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Wu R, Gragnoli C. The melanocortin receptor genes are linked to and associated with the risk of polycystic ovary syndrome in Italian families. J Ovarian Res 2024; 17:242. [PMID: 39633478 PMCID: PMC11619144 DOI: 10.1186/s13048-024-01567-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Accepted: 11/26/2024] [Indexed: 12/07/2024] Open
Abstract
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder occurring in women of reproductive age. The disease is caused by a complex interplay of genetic and environmental factors including genes encoding components of the hypothalamic-pituitary-adrenal (HPA) axis. We have recently reported the association of melanocortin receptor genes (MC1R, MC2R, MC3R, MC4R, and MC5R) with the risk of type 2 diabetes (T2D) and/or major depressive disorder (MDD). The latter 2 disorders are comorbid with PCOS. In this study, we used microarray to test 12 single nucleotide polymorphisms (SNPs) in the MC1R gene, 10 SNPs in the MC2R gene, 5 SNPs in the MC3R gene, 6 SNPs in the MC4R gene, and 4 SNPs in the MC5R gene in 212 original Italian families with PCOS. We identified 1 SNP in MC1R, 1 SNP in MC2R, 2 SNPs in MC3R, and 2 SNPs in MC5R significantly linked and/or associated to/with the risk of PCOS in Italian families. This is the first study to report the novel implication of melanocortin receptor genes (MC1R, MC2R, and MC5R) in PCOS. MC3R and MC4R were previously reported in PCOS. However, functional studies are needed to validate these results.
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MESH Headings
- Humans
- Polycystic Ovary Syndrome/genetics
- Female
- Polymorphism, Single Nucleotide
- Italy/epidemiology
- Genetic Predisposition to Disease
- Receptors, Melanocortin/genetics
- Receptor, Melanocortin, Type 1/genetics
- Receptor, Melanocortin, Type 4/genetics
- Adult
- Receptor, Melanocortin, Type 2/genetics
- Receptor, Melanocortin, Type 3/genetics
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Affiliation(s)
- Rongling Wu
- Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA, 17033, USA
- Department of Statistics, Penn State College of Medicine, Hershey, PA, 17033, USA
| | - Claudia Gragnoli
- Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA, 17033, USA.
- Division of Endocrinology, Department of Medicine, Creighton University School of Medicine, Omaha, NE, 68124, USA.
- Molecular Biology Laboratory, Bios Biotech Multi-Diagnostic Health Center, Rome, 00197, Italy.
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Pérez-Gutiérrez AM, Carmona R, Loucera C, Cervilla JA, Gutiérrez B, Molina E, Lopez-Lopez D, Pérez-Florido J, Zarza-Rebollo JA, López-Isac E, Dopazo J, Martínez-González LJ, Rivera M. Mutational landscape of risk variants in comorbid depression and obesity: a next-generation sequencing approach. Mol Psychiatry 2024; 29:3553-3566. [PMID: 38806690 DOI: 10.1038/s41380-024-02609-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 05/03/2024] [Accepted: 05/13/2024] [Indexed: 05/30/2024]
Abstract
Major depression (MD) and obesity are complex genetic disorders that are frequently comorbid. However, the study of both diseases concurrently remains poorly addressed and therefore the underlying genetic mechanisms involved in this comorbidity remain largely unknown. Here we examine the contribution of common and rare variants to this comorbidity through a next-generation sequencing (NGS) approach. Specific genomic regions of interest in MD and obesity were sequenced in a group of 654 individuals from the PISMA-ep epidemiological study. We obtained variants across the entire frequency spectrum and assessed their association with comorbid MD and obesity, both at variant and gene levels. We identified 55 independent common variants and a burden of rare variants in 4 genes (PARK2, FGF21, HIST1H3D and RSRC1) associated with the comorbid phenotype. Follow-up analyses revealed significantly enriched gene-sets associated with biological processes and pathways involved in metabolic dysregulation, hormone signaling and cell cycle regulation. Our results suggest that, while risk variants specific to the comorbid phenotype have been identified, the genes functionally impacted by the risk variants share cell biological processes and signaling pathways with MD and obesity phenotypes separately. To the best of our knowledge, this is the first study involving a targeted sequencing approach toward the study of the comorbid MD and obesity. The framework presented here allowed a deep characterization of the genetics of the co-occurring MD and obesity, revealing insights into the mutational and functional profile that underlies this comorbidity and contributing to a better understanding of the relationship between these two disabling disorders.
