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A Noncoding Variant Near PPP1R3B Promotes Liver Glycogen Storage and MetS, but Protects Against Myocardial Infarction.
Kahali, Bratati; Chen, Yue; Feitosa, Mary F; Bielak, Lawrence F; O'Connell, Jeffrey R; Musani, Solomon K; Hegde, Yash; Chen, Yanhua; Stetson, L C; Guo, Xiuqing; Fu, Yi-Ping; Smith, Albert Vernon; Ryan, Kathleen A; Eiriksdottir, Gudny; Cohain, Ariella T; Allison, Matthew; Bakshi, Andrew; Bowden, Donald W; Budoff, Matthew J; Carr, J Jeffrey; Carskadon, Shannon; Chen, Yii-Der I; Correa, Adolfo; Crudup, Breland F; Du, Xiaomeng; Harris, Tamara B; Yang, Jian; Kardia, Sharon L R; Launer, Lenore J; Liu, Jiankang; Mosley, Thomas H; Norris, Jill M; Terry, James G; Palanisamy, Nallasivam; Schadt, Eric E; O'Donnell, Christopher J; Yerges-Armstrong, Laura M; Rotter, Jerome I; Wagenknecht, Lynne E; Handelman, Samuel K; Gudnason, Vilmundur; Province, Michael A; Peyser, Patricia A; Halligan, Brian; Palmer, Nicholette D; Speliotes, Elizabeth K.
Afiliação
  • Kahali B; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • Chen Y; Centre for Brain Research, Indian Institute of Science, Bangalore, India.
  • Feitosa MF; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • Bielak LF; Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
  • O'Connell JR; School of Public Health, Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA.
  • Musani SK; Department of Endocrinology, Diabetes, and Nutrition, University of Maryland-Baltimore, Baltimore, MD, USA.
  • Hegde Y; Department of Medicine, University of Mississippi Medical Center, Jackson, MS, 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; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • Fu YP; Institute for Translational Genomics and Population Sciences, LABioMed and Department of Pediatrics at Harbor-UCLA, Torrance, CA, USA.
  • Smith AV; Framingham Heart Study, NHLBI, NIH, Framingham, MA, USA.
  • Ryan KA; Office of Biostatistics Research, Division of Cardiovascular Diseases, NHLBI, NIH, Bethesda, MD, USA.
  • Eiriksdottir G; School of Public Health, Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
  • Cohain AT; Department of Endocrinology, Diabetes, and Nutrition, University of Maryland-Baltimore, Baltimore, MD, USA.
  • Allison M; Icelandic Heart Association, Kopavogur, Iceland.
  • Bakshi A; Department of Genetics and Genomics Sciences, Icahn School of Medicine, New York, NY, USA.
  • Bowden DW; Department of Family Medicine and Public Health, University of California, San Diego, CA, USA.
  • Budoff MJ; Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.
  • Carr JJ; Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
  • Carskadon S; Department of Internal Medicine, LA Biomedical Research Institute at Harbor-UCLA, Torrance, CA, USA.
  • Chen YI; Department of Radiology, Vanderbilt University School of Medicine, Nashville, TN, USA.
  • Correa A; Department of Urology, Henry Ford Health System, Detroit, MI, USA.
  • Crudup BF; Institute for Translational Genomics and Population Sciences, LABioMed and Department of Pediatrics at Harbor-UCLA, Torrance, CA, USA.
  • Du X; Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
  • Harris TB; Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
  • Yang J; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • Kardia SLR; Laboratory of Epidemiology and Population Sciences, National Institute of Aging, Bethesda, MD, USA.
  • Launer LJ; Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.
  • Liu J; Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
  • Mosley TH; School of Public Health, Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA.
  • Norris JM; Laboratory of Epidemiology and Population Sciences, National Institute of Aging, Bethesda, MD, USA.
  • Terry JG; Brigham and Women's Hospital, Havard University, Boston, MA, USA.
  • Palanisamy N; Department of Medicine, Division of Geriatrics, University of Mississippi Medical Center, Jackson, MS, USA.
  • Schadt EE; Department of Preventive Medicine and Biometrics, University of Colorado at Denver Health Sciences Center, Aurora, CO, USA.
  • O'Donnell CJ; Department of Radiology, Vanderbilt University School of Medicine, Nashville, TN, USA.
  • Yerges-Armstrong LM; Department of Urology, Henry Ford Health System, Detroit, MI, USA.
  • Rotter JI; Department of Genetics and Genomics Sciences, Icahn School of Medicine, New York, NY, USA.
  • Wagenknecht LE; Framingham Heart Study, NHLBI, NIH, Framingham, MA, USA.
  • Handelman SK; Cardiology Section, Department of Medicine, Boston Veteran's Administration Healthcare, Boston, MA, USA.
  • Gudnason V; Department of Endocrinology, Diabetes, and Nutrition, University of Maryland-Baltimore, Baltimore, MD, USA.
  • Province MA; Target Sciences, GlaxoSmithKline, Collegeville, PA, USA.
  • Peyser PA; Institute for Translational Genomics and Population Sciences, LABioMed and Department of Pediatrics at Harbor-UCLA, Torrance, CA, USA.
  • Halligan B; Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
  • Palmer ND; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • Speliotes EK; Icelandic Heart Association, Kopavogur, Iceland.
J Clin Endocrinol Metab ; 106(2): 372-387, 2021 01 23.
Article em En | MEDLINE | ID: mdl-33231259
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença de Depósito de Glicogênio / Polimorfismo de Nucleotídeo Único / Síndrome Metabólica / Proteína Fosfatase 1 / Glicogênio Hepático / Infarto do Miocárdio Tipo de estudo: Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Adult / Aged / Female / Humans / Male / Middle aged Idioma: En Revista: J Clin Endocrinol Metab Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença de Depósito de Glicogênio / Polimorfismo de Nucleotídeo Único / Síndrome Metabólica / Proteína Fosfatase 1 / Glicogênio Hepático / Infarto do Miocárdio Tipo de estudo: Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Adult / Aged / Female / Humans / Male / Middle aged Idioma: En Revista: J Clin Endocrinol Metab Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos