A Noncoding Variant near PPP1R3B Promotes Liver Glycogen Storage and MetS, but Protects against Myocardial Infarction

Bratati Kahali, Yue Chen, Mary F. Feitosa, Lawrence F. Bielak, Jeffrey R. Oconnell, Solomon K. Musani, Yash Hegde, Yanhua Chen, L. C. Stetson, Xiuqing Guo, Yi Ping Fu, Albert Vernon Smith, Kathleen A. Ryan, Gudny Eiriksdottir, Ariella T. Cohain, Matthew Allison, Andrew Bakshi, Donald W. Bowden, Matthew J. Budoff, J. Jeffrey CarrShannon Carskadon, Yii Der I. Chen, Adolfo Correa, Breland F. Crudup, Xiaomeng Du, Tamara B. Harris, Jian Yang, Sharon L.R. Kardia, Lenore J. Launer, Jiankang Liu, Thomas H. Mosley, Jill M. Norris, James G. Terry, Nallasivam Palanisamy, Eric E. Schadt, Christopher J. O'Donnell, Laura M. Yerges-Armstrong, Jerome I. Rotter, Lynne E. Wagenknecht, Samuel K. Handelman, Vilmundur Gudnason, Michael A. Province, Patricia A. Peyser, Brian Halligan, Nicholette D. Palmer, Elizabeth K. Speliotes

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish
Pages (from-to)372-387
Number of pages16
JournalJournal of Clinical Endocrinology and Metabolism
Volume106
Issue number2
DOIs
StatePublished - Feb 1 2021

Keywords

  • GWAS
  • NALFD
  • genetics
  • glycogen
  • metabolic syndrome
  • triglyceride

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