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Affiliation(s)
- Ana M Pérez-Gutiérrez
- Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, Granada, Spain
- Institute of Neurosciences "Federico Olóriz", Biomedical Research Center (CIBM), University of Granada, Granada, Spain
- Instituto de Investigación Biosanitaria, Ibs Granada, Granada, Spain
| | - Rosario Carmona
- Platform for Computational Medicine, Andalusian Public Foundation Progress and Health-FPS, Seville, Spain
- Computational Systems Medicine, Institute of Biomedicine of Seville (IBIS), Hospital Virgen del Rocío, Seville, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER-ISCIII), U715, Seville, Spain
| | - Carlos Loucera
- Platform for Computational Medicine, Andalusian Public Foundation Progress and Health-FPS, Seville, Spain
- Computational Systems Medicine, Institute of Biomedicine of Seville (IBIS), Hospital Virgen del Rocío, Seville, Spain
| | - Jorge A Cervilla
- Institute of Neurosciences "Federico Olóriz", Biomedical Research Center (CIBM), University of Granada, Granada, Spain
- Instituto de Investigación Biosanitaria, Ibs Granada, Granada, Spain
- Department of Psychiatry, Faculty of Medicine, University of Granada, Granada, Spain
| | - Blanca Gutiérrez
- Institute of Neurosciences "Federico Olóriz", Biomedical Research Center (CIBM), University of Granada, Granada, Spain
- Instituto de Investigación Biosanitaria, Ibs Granada, Granada, Spain
- Department of Psychiatry, Faculty of Medicine, University of Granada, Granada, Spain
| | - Esther Molina
- Institute of Neurosciences "Federico Olóriz", Biomedical Research Center (CIBM), University of Granada, Granada, Spain
- Instituto de Investigación Biosanitaria, Ibs Granada, Granada, Spain
- Department of Nursing, Faculty of Health Sciences, University of Granada, Granada, Spain
| | - Daniel Lopez-Lopez
- Platform for Computational Medicine, Andalusian Public Foundation Progress and Health-FPS, Seville, Spain
- Computational Systems Medicine, Institute of Biomedicine of Seville (IBIS), Hospital Virgen del Rocío, Seville, Spain
| | - Javier Pérez-Florido
- Platform for Computational Medicine, Andalusian Public Foundation Progress and Health-FPS, Seville, Spain
- Computational Systems Medicine, Institute of Biomedicine of Seville (IBIS), Hospital Virgen del Rocío, Seville, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER-ISCIII), U715, Seville, Spain
| | - Juan Antonio Zarza-Rebollo
- Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, Granada, Spain
- Institute of Neurosciences "Federico Olóriz", Biomedical Research Center (CIBM), University of Granada, Granada, Spain
- Instituto de Investigación Biosanitaria, Ibs Granada, Granada, Spain
| | - Elena López-Isac
- Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, Granada, Spain
- Institute of Neurosciences "Federico Olóriz", Biomedical Research Center (CIBM), University of Granada, Granada, Spain
- Instituto de Investigación Biosanitaria, Ibs Granada, Granada, Spain
| | - Joaquín Dopazo
- Platform for Computational Medicine, Andalusian Public Foundation Progress and Health-FPS, Seville, Spain
- Computational Systems Medicine, Institute of Biomedicine of Seville (IBIS), Hospital Virgen del Rocío, Seville, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER-ISCIII), U715, Seville, Spain
| | - Luis Javier Martínez-González
- Genomics Unit, Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research (GENYO), Granada, Spain
| | - Margarita Rivera
- Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, Granada, Spain.
- Institute of Neurosciences "Federico Olóriz", Biomedical Research Center (CIBM), University of Granada, Granada, Spain.
- Instituto de Investigación Biosanitaria, Ibs Granada, Granada, Spain.
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Next-Generation Sequencing of a Large Gene Panel for Outcome Prediction of Bariatric Surgery in Patients with Severe Obesity. J Clin Med 2022; 11:jcm11247531. [PMID: 36556146 PMCID: PMC9783894 DOI: 10.3390/jcm11247531] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 12/14/2022] [Accepted: 12/15/2022] [Indexed: 12/23/2022] Open
Abstract
Obesity is a chronic disease in which abnormal deposition of fat threatens health, leading to diabetes, cardiovascular diseases, cancer, and other chronic illnesses. According to the WHO, 19.8% of the adult population in Italy is obese, and the prevalence is higher among men. It is important to know the predisposition of an individual to become obese and to respond to bariatric surgery, the most up-to-date treatment for severe obesity. To this purpose, we developed an NGS gene panel, comprising 72 diagnostic genes and 244 candidate genes, and we sequenced 247 adult obese Italian patients. Eleven deleterious variants in 9 diagnostic genes and 17 deleterious variants in 11 candidate genes were identified. Interestingly, mutations were found in several genes correlated to the Bardet-Biedl syndrome. Then, 25 patients were clinically followed to evaluate their response to bariatric surgery. After a 12-month follow-up, the patients that carried deleterious variants in diagnostic or candidate genes had a reduced weight loss, as compared to the other patients. The NGS-based panel, including diagnostic and candidate genes used in this study, could play a role in evaluating, diagnosing, and managing obese individuals, and may help in predicting the outcome of bariatric surgery.
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Alsaif F, Al-hamoudi W, Alotaiby M, Alsadoon A, Almayouf M, Almadany H, Abuhaimed J, Ghufran N, Merajuddin A, Ali Khan I. Molecular Screening via Sanger Sequencing of the Genetic Variants in Non-Alcoholic Fatty Liver Disease Subjects in the Saudi Population: A Hospital-Based Study. Metabolites 2022; 12:metabo12121240. [PMID: 36557278 PMCID: PMC9784496 DOI: 10.3390/metabo12121240] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 11/29/2022] [Accepted: 12/03/2022] [Indexed: 12/13/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, along with steatosis and non-alcoholic steatohepatitis (NASH), and is associated with cirrhosis and hepatocellular carcinoma. Candidate gene and genome-wide association studies have validated the relationships between NAFLD, NASH, PNPLA3, TM6SF2, and HFE. The present study utilized five polymorphisms in three genes: PNPLA3 (I148M and K434E) TM6SF2 (E167K), and HFE (H63D and C282Y), based on undocumented case−control studies in the Saudi Arabian population. A total of 95 patients with NAFLD and 78 non-NAFLD subjects were recruited. Genomic DNA was isolated, and polymerase chain reaction and Sanger sequencing were performed using specific primers for the I148M, K434E, E167K, H63D, and C282Y. NAFLD subjects were older when compared to controls and showed the significant association (p = 0.0001). Non-significant association was found between gender (p = 0.26). However, both weight and BMI were found to be associated. Hardy−Weinberg equilibrium analysis confirmed that H63D, I148M, and K434E polymorphisms were associated. Genotype analysis showed only K434E variant was associated with NAFLD and non-NAFLD (OR-2.16; 95% CI: 1.08−4.31; p = 0.02). However, other polymorphisms performed with NAFLD and NASH were not associated (p > 0.05), and similar analysis was found when ANOVA was performed (p > 0.05). In conclusion, we confirmed that K434E polymorphism showed a positive association in the Saudi population.
