Bratati Kahali1,2, Yue Chen1, Mary F Feitosa3, Lawrence F Bielak4, Jeffrey R O'Connell5, Solomon K Musani6, Yash Hegde1, Yanhua Chen1, L C Stetson1, Xiuqing Guo7, Yi-Ping Fu8,9, Albert Vernon Smith10, Kathleen A Ryan5, Gudny Eiriksdottir11, Ariella T Cohain12, Matthew Allison13, Andrew Bakshi14, Donald W Bowden15, Matthew J Budoff16, J Jeffrey Carr17, Shannon Carskadon18, Yii-Der I Chen7, Adolfo Correa6, Breland F Crudup6, Xiaomeng Du1, Tamara B Harris19, Jian Yang14,20, Sharon L R Kardia4, Lenore J Launer19, Jiankang Liu21, Thomas H Mosley22, Jill M Norris23, James G Terry17, Nallasivam Palanisamy18, Eric E Schadt12, Christopher J O'Donnell8,24, Laura M Yerges-Armstrong5,25, Jerome I Rotter7, Lynne E Wagenknecht26, Samuel K Handelman1, Vilmundur Gudnason11,27, Michael A Province3, Patricia A Peyser4, Brian Halligan1, Nicholette D Palmer15, Elizabeth K Speliotes1,28. 1. Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA. 2. Centre for Brain Research, Indian Institute of Science, Bangalore, India. 3. Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA. 4. School of Public Health, Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA. 5. Department of Endocrinology, Diabetes, and Nutrition, University of Maryland-Baltimore, Baltimore, MD, USA. 6. Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA. 7. Institute for Translational Genomics and Population Sciences, LABioMed and Department of Pediatrics at Harbor-UCLA, Torrance, CA, USA. 8. Framingham Heart Study, NHLBI, NIH, Framingham, MA, USA. 9. Office of Biostatistics Research, Division of Cardiovascular Diseases, NHLBI, NIH, Bethesda, MD, USA. 10. School of Public Health, Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA. 11. Icelandic Heart Association, Kopavogur, Iceland. 12. Department of Genetics and Genomics Sciences, Icahn School of Medicine, New York, NY, USA. 13. Department of Family Medicine and Public Health, University of California, San Diego, CA, USA. 14. Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia. 15. Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA. 16. Department of Internal Medicine, LA Biomedical Research Institute at Harbor-UCLA, Torrance, CA, USA. 17. Department of Radiology, Vanderbilt University School of Medicine, Nashville, TN, USA. 18. Department of Urology, Henry Ford Health System, Detroit, MI, USA. 19. Laboratory of Epidemiology and Population Sciences, National Institute of Aging, Bethesda, MD, USA. 20. Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia. 21. Brigham and Women's Hospital, Havard University, Boston, MA, USA. 22. Department of Medicine, Division of Geriatrics, University of Mississippi Medical Center, Jackson, MS, USA. 23. Department of Preventive Medicine and Biometrics, University of Colorado at Denver Health Sciences Center, Aurora, CO, USA. 24. Cardiology Section, Department of Medicine, Boston Veteran's Administration Healthcare, Boston, MA, USA. 25. Target Sciences, GlaxoSmithKline, Collegeville, PA, USA. 26. Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA. 27. Department of Medicine, University of Iceland, Reykjavik, Iceland. 28. Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
Abstract
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.
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.
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