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Maurantonio M, Ballestri S, Odoardi MR, Lonardo A, Loria P. Treatment of atherogenic liver based on the pathogenesis of nonalcoholic fatty liver disease: a novel approach to reduce cardiovascular risk? Arch Med Res 2011; 42:337-353. [PMID: 21843565 DOI: 10.1016/j.arcmed.2011.08.004] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2011] [Accepted: 07/18/2011] [Indexed: 12/13/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD), which spans a spectrum of conditions ranging from simple steatosis to progressive nonalcoholic steatohepatitis (NASH), is the most common chronic liver disease and a relevant public health issue. The prevalence of NAFLD depends on adiposity, age, gender and ethnicity. The natural history of liver disease in those with NAFLD critically depends on liver histological changes. However, cardiovascular mortality is increased in NAFLD, particularly in middle-aged adults. Against such a background, this review consists of three sections. First, data on NAFLD as a novel mechanism of increased cardiovascular risk via hyperinsulinism, pro-thrombotic potential, and subclinical inflammation are summarized. Next, the role of atherogenic liver in the development of manifestations of oxidative stress and atherosclerosis is emphasized. Finally, whether and how treating NAFLD will mechanistically result in reduced cardiovascular risk through ameliorated metabolic syndrome is discussed.
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Affiliation(s)
- Mauro Maurantonio
- Department of Internal Medicine, Endocrinology, Metabolism and Geriatrics, Nuovo Ospedale Civile Sant'Agostino-Estense di Modena, University of Modena and Reggio Emilia, Modena, Italy.
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Duvnjak M, Baršić N, Tomašić V, Lerotić I. Genetic polymorphisms in non-alcoholic fatty liver disease: Clues to pathogenesis and disease progression. World J Gastroenterol 2009; 15:6023-7. [PMID: 20027673 PMCID: PMC2797657 DOI: 10.3748/wjg.15.6023] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The spectrum of non-alcoholic fatty liver disease (NAFLD) ranges from simple steatosis through steatohepatitis to advanced fibrosis and cirrhosis. Although the reason why only a minority of patients develop progressive forms of disease still remains largely unclear, recent research has identified genetic factors as a possible basis for this variation in disease presentation. Most of the studies have been focused on finding associations between advanced disease forms and selected single nucleotide polymorphisms in genes encoding various proteins involved in disease pathogenesis. Although there are many limitations regarding the study design and interpretation of published data, further carefully planned studies together with implementation of new genetic technologies will likely bring new insights into disease pathogenesis and potential benefits to the management of patients with NAFLD.
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DiBello PM, Dayal S, Kaveti S, Zhang D, Kinter M, Lentz SR, Jacobsen DW. The nutrigenetics of hyperhomocysteinemia: quantitative proteomics reveals differences in the methionine cycle enzymes of gene-induced versus diet-induced hyperhomocysteinemia. Mol Cell Proteomics 2009; 9:471-85. [PMID: 20008833 DOI: 10.1074/mcp.m900406-mcp200] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Hyperhomocysteinemia has long been associated with atherosclerosis and thrombosis and is an independent risk factor for cardiovascular disease. Its causes include both genetic and environmental factors. Although homocysteine is produced in every cell as an intermediate of the methionine cycle, the liver contributes the major portion found in circulation, and fatty liver is a common finding in homocystinuric patients. To understand the spectrum of proteins and associated pathways affected by hyperhomocysteinemia, we analyzed the mouse liver proteome of gene-induced (cystathionine beta-synthase (CBS)) and diet-induced (high methionine) hyperhomocysteinemic mice using two-dimensional difference gel electrophoresis and Ingenuity Pathway Analysis. Nine proteins were identified whose expression was significantly changed by 2-fold (p < or = 0.05) as a result of genotype, 27 proteins were changed as a result of diet, and 14 proteins were changed in response to genotype and diet. Importantly, three enzymes of the methionine cycle were up-regulated. S-Adenosylhomocysteine hydrolase increased in response to genotype and/or diet, whereas glycine N-methyltransferase and betaine-homocysteine methyltransferase only increased in response to diet. The antioxidant proteins peroxiredoxins 1 and 2 increased in wild-type mice fed the high methionine diet but not in the CBS mutants, suggesting a dysregulation in the antioxidant capacity of those animals. Furthermore, thioredoxin 1 decreased in both wild-type and CBS mutants on the diet but not in the mutants fed a control diet. Several urea cycle proteins increased in both diet groups; however, arginase 1 decreased in the CBS(+/-) mice fed the control diet. Pathway analysis identified the retinoid X receptor signaling pathway as the top ranked network associated with the CBS(+/-) genotype, whereas xenobiotic metabolism and the NRF2-mediated oxidative stress response were associated with the high methionine diet. Our results show that hyperhomocysteinemia, whether caused by a genetic mutation or diet, alters the abundance of several liver proteins involved in homocysteine/methionine metabolism, the urea cycle, and antioxidant defense.