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Affiliation(s)
- Faisal Alsaif
- Surgery Department, College of Medicine, King Saud University, Riyadh 12372, Saudi Arabia
- Molecular Genetic Pathology Unit, Pathology Department, College of Medicine, King Saud University, Riyadh 12372, Saudi Arabia
| | - Waleed Al-hamoudi
- Molecular Genetic Pathology Unit, Pathology Department, College of Medicine, King Saud University, Riyadh 12372, Saudi Arabia
- Medicine Department, College of Medicine, King Saud University, Riyadh 12372, Saudi Arabia
| | - Maram Alotaiby
- Molecular Genetic Pathology Unit, Pathology Department, College of Medicine, King Saud University, Riyadh 12372, Saudi Arabia
- Laboratories and Blood Bank Services Ministry of Health, Riyadh 12746, Saudi Arabia
- Correspondence: (M.A.); (I.A.K.)
| | - Amani Alsadoon
- Liver Disease Research Center, King Saud University Medical City, Riyadh 12746, Saudi Arabia
| | - Mohammed Almayouf
- Surgery Department, College of Medicine, Prince Sattam bin Abdulaziz University, Riyadh 11942, Saudi Arabia
| | - Hadeel Almadany
- Surgery Department, College of Medicine, King Saud University, Riyadh 12372, Saudi Arabia
| | - Jawahir Abuhaimed
- College of Medicine, Al-Faisal University, Riyadh P.O. Box 400, Saudi Arabia
| | - Noman Ghufran
- Molecular Genetic Pathology Unit, Pathology Department, College of Medicine, King Saud University, Riyadh 12372, Saudi Arabia
| | - Ahmed Merajuddin
- Molecular Genetic Pathology Unit, Pathology Department, College of Medicine, King Saud University, Riyadh 12372, Saudi Arabia
- Research and Development Unit, Adela Inc. 610, University of Avenue, Toronto, ON M5G 2R5, Canada
| | - Imran Ali Khan
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh 12372, Saudi Arabia
- Correspondence: (M.A.); (I.A.K.)
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Sharma A, Albhaisi S, Sanyal AJ. Behavioral health disorders related to nonalcoholic steatohepatitis. Clin Liver Dis (Hoboken) 2022; 20:43-47. [PMID: 36033424 PMCID: PMC9405487 DOI: 10.1002/cld.1211] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 11/26/2021] [Accepted: 01/19/2022] [Indexed: 02/04/2023] Open
Abstract
Content available: Author Interview and Audio Recording.
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Affiliation(s)
- Aadi Sharma
- University of VirginiaCharlottesvilleVirginiaUSA
| | - Somaya Albhaisi
- Department of Internal MedicineVirginia Commonwealth UniversityRichmondVirginiaUSA
| | - Arun J. Sanyal
- Division of Gastroenterology, Hepatology and NutritionDepartment of Internal MedicineVirginia Commonwealth UniversityRichmondVirginiaUSA
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Amin M, Ott J, Wu R, Postolache TT, Gragnoli C. Implication of Melanocortin Receptor Genes in the Familial Comorbidity of Type 2 Diabetes and Depression. Int J Mol Sci 2022; 23:8350. [PMID: 35955479 PMCID: PMC9369258 DOI: 10.3390/ijms23158350] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 07/22/2022] [Accepted: 07/25/2022] [Indexed: 12/20/2022] Open
Abstract
The melanocortin receptors are G-protein-coupled receptors, which are essential components of the hypothalamic-pituitary-adrenal axis, and they mediate the actions of melanocortins (melanocyte-stimulating hormones: α-MSH, β-MSH, and γ-MSH) as well as the adrenocorticotropin hormone (ACTH) in skin pigmentation, adrenal steroidogenesis, and stress response. Three melanocortin receptor genes (MC1R, MC2R, and MC5R) contribute to the risk of major depressive disorder (MDD), and one melanocortin receptor gene (MC4R) contributes to the risk of type 2 diabetes (T2D). MDD increases T2D risk in drug-naïve patients; thus, MDD and T2D commonly coexist. The five melanocortin receptor genes might confer risk for both disorders. However, they have never been investigated jointly to evaluate their potential contributing roles in the MDD-T2D comorbidity, specifically within families. In 212 Italian families with T2D and MDD, we tested 11 single nucleotide polymorphisms (SNPs) in the MC1R gene, 9 SNPs in MC2R, 3 SNPs in MC3R, 4 SNPs in MC4R, and 2 SNPs in MC5R. The testing used 2-point parametric linkage and linkage disequilibrium (LD) (i.e., association) analysis with four models (dominant with complete penetrance (D1), dominant with incomplete penetrance (D2), recessive with complete penetrance (R1), and recessive with incomplete penetrance (R2)). We detected significant (p ≤ 0.05) linkage and/or LD (i.e., association) to/with MDD for one SNP in MC2R (rs111734014) and one SNP in MC5R (rs2236700), and to/with T2D for three SNPs in MC1R (rs1805007 and rs201192930, and rs2228479), one SNP in MC2R (rs104894660), two SNPs in MC3R (rs3746619 and rs3827103), and one SNP in MC4R genes (Chr18-60372302). The linkage/LD/association was significant across different linkage patterns and different modes of inheritance. All reported variants are novel in MDD and T2D. This is the first study to report risk variants in MC1R, MC2R, and MC3R genes in T2D. MC2R and MC5R genes are replicated in MDD, with one novel variant each. Within our dataset, only the MC2R gene appears to confer risk for both MDD and T2D, albeit with different risk variants. To further clarity the role of the melanocortin receptor genes in MDD-T2D, these findings should be sought among other ethnicities as well.
