A Noncoding Variant Near PPP1R3B Promotes Liver Glycogen Storage and MetS, but Protects Against Myocardial Infarction
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 Ob...
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| creator | 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 |
| description | 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. |
| doi_str_mv | 10.1210/clinem/dgaa855 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_pubme</sourceid><recordid>TN_cdi_gale_infotracmisc_A702287704</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A702287704</galeid><oup_id>10.1210/clinem/dgaa855</oup_id><sourcerecordid>A702287704</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4708-966aa8a639d4df3f7800964c69efbf4701572f6af1b769cc6cc4cb3032ddc72b3</originalsourceid><addsrcrecordid>eNqFks1vFCEYxidGY2v16tGQeNHotnwNDJcma6O1ybZurBpvhGFgpJmBFZia_e9ls-v6kSaGAwR-z_PywlNVTxE8RhjBEz04b8aTrleqqet71SEStJ5xJPj96hBCjGaC468H1aOUbiBElNbkYXVACCYI1-KwmubgKngdOud78EVFp3wGV0ZFsFwu0UfyBixjGEM2CSzcrYngfFjr0BsPrnOIqjdA-Q5cmnz9GrRT3tDZ6JzAvFfOpwwu10Gr2Dk1gAtvVdTZBf-4emDVkMyT3XxUfX739tPZ-9niw_nF2Xwx05TDZiYYK20pRkRHO0ssbyAUjGomjG1tQVDNsWXKopYzoTXTmuqWQIK7TnPckqPqdOu7mtrRdNr4HNUgV9GNKq5lUE7-feLdN9mHW8kbTDAVxeDFziCG75NJWY4uaTMMypswJYkpo4gKKHhBn_-D3oQp-tKexKJmiJTPaH5TvRqMdN6GUldvTOWcQ4wbziEt1PEdVBmdGZ0O3lhX9u8S6BhSisbue0RQboIit0GRu6AUwaut4Idpg03aGa_NXgQhZIQTXJOygptbP_vzHffcrxwV4OUWCNPqf6V_AozI1ks</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2956130218</pqid></control><display><type>article</type><title>A Noncoding Variant Near PPP1R3B Promotes Liver Glycogen Storage and MetS, but Protects Against Myocardial Infarction</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Oxford University Press Journals All Titles (1996-Current)</source><source>Web of Science - Science Citation Index Expanded - 2021<img src="https://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /></source><source>Alma/SFX Local Collection</source><creator>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</creator><creatorcontrib>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</creatorcontrib><description>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.</description><identifier>ISSN: 0021-972X</identifier><identifier>EISSN: 1945-7197</identifier><identifier>DOI: 10.1210/clinem/dgaa855</identifier><identifier>PMID: 33231259</identifier><language>eng</language><publisher>US: Oxford University Press</publisher><subject>Adult ; Aged ; Antisense RNA ; Biomarkers - analysis ; Cholesterol ; Clinical s ; Computed tomography ; CRISPR ; Electronic health records ; Electronic medical records ; Endocrinology & Metabolism ; Fatty liver ; Female ; Follow-Up Studies ; Gene deletion ; Glycogen ; Glycogen Storage Disease - etiology ; Glycogen Storage Disease - metabolism ; Glycogen Storage Disease - pathology ; Glycogenosis ; Heart attack ; Heart attacks ; Hepatocellular carcinoma ; Humans ; Life Sciences & Biomedicine ; Liver diseases ; Liver Glycogen - metabolism ; Low density lipoproteins ; Male ; Medical records ; Metabolic syndrome ; Metabolic Syndrome - etiology ; Metabolic Syndrome - metabolism ; Metabolic Syndrome - pathology ; Metabolism ; Middle Aged ; Myocardial infarction ; Myocardial Infarction - genetics ; Myocardial Infarction - pathology ; Myocardial Infarction - prevention & control ; Polymorphism, Single Nucleotide ; Prognosis ; Prospective Studies ; Protein Phosphatase 1 - genetics ; Science & Technology ; Scientific equipment and supplies industry ; Steatosis ; Storage diseases ; Trans fatty acids ; Triglycerides</subject><ispartof>The journal of clinical endocrinology and metabolism, 2021-02, Vol.106 (2), p.372-387</ispartof><rights>The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com 2020</rights><rights>The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.