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Affiliation(s)
- Patricia M DiBello
- Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
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Abstract
PURPOSE OF REVIEW This review focuses on recent advances in the study of the epidemiology, pathogenesis, natural history and treatment of nonalcoholic fatty liver disease (NAFLD). RECENT FINDINGS Study of hepatic lipid metabolism with respect to the contribution of de-novo lipogenesis to hepatic steatosis and insulin resistance and the dysregulation of cellular adaptive response to stress, that is, the unfolded protein response has added to our current understanding of NAFLD. microRNA has recently emerged and has been shown to be differentially expressed in patients with nonalcoholic steatohepatitis. Its mechanism of action remains to be further explored. There is no proven pharmacotherapy for the treatment of NAFLD. Lifestyle intervention to achieve weight loss and increase exercise is persistently associated with improved liver histology. The diagnostic utility of noninvasive markers and imaging modalities in assessing fibrosis remains to be elucidated. SUMMARY The underlying mechanism and pathogenesis of NAFLD remain elusive. Although research effort has advanced the understanding of the natural history, pathogenesis and management of the disease, there is no proven therapy for this medical condition. At present, treatment concentrates on managing underlying metabolic risk factors.
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Genetic factors contribute to variation in serum alanine aminotransferase activity independent of obesity and alcohol: a study in monozygotic and dizygotic twins. J Hepatol 2009; 50:1035-42. [PMID: 19303161 DOI: 10.1016/j.jhep.2008.12.025] [Citation(s) in RCA: 98] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2008] [Revised: 11/13/2008] [Accepted: 12/02/2008] [Indexed: 02/06/2023]
Abstract
BACKGROUND/AIMS This study aimed to determine the heritability of serum alanine aminotransferase (S-ALT) and fasting serum insulin (fS-insulin) concentration as well as determine the association of these measures with liver fat content in young adult monozygotic (MZ) and dizygotic (DZ) twins. METHODS Three hundred and thirteen individual twins were recruited from a population-based cohort (n = 4929). The study subjects represented a wide range of body mass indexes (BMI), were free of any diseases or regular medications and had an intake of less than two drinks of alcohol/day. To verify that S-ALT is a marker of liver fat, it was measured by proton magnetic resonance spectroscopy ((1)H MRS) in 66 subjects. Heritability estimations were performed using BMI- and gender-adjusted values. RESULTS Intra-pair correlations were significantly higher in the MZ twins than the DZ twins for both S-ALT (0.65 for MZ and 0.04 for DZ) and fS-insulin (0.58 and 0.34, respectively). Heritability of S-ALT was 55% and that of fS-insulin 61%. In the 66 subjects S-ALT (r = 0.70 for women and r = 0.50 for men, p < or = 0.01 for both) and fS-insulin (r = 0.58 and r = 0.59, respectively, p < or = 0.01 for both) concentrations correlated significantly with liver fat content. CONCLUSIONS These twin data suggest that approximately 60% of the variation in S-ALT, a marker of liver fat content, is genetically determined.
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Routine liver biopsy to screen for nonalcoholic fatty liver disease (NAFLD) during cholecystectomy for gallstone disease: is it justified? J Gastrointest Surg 2008; 12:2097-102; discussion 2102. [PMID: 18825466 DOI: 10.1007/s11605-008-0704-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2008] [Accepted: 09/08/2008] [Indexed: 01/31/2023]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) and gallstone disease (GD) share common risk factors. There are no firm recommendations regarding screening of NAFLD in patients at risk. Our aim was to assess the prevalence of and factors associated with NAFLD in a cohort of patients operated for symptomatic GD and evaluate the usefulness of routine liver biopsy. METHODS Ninety-five consecutive patients underwent a liver biopsy at the end of a standard laparoscopic cholecystectomy for symptomatic GD. Clinical, biochemical, demographic, and anthropometric variables were obtained prospectively. RESULTS Fifty-two patients (55%) had biopsies compatible with NAFLD. These patients were classified according to the system proposed by Brunt et al. as follows: grade I, n = 27 (52%); grade II, n = 15 (29%); grade III, n = 10 (19%). Two grade III patients had zone III focal perisinusoidal fibrosis and three had overt cirrhosis. Only 13% of subjects had a suspected diagnosis of NAFLD preoperatively. In multivariate logistic regression, only obesity was significantly associated with NAFLD. There were no complications or mortality. DISCUSSION Fifty-five percent of patients with GD have associated NAFLD. Awareness of this association may result in an earlier diagnosis. The high prevalence of NAFLD in patients with GD may justify routine liver biopsy during cholecystectomy to establish the diagnosis, stage, and possible direct therapy.
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Loria P, Lonardo A, Targher G. Is liver fat detrimental to vessels?: intersections in the pathogenesis of NAFLD and atherosclerosis. Clin Sci (Lond) 2008; 115:1-12. [PMID: 19016656 DOI: 10.1042/cs20070311] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
NAFLD (non-alcoholic fatty liver disease) encompasses the spectrum of fatty liver disease in insulin-resistant individuals who often display T2DM (Type 2 diabetes mellitus) and obesity. The present review highlights the pathophysiological basis and clinical evidence for a possible causal linkage between NAFLD and CVD (cardiovascular disease). The role of traditional and non-traditional CVD risk factors in the pathophysiology of NAFLD is considered in the first part of the review, with the basic science shared by atherogenesis and hepatic steatogenesis discussed in depth in the second part. In conclusion, NAFLD is not an innocent bystander, but a major player in the development and progression of CVD. NAFLD and CVD also share similar molecular mechanisms and targeted treatment strategies. On the research side, studies should focus on interventions aimed at restoring energy homoeostasis in lipotoxic tissues and at improving hepatic (micro)vascular blood supply.
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Affiliation(s)
- Paola Loria
- Department of Internal Medicine, Metabolism, Endocrinology and Geriatrics, University of Modena and Reggio Emilia, Modena, Italy.
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