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Affiliation(s)
- Mutaz Amin
- Institut National de la Santé et de la Recherche Médicale (INSERM), US14-Orphanet, 75014 Paris, France;
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Al-Neelain University, Khartoum 11121, Sudan
| | - Jurg Ott
- Laboratory of Statistical Genetics, Rockefeller University, New York City, NY 10065, USA;
| | - Rongling Wu
- Department of Statistics and Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA 17033, USA;
| | - Teodor T. Postolache
- Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21201, USA;
- Rocky Mountain Mental Illness Research Education and Clinical Center (MIRECC), Veterans Integrated Service Network (VISN) 19, Denver, CO 80246, USA
- Military and Veteran Microbiome: Consortium for Research and Education (MVM-CoRE), Denver, CO 80246, USA
- Mental Illness Research Education and Clinical Center (MIRECC), Veterans Integrated Service Network (VISN) 5, VA Capitol Health Care Network, Baltimore, MD 21090, USA
| | - Claudia Gragnoli
- Division of Endocrinology, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA
- Division of Endocrinology, Department of Medicine, Creighton University School of Medicine, Omaha, NE 68124, USA
- Molecular Biology Laboratory, Bios Biotech Multi-Diagnostic Health Center, 00197 Rome, Italy
- Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA 17033, USA
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Lardone MC, Busch AS, Santos JL, Miranda P, Eyheramendy S, Pereira A, Juul A, Almstrup K, Mericq V. A Polygenic Risk Score Suggests Shared Genetic Architecture of Voice Break With Early Markers of Pubertal Onset in Boys. J Clin Endocrinol Metab 2020; 105:dgaa003. [PMID: 31915828 DOI: 10.1210/clinem/dgaa003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 01/07/2020] [Indexed: 02/03/2023]
Abstract
CONTEXT Voice break, as a landmark of advanced male puberty in genome-wide association studies (GWAS), has revealed that pubertal timing is a highly polygenic trait. Although voice break is easily recorded in large cohorts, it holds quite low precision as a marker of puberty. In contrast, gonadarche and pubarche are early and clinically well-defined measures of puberty onset. OBJECTIVE To determine whether a polygenic risk score (PRS) of alleles that confer risk for voice break associates with age at gonadarche (AAG) and age at pubarche (AAP) in Chilean boys. EXPERIMENTAL DESIGN Longitudinal study. SUBJECTS AND METHODS 401 boys from the Growth and Obesity Chilean Cohort Study (n = 1194; 49.2% boys). MAIN OUTCOME MEASURES Biannual clinical pubertal staging including orchidometry. AAG and AAP were estimated by censoring methods. Genotyping was performed using the Multi-Ethnic Global Array (Illumina). Using GWAS summary statistics from the UK-Biobank, 29 significant and independent single nucleotide polymorphisms associated with age at voice break were extracted. Individual PRS were computed as the sum of risk alleles weighted by the effect size. RESULTS The PRS was associated with AAG (β=0.01, P = 0.04) and AAP (β=0.185, P = 0.0004). In addition, boys within the 20% highest PRS experienced gonadarche and pubarche 0.55 and 0.67 years later than those in the lowest 20%, respectively (P = 0.013 and P = 0.007). CONCLUSIONS Genetic variants identified in large GWAS on age at VB significantly associate with age at testicular growth and pubic hair development, suggesting that these events share a genetic architecture across ethnically distinct populations.
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Affiliation(s)
- María C Lardone
- Institute of Maternal and Child Research, School of Medicine, University of Chile, Santiago, Chile
| | - Alexander S Busch
- Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - José L Santos
- Department of Nutrition, Diabetes and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Patricio Miranda
- Department of Nutrition, Diabetes and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Susana Eyheramendy
- Faculty of Engineering and Sciences, Universidad Adolfo Ibañez, Santiago, Chile
| | - Ana Pereira
- Institute of Nutrition and Food Technology, University of Chile, Santiago, Chile
| | - Anders Juul
- Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Kristian Almstrup
- Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Verónica Mericq
- Institute of Maternal and Child Research, School of Medicine, University of Chile, Santiago, Chile
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M3 muscarinic receptor activation reduces hepatocyte lipid accumulation via CaMKKβ/AMPK pathway. Biochem Pharmacol 2019; 169:113613. [PMID: 31445019 DOI: 10.1016/j.bcp.2019.08.015] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 08/19/2019] [Indexed: 12/21/2022]
Abstract
Previously, we reported that hepatic muscarinic receptors modulate both acute and chronic liver injury, however, the role of muscarinic receptors in fatty liver disease is unclear. We observed in patients who underwent weight loss surgery, a decrease in hepatic expression of M3 muscarinic receptors (M3R). We also observed that fat loading of hepatocytes, increased M3R expression. Based on these observations, we tested the hypothesis that M3R regulate hepatocyte lipid accumulation. Incubation of AML12 hepatocytes with 1 mM oleic acid resulted in lipid accumulation that was significantly reduced by co-treatment with a muscarinic agonist (pilocarpine or carbachol), an effect blocked by atropine (a muscarinic antagonist). Similar treatment of Hepa 1-6 cells, a mouse hepatoblastoma cell line, showed comparable results. In both, control and fat-loaded AML12 cells, pilocarpine induced time-dependent AMPKα phosphorylation and significantly up-regulated lipolytic genes (ACOX1, CPT1, and PPARα). Compound C, a selective and reversible AMPK inhibitor, significantly blunted pilocarpine-mediated reduction of lipid accumulation and pilocarpine-mediated up-regulation of lipolytic genes. BAPTA-AM, a calcium chelator, and STO-609, a calcium/calmodulin-dependent protein kinase kinase inhibitor, attenuated agonist-induced AMPKα phosphorylation. Finally, M3R siRNA attenuated agonist-induced AMPKα phosphorylation as well as agonist-mediated reduction of hepatocyte steatosis. In conclusion, this proof-of-concept study demonstrates that M3R has protective effects against hepatocyte lipid accumulation by activating AMPK pathway and is a potential therapeutic target for non-alcoholic fatty liver disease.
