دورية أكاديمية
A Noncoding Variant Near PPP1R3B Promotes Liver Glycogen Storage and MetS, but Protects Against Myocardial Infarction.
العنوان: | A Noncoding Variant Near PPP1R3B Promotes Liver Glycogen Storage and MetS, but Protects Against Myocardial Infarction. |
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المؤلفون: | Kahali B; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.; Centre for Brain Research, Indian Institute of Science, Bangalore, India., Chen Y; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA., Feitosa MF; Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA., Bielak LF; School of Public Health, Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA., O'Connell JR; Department of Endocrinology, Diabetes, and Nutrition, University of Maryland-Baltimore, Baltimore, MD, USA., Musani SK; Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA., Hegde Y; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA., Chen Y; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA., Stetson LC; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA., Guo X; Institute for Translational Genomics and Population Sciences, LABioMed and Department of Pediatrics at Harbor-UCLA, Torrance, CA, USA., Fu YP; Framingham Heart Study, NHLBI, NIH, Framingham, MA, USA.; Office of Biostatistics Research, Division of Cardiovascular Diseases, NHLBI, NIH, Bethesda, MD, USA., Smith AV; School of Public Health, Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA., Ryan KA; Department of Endocrinology, Diabetes, and Nutrition, University of Maryland-Baltimore, Baltimore, MD, USA., Eiriksdottir G; Icelandic Heart Association, Kopavogur, Iceland., Cohain AT; Department of Genetics and Genomics Sciences, Icahn School of Medicine, New York, NY, USA., Allison M; Department of Family Medicine and Public Health, University of California, San Diego, CA, USA., Bakshi A; Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia., Bowden DW; Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA., Budoff MJ; Department of Internal Medicine, LA Biomedical Research Institute at Harbor-UCLA, Torrance, CA, USA., Carr JJ; Department of Radiology, Vanderbilt University School of Medicine, Nashville, TN, USA., Carskadon S; Department of Urology, Henry Ford Health System, Detroit, MI, USA., Chen YI; Institute for Translational Genomics and Population Sciences, LABioMed and Department of Pediatrics at Harbor-UCLA, Torrance, CA, USA., Correa A; Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA., Crudup BF; Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA., Du X; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA., Harris TB; Laboratory of Epidemiology and Population Sciences, National Institute of Aging, Bethesda, MD, USA., Yang J; Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.; Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia., Kardia SLR; School of Public Health, Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA., Launer LJ; Laboratory of Epidemiology and Population Sciences, National Institute of Aging, Bethesda, MD, USA., Liu J; Brigham and Women's Hospital, Havard University, Boston, MA, USA., Mosley TH; Department of Medicine, Division of Geriatrics, University of Mississippi Medical Center, Jackson, MS, USA., Norris JM; Department of Preventive Medicine and Biometrics, University of Colorado at Denver Health Sciences Center, Aurora, CO, USA., Terry JG; Department of Radiology, Vanderbilt University School of Medicine, Nashville, TN, USA., Palanisamy N; Department of Urology, Henry Ford Health System, Detroit, MI, USA., Schadt EE; Department of Genetics and Genomics Sciences, Icahn School of Medicine, New York, NY, USA., O'Donnell CJ; Framingham Heart Study, NHLBI, NIH, Framingham, MA, USA.; Cardiology Section, Department of Medicine, Boston Veteran's Administration Healthcare, Boston, MA, USA., Yerges-Armstrong LM; Department of Endocrinology, Diabetes, and Nutrition, University of Maryland-Baltimore, Baltimore, MD, USA.; Target Sciences, GlaxoSmithKline, Collegeville, PA, USA., Rotter JI; Institute for Translational Genomics and Population Sciences, LABioMed and Department of Pediatrics at Harbor-UCLA, Torrance, CA, USA., Wagenknecht LE; Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA., Handelman SK; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA., Gudnason V; Icelandic Heart Association, Kopavogur, Iceland.; Department of Medicine, University of Iceland, Reykjavik, Iceland., Province MA; Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA., Peyser PA; School of Public Health, Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA., Halligan B; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA., Palmer ND; Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA., Speliotes EK; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA. |
المصدر: | The Journal of clinical endocrinology and metabolism [J Clin Endocrinol Metab] 2021 Jan 23; Vol. 106 (2), pp. 372-387. |
نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: Oxford University Press Country of Publication: United States NLM ID: 0375362 Publication Model: Print Cited Medium: Internet ISSN: 1945-7197 (Electronic) Linking ISSN: 0021972X NLM ISO Abbreviation: J Clin Endocrinol Metab Subsets: MEDLINE |
أسماء مطبوعة: | Publication: 2017- : New York : Oxford University Press Original Publication: Springfield, Ill. : Charles C. Thomas |