</rights><rights>COPYRIGHT 2021 Oxford University Press</rights><rights>The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>true</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4708-966aa8a639d4df3f7800964c69efbf4701572f6af1b769cc6cc4cb3032ddc72b3</citedby><cites>FETCH-LOGICAL-c4708-966aa8a639d4df3f7800964c69efbf4701572f6af1b769cc6cc4cb3032ddc72b3</cites><orcidid>0000-0002-8197-0652 ; 0000-0001-8883-2511 ; 0000-0001-6659-3441 ; 0000-0001-5696-0084 ; 0000-0003-2001-2474 ; 0000-0002-0633-9772 ; 0000-0003-1942-5845</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,782,786,887,27933,27934,39267</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33231259$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kahali, Bratati</creatorcontrib><creatorcontrib>Chen, Yue</creatorcontrib><creatorcontrib>Feitosa, Mary F</creatorcontrib><creatorcontrib>Bielak, Lawrence F</creatorcontrib><creatorcontrib>O’Connell, Jeffrey R</creatorcontrib><creatorcontrib>Musani, Solomon K</creatorcontrib><creatorcontrib>Hegde, Yash</creatorcontrib><creatorcontrib>Chen, Yanhua</creatorcontrib><creatorcontrib>Stetson, L C</creatorcontrib><creatorcontrib>Guo, Xiuqing</creatorcontrib><creatorcontrib>Fu, Yi-ping</creatorcontrib><creatorcontrib>Smith, Albert Vernon</creatorcontrib><creatorcontrib>Ryan, Kathleen A</creatorcontrib><creatorcontrib>Eiriksdottir, Gudny</creatorcontrib><creatorcontrib>Cohain, Ariella T</creatorcontrib><creatorcontrib>Allison, Matthew</creatorcontrib><creatorcontrib>Bakshi, Andrew</creatorcontrib><creatorcontrib>Bowden, Donald W</creatorcontrib><creatorcontrib>Budoff, Matthew J</creatorcontrib><creatorcontrib>Carr, J Jeffrey</creatorcontrib><creatorcontrib>Carskadon, Shannon</creatorcontrib><creatorcontrib>Chen, Yii-Der I</creatorcontrib><creatorcontrib>Correa, Adolfo</creatorcontrib><creatorcontrib>Crudup, Breland F</creatorcontrib><creatorcontrib>Du, Xiaomeng</creatorcontrib><creatorcontrib>Harris, Tamara B</creatorcontrib><creatorcontrib>Yang, Jian</creatorcontrib><creatorcontrib>Kardia, Sharon L R</creatorcontrib><creatorcontrib>Launer, Lenore J</creatorcontrib><creatorcontrib>Liu, Jiankang</creatorcontrib><creatorcontrib>Mosley, Thomas H</creatorcontrib><creatorcontrib>Norris, Jill M</creatorcontrib><creatorcontrib>Terry, James G</creatorcontrib><creatorcontrib>Palanisamy, Nallasivam</creatorcontrib><creatorcontrib>Schadt, Eric E</creatorcontrib><creatorcontrib>O’Donnell, Christopher J</creatorcontrib><creatorcontrib>Yerges-Armstrong, Laura M</creatorcontrib><creatorcontrib>Rotter, Jerome I</creatorcontrib><creatorcontrib>Wagenknecht, Lynne E</creatorcontrib><creatorcontrib>Handelman, Samuel K</creatorcontrib><creatorcontrib>Gudnason, Vilmundur</creatorcontrib><creatorcontrib>Province, Michael A</creatorcontrib><creatorcontrib>Peyser, Patricia A</creatorcontrib><creatorcontrib>Halligan, Brian</creatorcontrib><creatorcontrib>Palmer, Nicholette D</creatorcontrib><creatorcontrib>Speliotes, Elizabeth K</creatorcontrib><title>A Noncoding Variant Near PPP1R3B Promotes Liver Glycogen Storage and MetS, but Protects Against Myocardial Infarction</title><title>The journal of clinical endocrinology and metabolism</title><addtitle>J CLIN ENDOCR METAB</addtitle><addtitle>J Clin Endocrinol Metab</addtitle><description>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.