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Tam V, Turcotte M, Meyre D. Established and emerging strategies to crack the genetic code of obesity. Obes Rev 2019; 20:212-240. [PMID: 30353704 DOI: 10.1111/obr.12770] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Revised: 08/27/2018] [Accepted: 08/28/2018] [Indexed: 12/11/2022]
Abstract
Tremendous progress has been made in the genetic elucidation of obesity over the past two decades, driven largely by technological, methodological and organizational innovations. Current strategies for identifying obesity-predisposing loci/genes, including cytogenetics, linkage analysis, homozygosity mapping, admixture mapping, candidate gene studies, genome-wide association studies, custom genotyping arrays, whole-exome sequencing and targeted exome sequencing, have achieved differing levels of success, and the identified loci in aggregate explain only a modest fraction of the estimated heritability of obesity. This review outlines the successes and limitations of these approaches and proposes novel strategies, including the use of exceptionally large sample sizes, the study of diverse ethnic groups and deep phenotypes and the application of innovative methods and study designs, to identify the remaining obesity-predisposing genes. The use of both established and emerging strategies has the potential to crack the genetic code of obesity in the not-too-distant future. The resulting knowledge is likely to yield improvements in obesity prediction, prevention and care.
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Affiliation(s)
- V Tam
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada
| | - M Turcotte
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada
| | - D Meyre
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada.,Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
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10
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Pirola CJ, Flichman D, Dopazo H, Fernández Gianotti T, San Martino J, Rohr C, Garaycoechea M, Gazzi C, Castaño GO, Sookoian S. A Rare Nonsense Mutation in the Glucokinase Regulator Gene Is Associated With a Rapidly Progressive Clinical Form of Nonalcoholic Steatohepatitis. Hepatol Commun 2018; 2:1030-1036. [PMID: 30202818 PMCID: PMC6128235 DOI: 10.1002/hep4.1235] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Accepted: 06/20/2018] [Indexed: 12/23/2022] Open
Abstract
We report on the presence of a rare nonsense mutation (rs149847328, p.Arg227Ter) in the glucokinase regulator (GCKR) gene in an adult patient with nonalcoholic fatty liver disease (NAFLD), morbid obesity, and type 2 diabetes; this patient developed a progressive histological form of the disease. Analysis of paired (5 years apart) liver biopsies (at baseline and follow‐up) showed progression of simple steatosis to severe nonalcoholic steatohepatitis and cirrhosis. Study design involved an initial exploration that consisted of deep sequencing of 14 chromosomal regions in 96 individuals (64 of whom were patients with NAFLD who were diagnosed by liver biopsy that showed the full spectrum of histological severity). We further performed a replication study to explore the presence of rs149847328 that included a sample of 517 unrelated individuals in a case‐control study (n = 390), including patients who were morbidly obese (n = 127). Exploration of sequence variation by next‐generation sequencing of exons, exon–intron boundaries, and 5′ and 3′ untranslated regions of 14 genomic loci that encode metabolic enzymes of the tricarboxylic acid cycle revealed the presence of heterozygosity for the p.Arg227Ter mutation, the frequency of which is 0.0003963 (4:10,000; Exome Aggregation Consortium database). GCKR protein expression was markedly decreased in the liver of the affected patient compared with patients with NAFLD who carry the wild‐type allele. Sequencing of the same 14 genomic loci in 95 individuals failed to reveal the rare mutation. The rarity of p.Arg227Ter was confirmed in a more extensive screening. Conclusion: While rare variants/mutations are difficult to detect in even reasonably large samples (frequency of the mutant allele of p.Arg227Ter was ~1:1,000 in our data set), the presence of this mutation should be suspected as potentially associated with NAFLD, particularly in young adults at the extreme of histological phenotypes. Hepatology Communications 2018;0:0‐0)
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Affiliation(s)
- Carlos J Pirola
- Institute of Medical Research A. Lanari University of Buenos Aires Buenos Aires Argentina.,Department of Molecular Genetics and Biology of Complex Diseases, Institute of Medical Research National Scientific and Technical Research Council-University of Buenos Aires Buenos Aires Argentina
| | - Diego Flichman
- Department of Virology, School of Pharmacy and Biochemistry University of Buenos Aires Buenos Aires Argentina
| | - Hernán Dopazo
- Biomedical Genomics and Evolution Laboratory, Ecology, Genetics, and Evolution Department, Faculty of Science Institute of Ecology, Genetics, and Evolution of Buenos Aires, National Scientific and Technical Research Council-University of Buenos Aires Buenos Aires Argentina
| | - Tomas Fernández Gianotti
- Department of Molecular Genetics and Biology of Complex Diseases, Institute of Medical Research National Scientific and Technical Research Council-University of Buenos Aires Buenos Aires Argentina
| | - Julio San Martino
- Department of Pathology, Hospital Diego Thompson, San Martin Buenos Aires Argentina
| | - Cristian Rohr
