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

TitleA Noncoding Variant Near PPP1R3B Promotes Liver Glycogen Storage and MetS, but Protects Against Myocardial Infarction.
Publication TypeJournal Article
Year of Publication2021
AuthorsKahali B, Chen Y, Feitosa MF, Bielak LF, O'Connell JR, Musani SK, Hegde Y, Chen Y, Stetson LC, Guo X, Fu Y-P, Smith A V, Ryan KA, Eiriksdottir G, Cohain AT, Allison M, Bakshi A, Bowden DW, Budoff MJ, J Carr J, Carskadon S, Chen Y-DI, Correa A, Crudup BF, Du X, Harris TB, Yang J, Kardia SLR, Launer LJ, Liu J, Mosley TH, Norris JM, Terry JG, Palanisamy N, Schadt EE, O'Donnell CJ, Yerges-Armstrong LM, Rotter JI, Wagenknecht LE, Handelman SK, Gudnason V, Province MA, Peyser PA, Halligan B, Palmer ND, Speliotes EK
JournalJ Clin Endocrinol Metab
Volume106
Issue2
Pagination372-387
Date Published2021 01 23
ISSN1945-7197
KeywordsAdult, Aged, Biomarkers, Female, Follow-Up Studies, Glycogen Storage Disease, Humans, Liver Glycogen, Male, Metabolic Syndrome, Middle Aged, Myocardial Infarction, Polymorphism, Single Nucleotide, Prognosis, Prospective Studies, Protein Phosphatase 1
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.

DOI10.1210/clinem/dgaa855
Alternate JournalJ Clin Endocrinol Metab
PubMed ID33231259
PubMed Central IDPMC7823249
Grant ListHHSN268201500003C / HL / NHLBI NIH HHS / United States
R01 HL061210 / HL / NHLBI NIH HHS / United States
R01 HL087660 / HL / NHLBI NIH HHS / United States
R01 HL071250 / HL / NHLBI NIH HHS / United States
N01HC95164 / HL / NHLBI NIH HHS / United States
N01HC95168 / HL / NHLBI NIH HHS / United States
HHSN268201500003I / HL / NHLBI NIH HHS / United States
UL1 TR001881 / TR / NCATS NIH HHS / United States
R01 HL071258 / HL / NHLBI NIH HHS / United States
N01WH22110 / WH / WHI NIH HHS / United States
RC4 AG039029 / AG / NIA NIH HHS / United States
UL1 RR033176 / RR / NCRR NIH HHS / United States
R01 DK106621 / DK / NIDDK NIH HHS / United States
N01HC95160 / HL / NHLBI NIH HHS / United States
R01 HL071251 / HL / NHLBI NIH HHS / United States
R01 HL071259 / HL / NHLBI NIH HHS / United States
U01 AG009740 / AG / NIA NIH HHS / United States
N01HC95163 / HL / NHLBI NIH HHS / United States
HHSN268201500001C / HL / NHLBI NIH HHS / United States
UL1 TR001079 / TR / NCATS NIH HHS / United States
U10 HL054464 / HL / NHLBI NIH HHS / United States
N01HC95169 / HL / NHLBI NIH HHS / United States
N02HL64278 / HL / NHLBI NIH HHS / United States
R01 HL060944 / HL / NHLBI NIH HHS / United States
N01HC95162 / HL / NHLBI NIH HHS / United States
U01 HL054464 / HL / NHLBI NIH HHS / United States
U10 HL054457 / HL / NHLBI NIH HHS / United States
U10 HL054481 / HL / NHLBI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
R01 HL071051 / HL / NHLBI NIH HHS / United States
U01 HL054457 / HL / NHLBI NIH HHS / United States
R01 HL061019 / HL / NHLBI NIH HHS / United States
N01HC95165 / HL / NHLBI NIH HHS / United States
N01HC95159 / HL / NHLBI NIH HHS / United States
HHSN268201500001I / HL / NHLBI NIH HHS / United States
N01HC95161 / HL / NHLBI NIH HHS / United States
UL1 TR001420 / TR / NCATS NIH HHS / United States
R01 DK107904 / DK / NIDDK NIH HHS / United States
R01 DK089256 / DK / NIDDK NIH HHS / United States
N01HC95167 / HL / NHLBI NIH HHS / United States
R01 HL060919 / HL / NHLBI NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
R01 HL085571 / HL / NHLBI NIH HHS / United States
R01 HL071205 / HL / NHLBI NIH HHS / United States
U01 HL054481 / HL / NHLBI NIH HHS / United States
UL1 TR000040 / TR / NCATS NIH HHS / United States
RC2 AG036495 / AG / NIA NIH HHS / United States
N01HC95166 / HL / NHLBI NIH HHS / United States
R01 HL117078 / HL / NHLBI NIH HHS / United States
R01 HL060894 / HL / NHLBI NIH HHS / United States