</description><subject>Adult</subject><subject>Aged</subject><subject>Antisense RNA</subject><subject>Biomarkers - analysis</subject><subject>Cholesterol</subject><subject>Clinical s</subject><subject>Computed tomography</subject><subject>CRISPR</subject><subject>Electronic health records</subject><subject>Electronic medical records</subject><subject>Endocrinology & Metabolism</subject><subject>Fatty liver</subject><subject>Female</subject><subject>Follow-Up Studies</subject><subject>Gene deletion</subject><subject>Glycogen</subject><subject>Glycogen Storage Disease - etiology</subject><subject>Glycogen Storage Disease - metabolism</subject><subject>Glycogen Storage Disease - pathology</subject><subject>Glycogenosis</subject><subject>Heart attack</subject><subject>Heart attacks</subject><subject>Hepatocellular carcinoma</subject><subject>Humans</subject><subject>Life Sciences & Biomedicine</subject><subject>Liver diseases</subject><subject>Liver Glycogen - metabolism</subject><subject>Low density lipoproteins</subject><subject>Male</subject><subject>Medical records</subject><subject>Metabolic syndrome</subject><subject>Metabolic Syndrome - etiology</subject><subject>Metabolic Syndrome - metabolism</subject><subject>Metabolic Syndrome - pathology</subject><subject>Metabolism</subject><subject>Middle Aged</subject><subject>Myocardial infarction</subject><subject>Myocardial Infarction - genetics</subject><subject>Myocardial Infarction - pathology</subject><subject>Myocardial Infarction - prevention & control</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Prognosis</subject><subject>Prospective Studies</subject><subject>Protein Phosphatase 1 - genetics</subject><subject>Science & Technology</subject><subject>Scientific equipment and supplies industry</subject><subject>Steatosis</subject><subject>Storage diseases</subject><subject>Trans fatty acids</subject><subject>Triglycerides</subject><issn>0021-972X</issn><issn>1945-7197</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>HGBXW</sourceid><recordid>eNqFks1vFCEYxidGY2v16tGQeNHotnwNDJcma6O1ybZurBpvhGFgpJmBFZia_e9ls-v6kSaGAwR-z_PywlNVTxE8RhjBEz04b8aTrleqqet71SEStJ5xJPj96hBCjGaC468H1aOUbiBElNbkYXVACCYI1-KwmubgKngdOud78EVFp3wGV0ZFsFwu0UfyBixjGEM2CSzcrYngfFjr0BsPrnOIqjdA-Q5cmnz9GrRT3tDZ6JzAvFfOpwwu10Gr2Dk1gAtvVdTZBf-4emDVkMyT3XxUfX739tPZ-9niw_nF2Xwx05TDZiYYK20pRkRHO0ssbyAUjGomjG1tQVDNsWXKopYzoTXTmuqWQIK7TnPckqPqdOu7mtrRdNr4HNUgV9GNKq5lUE7-feLdN9mHW8kbTDAVxeDFziCG75NJWY4uaTMMypswJYkpo4gKKHhBn_-D3oQp-tKexKJmiJTPaH5TvRqMdN6GUldvTOWcQ4wbziEt1PEdVBmdGZ0O3lhX9u8S6BhSisbue0RQboIit0GRu6AUwaut4Idpg03aGa_NXgQhZIQTXJOygptbP_vzHffcrxwV4OUWCNPqf6V_AozI1ks</recordid><startdate>20210201</startdate><enddate>20210201</enddate><creator>Kahali, Bratati</creator><creator>Chen, Yue</creator><creator>Feitosa, Mary F</creator><creator>Bielak, Lawrence F</creator><creator>O’Connell, Jeffrey R</creator><creator>Musani, Solomon K</creator><creator>Hegde, Yash</creator><creator>Chen, Yanhua</creator><creator>Stetson, L C</creator><creator>Guo, Xiuqing</creator><creator>Fu, Yi-ping</creator><creator>Smith, Albert Vernon</creator><creator>Ryan, Kathleen A</creator><creator>Eiriksdottir, Gudny</creator><creator>Cohain, Ariella T</creator><creator>Allison, Matthew</creator><creator>Bakshi, Andrew</creator><creator>Bowden, Donald W</creator><creator>Budoff, Matthew J</creator><creator>Carr, J Jeffrey</creator><creator>Carskadon, Shannon</creator><creator>Chen, Yii-Der I</creator><creator>Correa, Adolfo</creator><creator>Crudup, Breland F</creator><creator>Du, Xiaomeng</creator><creator>Harris, Tamara