- Biomedical Genomics and Evolution Laboratory, Ecology, Genetics, and Evolution Department, Faculty of Science Institute of Ecology, Genetics, and Evolution of Buenos Aires, National Scientific and Technical Research Council-University of Buenos Aires Buenos Aires Argentina
| | - Martin Garaycoechea
- Deparment of Surgery and the Center for Translational Medicine Excellence Hospital de Alta Complejidad en Red "El Cruce," Florencio Varela Buenos Aires Argentina
| | - Carla Gazzi
- Pathology Department, Institute of Medical Research A. Lanari University of Buenos Aires Buenos Aires Argentina
| | - Gustavo O Castaño
- Liver Unit, Medicine and Surgery Department Hospital Abel Zubizarreta Buenos Aires Argentina
| | - Silvia Sookoian
- Institute of Medical Research A. Lanari University of Buenos Aires Buenos Aires Argentina.,Department of Clinical and Molecular Hepatology, Institute of Medical Research National Scientific and Technical Research Council-University of Buenos Aires Buenos Aires Argentina
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11
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Nordang GBN, Busk ØL, Tveten K, Hanevik HI, Fell AKM, Hjelmesæth J, Holla ØL, Hertel JK. Next-generation sequencing of the monogenic obesity genes LEP, LEPR, MC4R, PCSK1 and POMC in a Norwegian cohort of patients with morbid obesity and normal weight controls. Mol Genet Metab 2017; 121:51-56. [PMID: 28377240 DOI: 10.1016/j.ymgme.2017.03.007] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Revised: 03/27/2017] [Accepted: 03/27/2017] [Indexed: 12/19/2022]
Abstract
BACKGROUND Rare sequence variants in at least five genes are known to cause monogenic obesity. In this study we aimed to investigate the prevalence of, and characterize, rare coding and splice site variants in LEP, LEPR, MC4R, PCSK1 and POMC in patients with morbid obesity and normal weight controls. METHOD Targeted next-generation sequencing of all exons in LEP, LEPR, MC4R, PCSK1 and POMC was performed in 485 patients with morbid obesity and 327 normal weight population-based controls from Norway. RESULTS In total 151 variants were detected. Twenty-eight (18.5%) of these were rare, coding or splice variants and five (3.3%) were novel. All individuals, except one control, were heterozygous for the 28 variants, and the distribution of the rare variants showed a significantly higher carrier frequency among cases than controls (9.9% vs. 4.9%, p=0.011). Four variants in MC4R were classified as pathogenic or likely pathogenic. CONCLUSION Four cases (0.8%) of monogenic obesity were detected, all due to MC4R variants previously linked to monogenic obesity. Significant differences in carrier frequencies among patients with morbid obesity and normal weight controls suggest an association between heterozygous rare coding variants in these five genes and morbid obesity. However, additional studies in larger cohorts and functional testing of the novel variants identified are required to confirm the findings.
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Affiliation(s)
- Gry B N Nordang
- Morbid Obesity Centre, Vestfold Hospital Trust, Tønsberg, Norway; Department of Occupational and Environmental Medicine, Telemark Hospital, Skien, Norway; Section of Medical Genetics, Department of Laboratory Medicine, Telemark Hospital, Skien, Norway.
| | - Øyvind L Busk
- Section of Medical Genetics, Department of Laboratory Medicine, Telemark Hospital, Skien, Norway
| | - Kristian Tveten
- Section of Medical Genetics, Department of Laboratory Medicine, Telemark Hospital, Skien, Norway
| | | | - Anne Kristin M Fell
- Department of Occupational and Environmental Medicine, Telemark Hospital, Skien, Norway
| | - Jøran Hjelmesæth
- Morbid Obesity Centre, Vestfold Hospital Trust, Tønsberg, Norway; Department of Endocrinology, Morbid Obesity and Preventive Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Øystein L Holla
- Section of Medical Genetics, Department of Laboratory Medicine, Telemark Hospital, Skien, Norway
| | - Jens K Hertel
- Morbid Obesity Centre, Vestfold Hospital Trust, Tønsberg, Norway
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12
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Singh RK, Kumar P, Mahalingam K. Molecular genetics of human obesity: A comprehensive review. C R Biol 2017; 340:87-108. [PMID: 28089486 DOI: 10.1016/j.crvi.2016.11.007] [Citation(s) in RCA: 126] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Revised: 10/03/2016] [Accepted: 11/10/2016] [Indexed: 12/25/2022]
Abstract
Obesity and its related health complications is a major problem worldwide. Hypothalamus and their signalling molecules play a critical role in the intervening and coordination with energy balance and homeostasis. Genetic factors play a crucial role in determining an individual's predisposition to the weight gain and being obese. In the past few years, several genetic variants were identified as monogenic forms of human obesity having success over common polygenic forms. In the context of molecular genetics, genome-wide association studies (GWAS) approach and their findings signified a number of genetic variants predisposing to obesity. However, the last couple of years, it has also been noticed that alterations in the environmental and epigenetic factors are one of the key causes of obesity. Hence, this review might be helpful in the current scenario of molecular genetics of human obesity, obesity-related health complications (ORHC), and energy homeostasis. Future work based on the clinical discoveries may play a role in the molecular dissection of genetic approaches to find more obesity-susceptible gene loci.