مواضيع طبية MeSH: | Polymorphism, Single Nucleotide*, Glycogen Storage Disease/*etiology , Liver Glycogen/*metabolism , Metabolic Syndrome/*etiology , Myocardial Infarction/*prevention & control , Protein Phosphatase 1/*genetics, Adult ; Aged ; Biomarkers/analysis ; Female ; Follow-Up Studies ; Glycogen Storage Disease/metabolism ; Glycogen Storage Disease/pathology ; Humans ; Male ; Metabolic Syndrome/metabolism ; Metabolic Syndrome/pathology ; Middle Aged ; Myocardial Infarction/genetics ; Myocardial Infarction/pathology ; Prognosis ; Prospective Studies |
مستخلص: | Context: Glycogen storage diseases are rare. Increased glycogen in the liver results in increased attenuation. Objective: Investigate the association and function of a noncoding region associated with liver attenuation but not histologic nonalcoholic fatty liver disease. Design: Genetics of Obesity-associated Liver Disease Consortium. Setting: Population-based. Main Outcome: Computed tomography measured liver attenuation. Results: Carriers of rs4841132-A (frequency 2%-19%) do not show increased hepatic steatosis; they have increased liver attenuation indicative of increased glycogen deposition. rs4841132 falls in a noncoding RNA LOC157273 ~190 kb upstream of PPP1R3B. We demonstrate that rs4841132-A increases PPP1R3B through a cis genetic effect. Using CRISPR/Cas9 we engineered a 105-bp deletion including rs4841132-A in human hepatocarcinoma cells that increases PPP1R3B, decreases LOC157273, and increases glycogen perfectly mirroring the human disease. Overexpression of PPP1R3B or knockdown of LOC157273 increased glycogen but did not result in decreased LOC157273 or increased PPP1R3B, respectively, suggesting that the effects may not all occur via affecting RNA levels. Based on electronic health record (EHR) data, rs4841132-A associates with all components of the metabolic syndrome (MetS). However, rs4841132-A associated with decreased low-density lipoprotein (LDL) cholesterol and risk for myocardial infarction (MI). A metabolic signature for rs4841132-A includes increased glycine, lactate, triglycerides, and decreased acetoacetate and beta-hydroxybutyrate. Conclusions: These results show that rs4841132-A promotes a hepatic glycogen storage disease by increasing PPP1R3B and decreasing LOC157273. rs4841132-A promotes glycogen accumulation and development of MetS but lowers LDL cholesterol and risk for MI. These results suggest that elevated hepatic glycogen is one cause of MetS that does not invariably promote MI. (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.) |
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معلومات مُعتمدة: | HHSN268201500003C United States HL NHLBI NIH HHS; R01 HL061210 United States HL NHLBI NIH HHS; R01 HL087660 United States HL NHLBI NIH HHS; R01 HL071250 United States HL NHLBI NIH HHS; P30 DK056341 United States DK NIDDK NIH HHS; N01HC95164 United States HL NHLBI NIH HHS; N01HC95168 United States HL NHLBI NIH HHS; HHSN268201500003I United States HL NHLBI NIH HHS; UL1 TR001881 United States TR NCATS NIH HHS; R01 HL071258 United States HL NHLBI NIH HHS; N01WH22110 United States WH WHI NIH HHS; RC4 AG039029 United States AG NIA NIH HHS; UL1 RR033176 United States RR NCRR NIH HHS; R01 DK106621 United States DK NIDDK NIH HHS; N01HC95160 United States HL NHLBI NIH HHS; R01 HL071251 United States HL NHLBI NIH HHS; R01 HL071259 United States HL NHLBI NIH HHS; U01 AG009740 United States AG NIA NIH HHS; N01HC95163 United States HL NHLBI NIH HHS; HHSN268201500001C United States HL NHLBI NIH HHS; UL1 TR001079 United States TR NCATS NIH HHS; U10 HL054464 United States HL NHLBI NIH HHS; N01HC95169 United States HL NHLBI NIH HHS; N02HL64278 United States HL NHLBI NIH HHS; R01 HL060944 United States HL NHLBI NIH HHS; N01HC95162 United States HL NHLBI NIH HHS; U01 HL054464 United States HL NHLBI NIH HHS; U10 HL054457 United States HL NHLBI NIH HHS; U10 HL054481 United States HL NHLBI NIH HHS; P30 DK063491 United States DK NIDDK NIH HHS; R01 HL071051 United States HL NHLBI NIH HHS; U01 HL054457 United States HL NHLBI NIH HHS; R01 HL061019 United States HL NHLBI NIH HHS; N01HC95165 United States HL NHLBI NIH HHS; N01HC95159 United States HL NHLBI NIH HHS; HHSN268201500001I United States HL NHLBI NIH HHS; N01HC95161 United States HL NHLBI NIH HHS; UL1 TR001420 United States TR NCATS NIH HHS; R01 DK107904 United States DK NIDDK NIH HHS; R01 DK089256 United States DK NIDDK NIH HHS; N01HC95167 United States HL NHLBI NIH HHS; R01 HL060919 United States HL NHLBI NIH HHS; N01HC25195 United States HL NHLBI NIH HHS; R01 HL085571 United States HL NHLBI NIH HHS; R01 HL071205 United States HL NHLBI NIH HHS; U01 HL054481 United States HL NHLBI NIH HHS; UL1 TR000040 United States TR NCATS NIH HHS; RC2 AG036495 United States AG NIA NIH HHS; N01HC95166 United States HL NHLBI NIH HHS; R01 HL117078 United States HL NHLBI NIH HHS; R01 HL060894 United States HL NHLBI NIH HHS |
فهرسة مساهمة: | Keywords: GWAS; NALFD; genetics; glycogen; metabolic syndrome; triglyceride |
المشرفين على المادة: | 0 (Biomarkers) 0 (Liver Glycogen) EC 3.1.3.16 (PPP1R3B protein, human) EC 3.1.3.16 (Protein Phosphatase 1) |
تواريخ الأحداث: | Date Created: 20201124 Date Completed: 20210920 Latest Revision: 20240403 |
رمز التحديث: | 20240403 |
مُعرف محوري في PubMed: | PMC7823249 |
DOI: | 10.1210/clinem/dgaa855 |
PMID: | 33231259 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1945-7197 |
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DOI: | 10.1210/clinem/dgaa855 |