A noncoding variant near PPP1R3B promotes liver glycogen storage and MetS, but protects against myocardial infarction
Kahali B, Chen Y, Feitosa MF, Bielak LF, O'Connell JR, Musani SK, Hegde Y, Chen Y, Stetson LC, Guo X, Fu YP, Smith AV, Ryan KA, Eiriksdottir G, Cohain AT, Allison M, Bakshi A, Bowden DW, Budoff MJ, Carr JJ, Carskadon S, Chen YI, 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, and Speliotes EK. A noncoding variant near PPP1R3B promotes liver glycogen storage and MetS, but protects against myocardial infarction. J Clin Endocrinol Metab 2020.
The Journal of clinical endocrinology and metabolism
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 ~190kb upstream of PPP1R3B. We demonstrate that rs4841132-A increases PPP1R3B through a cis genetic effect. Using CRISPR/Cas9 we engineered a 105bp deletion including rs4841132-A in human hepatocarcinoma cells which 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 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.
ePub ahead of print