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Affiliation(s)
- Rajan Kumar Singh
- Department of Bio-Medical Sciences, School of Biosciences and Technology, VIT University, 632014 Vellore, India
| | - Permendra Kumar
- Department of Bio-Medical Sciences, School of Biosciences and Technology, VIT University, 632014 Vellore, India
| | - Kulandaivelu Mahalingam
- Department of Bio-Medical Sciences, School of Biosciences and Technology, VIT University, 632014 Vellore, India.
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13
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Ravi Kanth VV, Sasikala M, Sharma M, Rao PN, Reddy DN. Genetics of non-alcoholic fatty liver disease: From susceptibility and nutrient interactions to management. World J Hepatol 2016; 8:827-837. [PMID: 27458502 PMCID: PMC4945502 DOI: 10.4254/wjh.v8.i20.827] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Revised: 05/04/2016] [Accepted: 06/14/2016] [Indexed: 02/06/2023] Open
Abstract
Genetics plays an important role in determining the susceptibility of an individual to develop a disease. Complex, multi factorial diseases of modern day (diabetes, cardiovascular disease, hypertension and obesity) are a result of disparity between the type of food consumed and genes, suggesting that food which does not match the host genes is probably one of the major reasons for developing life style diseases. Non-alcoholic fatty liver is becoming a global epidemic leading to substantial morbidity. While various genotyping approaches such as whole exome sequencing using next generation sequencers and genome wide association studies have identified susceptibility loci for non-alcoholic fatty liver disease (NAFLD) including variants in patatin-like phospholipase domain containing 3 and transmembrane 6 superfamily member 2 genes apart from others; nutrient based studies emphasized on a combination of vitamin D, E and omega-3 fatty acids to manage fatty liver disease. However majority of the studies were conducted independent of each other and very few studies explored the interactions between the genetic susceptibility and nutrient interactions. Identifying such interactions will aid in optimizing the nutrition tailor made to an individual's genetic makeup, thereby aiding in delaying the onset of the disease and its progression. The present topic focuses on studies that identified the genetic susceptibility for NAFLD, nutritional recommendations, and their interactions for better management of NAFLD.
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Affiliation(s)
- Vishnubhotla Venkata Ravi Kanth
- Vishnubhotla Venkata Ravi Kanth, Mitnala Sasikala, Asian Healthcare Foundation, a Research Wing of Asian Institute of Gastroenterology, Hyderabad 500082, Telangana, India
| | - Mitnala Sasikala
- Vishnubhotla Venkata Ravi Kanth, Mitnala Sasikala, Asian Healthcare Foundation, a Research Wing of Asian Institute of Gastroenterology, Hyderabad 500082, Telangana, India
| | - Mithun Sharma
- Vishnubhotla Venkata Ravi Kanth, Mitnala Sasikala, Asian Healthcare Foundation, a Research Wing of Asian Institute of Gastroenterology, Hyderabad 500082, Telangana, India
| | - Padaki Nagaraja Rao
- Vishnubhotla Venkata Ravi Kanth, Mitnala Sasikala, Asian Healthcare Foundation, a Research Wing of Asian Institute of Gastroenterology, Hyderabad 500082, Telangana, India
| | - Duvvuru Nageshwar Reddy
- Vishnubhotla Venkata Ravi Kanth, Mitnala Sasikala, Asian Healthcare Foundation, a Research Wing of Asian Institute of Gastroenterology, Hyderabad 500082, Telangana, India
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14
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Lückhoff HK, Kruger FC, Kotze MJ. Composite prognostic models across the non-alcoholic fatty liver disease spectrum: Clinical application in developing countries. World J Hepatol 2015; 7:1192-1208. [PMID: 26019735 PMCID: PMC4438494 DOI: 10.4254/wjh.v7.i9.1192] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 12/18/2014] [Accepted: 04/02/2015] [Indexed: 02/06/2023] Open
Abstract
Heterogeneity in clinical presentation, histological severity, prognosis and therapeutic outcomes characteristic of non-alcoholic fatty liver disease (NAFLD) necessitates the development of scientifically sound classification schemes to assist clinicians in stratifying patients into meaningful prognostic subgroups. The need for replacement of invasive liver biopsies as the standard method whereby NAFLD is diagnosed, graded and staged with biomarkers of histological severity injury led to the development of composite prognostic models as potentially viable surrogate alternatives. In the present article, we review existing scoring systems used to (1) confirm the presence of undiagnosed hepatosteatosis; (2) distinguish between simple steatosis and NASH; and (3) predict advanced hepatic fibrosis, with particular emphasis on the role of NAFLD as an independent cardio-metabolic risk factor. In addition, the incorporation of functional genomic markers and application of emerging imaging technologies are discussed as a means to improve the diagnostic accuracy and predictive performance of promising composite models found to be most appropriate for widespread clinical adoption.
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15
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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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16
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Apalasamy YD, Mohamed Z. Obesity and genomics: role of technology in unraveling the complex genetic architecture of obesity. Hum Genet 2015; 134:361-74. [PMID: 25687726 DOI: 10.1007/s00439-015-1533-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Accepted: 02/02/2015] [Indexed: 01/15/2023]
Abstract
Obesity is a complex and multifactorial disease that occurs as a result of the interaction between "obesogenic" environmental factors and genetic components. Although the genetic component of obesity is clear from the heritability studies, the genetic basis remains largely elusive. Successes have been achieved in identifying the causal genes for monogenic obesity using animal models and linkage studies, but these approaches are not fruitful for polygenic obesity. The developments of genome-wide association approach have brought breakthrough discovery of genetic variants for polygenic obesity where tens of new susceptibility loci were identified. However, the common SNPs only accounted for a proportion of heritability. The arrival of NGS technologies and completion of 1000 Genomes Project have brought other new methods to dissect the genetic architecture of obesity, for example, the use of exome genotyping arrays and deep sequencing of candidate loci identified from GWAS to study rare variants. In this review, we summarize and discuss the developments of these genetic approaches in human obesity.
