A Noncoding Variant Near PPP1R3B Promotes Liver Glycogen Storage and MetS, but Protects Against Myocardial Infarction-Reference-Cited by-同舟云学术

A Noncoding Variant Near PPP1R3B Promotes Liver Glycogen Storage and MetS, but Protects Against Myocardial Infarction

Published:2020-11-24 Issue:2 Volume:106 Page:372-387
ISSN:0021-972X
Container-title:The Journal of Clinical Endocrinology & Metabolism
language:en
Short-container-title:

Author:

Kahali Bratati¹²,Chen Yue¹,Feitosa Mary F³,Bielak Lawrence F⁴,O’Connell Jeffrey R⁵,Musani Solomon K⁶,Hegde Yash¹,Chen Yanhua¹,Stetson L C¹,Guo Xiuqing⁷,Fu Yi-ping⁸⁹,Smith Albert Vernon¹⁰,Ryan Kathleen A⁵,Eiriksdottir Gudny¹¹^ORCID,Cohain Ariella T¹²,Allison Matthew¹³,Bakshi Andrew¹⁴,Bowden Donald W¹⁵,Budoff Matthew J¹⁶,Carr J Jeffrey¹⁷,Carskadon Shannon¹⁸,Chen Yii-Der I⁷,Correa Adolfo⁶,Crudup Breland F⁶,Du Xiaomeng¹,Harris Tamara B¹⁹,Yang Jian¹⁴²⁰,Kardia Sharon L R⁴,Launer Lenore J¹⁹,Liu Jiankang²¹,Mosley Thomas H²²,Norris Jill M²³,Terry James G¹⁷,Palanisamy Nallasivam¹⁸,Schadt Eric E¹²,O’Donnell Christopher J⁸²⁴,Yerges-Armstrong Laura M⁵²⁵,Rotter Jerome I⁷,Wagenknecht Lynne E²⁶,Handelman Samuel K¹,Gudnason Vilmundur¹¹²⁷,Province Michael A³,Peyser Patricia A⁴,Halligan Brian¹,Palmer Nicholette D¹⁵^ORCID,Speliotes Elizabeth K¹²⁸

Affiliation:

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

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.

Funder

National Institutes of Health

National Center for Research Resources

National Center for Advancing Translational Sciences

U.S. Department of Health and Human Services

National Heart, Lung and Blood Institute

University of Michigan Department of Internal Medicine

Publisher

The Endocrine Society

Subject

Biochemistry (medical),Clinical Biochemistry,Endocrinology,Biochemistry,Endocrinology, Diabetes and Metabolism

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