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Affiliation(s)
- Yamunah Devi Apalasamy
- Department of Pharmacology, Pharmacogenomics Laboratory, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia,
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Machado MV, Cortez-Pinto H. Non-alcoholic fatty liver disease: what the clinician needs to know. World J Gastroenterol 2014; 20:12956-80. [PMID: 25278691 PMCID: PMC4177476 DOI: 10.3748/wjg.v20.i36.12956] [Citation(s) in RCA: 138] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2014] [Revised: 04/21/2014] [Accepted: 05/25/2014] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most frequent cause of liver disease in the Western world. Furthermore, it is increasing worldwide, paralleling the obesity pandemic. Though highly frequent, only about one fifth of affected subjects are at risk of developing the progressive form of the disease, non-alcoholic steatohepatitis with fibrosis. Even in the latter, liver disease is slowly progressive, though, since it is so prevalent, it is already the third cause of liver transplantation in the United States, and it is predicted to get to the top of the ranking in few years. Of relevance, fatty liver is also associated with increased overall mortality and particularly increased cardiovascular mortality. The literature and amount of published papers on NAFLD is increasing as fast as its prevalence, which makes it difficult to keep updated in this topic. This review aims to summarize the latest knowledge on NAFLD, in order to help clinicians understanding its pathogenesis and advances on diagnosis and treatment.
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18
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Parihar A, Wood GC, Chu X, Jin Q, Argyropoulos G, Still CD, Shuldiner AR, Mitchell BD, Gerhard GS. Extension of GWAS results for lipid-related phenotypes to extreme obesity using electronic health record (EHR) data and the Metabochip. Front Genet 2014; 5:222. [PMID: 25147553 PMCID: PMC4123014 DOI: 10.3389/fgene.2014.00222] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2014] [Accepted: 06/26/2014] [Indexed: 12/18/2022] Open
Abstract
A variety of health-related data are commonly deposited into electronic health records (EHRs), including laboratory, diagnostic, and medication information. The digital nature of EHR data facilitates efficient extraction of these data for research studies, including genome-wide association studies (GWAS). Previous GWAS have identified numerous SNPs associated with variation in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG). These findings have led to the development of specialized genotyping platforms that can be used for fine-mapping and replication in other populations. We have combined the efficiency of EHR data and the economic advantages of the Illumina Metabochip, a custom designed SNP chip targeted to traits related to coronary artery disease, myocardial infarction, and type 2 diabetes, to conduct an array-wide analysis of lipid traits in a population with extreme obesity. Our analyses identified associations with 12 of 21 previously identified lipid-associated SNPs with effect sizes similar to prior results. Association analysis using several approaches to account for lipid-lowering medication use resulted in fewer and less strongly associated SNPs. The availability of phenotype data from the EHR and the economic efficiency of the specialized Metabochip can be exploited to conduct multi-faceted genetic association analyses.
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Affiliation(s)
- Ankita Parihar
- Department of Medicine and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine Baltimore, MD, USA
| | - G Craig Wood
- Geisinger Clinic, Geisinger Obesity Institute Danville, PA, USA
| | - Xin Chu
- Geisinger Clinic, Geisinger Obesity Institute Danville, PA, USA
| | - Qunjan Jin
- Department of Pathology and Laboratory Medicine, Department of Biochemistry and Molecular Biology, Institute for Personalized Medicine, Pennsylvania State University College of Medicine Hershey, PA, USA
| | | | | | - Alan R Shuldiner
- Department of Medicine and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine Baltimore, MD, USA ; Geriatric Research and Education Clinical Center, Veterans Administration Medical Center Baltimore, MD, USA
| | - Braxton D Mitchell
- Department of Medicine and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine Baltimore, MD, USA ; Geriatric Research and Education Clinical Center, Veterans Administration Medical Center Baltimore, MD, USA
| | - Glenn S Gerhard
- Department of Pathology and Laboratory Medicine, Department of Biochemistry and Molecular Biology, Institute for Personalized Medicine, Pennsylvania State University College of Medicine Hershey, PA, USA
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Kalafati IP, Borsa D, Dedoussis GVZ. The Genetics of Nonalcoholic Fatty Liver Disease: Role of Diet as a Modifying Factor. Curr Nutr Rep 2014. [DOI: 10.1007/s13668-014-0085-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Mapping of the circulating metabolome reveals α-ketoglutarate as a predictor of morbid obesity-associated non-alcoholic fatty liver disease. Int J Obes (Lond) 2014; 39:279-87. [DOI: 10.1038/ijo.2014.53] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2014] [Revised: 03/10/2014] [Accepted: 03/17/2014] [Indexed: 12/14/2022]
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Wade JE, Ledbetter DH, Williams MS. Implementation of genomic medicine in a health care delivery system: a value proposition? AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS 2014; 166C:112-6. [PMID: 24619641 DOI: 10.1002/ajmg.c.31392] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
The United States health care system is undergoing significant change and is seeking innovations in care delivery and reimbursement models that will lead to improved value for patients, providers, payers, and employers. Genomic medicine has the potential to be a disruptive innovation that if implemented intelligently can improve value. The article presents the perspective of the leaders of a large integrated healthcare delivery system regarding the decision to invest in implementation of genomic medicine.
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