B</creator><creator>Yang, Jian</creator><creator>Kardia, Sharon L R</creator><creator>Launer, Lenore J</creator><creator>Liu, Jiankang</creator><creator>Mosley, Thomas H</creator><creator>Norris, Jill M</creator><creator>Terry, James G</creator><creator>Palanisamy, Nallasivam</creator><creator>Schadt, Eric E</creator><creator>O’Donnell, Christopher J</creator><creator>Yerges-Armstrong, Laura M</creator><creator>Rotter, Jerome I</creator><creator>Wagenknecht, Lynne E</creator><creator>Handelman, Samuel K</creator><creator>Gudnason, Vilmundur</creator><creator>Province, Michael A</creator><creator>Peyser, Patricia A</creator><creator>Halligan, Brian</creator><creator>Palmer, Nicholette D</creator><creator>Speliotes, Elizabeth K</creator><general>Oxford University Press</general><general>Endocrine Soc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>BLEPL</scope><scope>DTL</scope><scope>HGBXW</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7T5</scope><scope>7TM</scope><scope>H94</scope><scope>K9.</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-8197-0652</orcidid><orcidid>https://orcid.org/0000-0001-8883-2511</orcidid><orcidid>https://orcid.org/0000-0001-6659-3441</orcidid><orcidid>https://orcid.org/0000-0001-5696-0084</orcidid><orcidid>https://orcid.org/0000-0003-2001-2474</orcidid><orcidid>https://orcid.org/0000-0002-0633-9772</orcidid><orcidid>https://orcid.org/0000-0003-1942-5845</orcidid></search><sort><creationdate>20210201</creationdate><title>A Noncoding Variant Near PPP1R3B Promotes Liver Glycogen Storage and MetS, but Protects Against Myocardial Infarction</title><author>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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4708-966aa8a639d4df3f7800964c69efbf4701572f6af1b769cc6cc4cb3032ddc72b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Antisense RNA</topic><topic>Biomarkers - analysis</topic><topic>Cholesterol</topic><topic>Clinical s</topic><topic>Computed tomography</topic><topic>CRISPR</topic><topic>Electronic health records</topic><topic>Electronic medical records</topic><topic>Endocrinology & Metabolism</topic><topic>Fatty liver</topic><topic>Female</topic><topic>Follow-Up Studies</topic><topic>Gene deletion</topic><topic>Glycogen</topic><topic>Glycogen Storage Disease - etiology</topic><topic>Glycogen Storage Disease - metabolism</topic><topic>Glycogen Storage Disease - pathology</topic><topic>Glycogenosis</topic><topic>Heart attack</topic><topic>Heart attacks</topic><topic>Hepatocellular carcinoma</topic><topic>Humans</topic><topic>Life Sciences & Biomedicine</topic><topic>Liver diseases</topic><topic>Liver Glycogen - metabolism</topic><topic>Low density lipoproteins</topic><topic>Male</topic><topic>Medical records</topic><topic>Metabolic syndrome</topic><topic>Metabolic Syndrome - etiology</topic><topic>Metabolic Syndrome - metabolism</topic><topic>Metabolic Syndrome - pathology</topic><topic>Metabolism</topic><topic>Middle Aged</topic><topic>Myocardial infarction</topic><topic>Myocardial Infarction - genetics</topic><topic>Myocardial Infarction - pathology</topic><topic>Myocardial Infarction - prevention & control</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Prognosis</topic><topic>Prospective Studies</topic><topic>Protein Phosphatase 1 - genetics</topic><topic>Science & Technology</topic><topic>Scientific equipment and supplies industry</topic><topic>Steatosis</topic><topic>Storage diseases</topic><topic>Trans fatty acids</topic><topic>Triglycerides</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kahali, Bratati</creatorcontrib><creatorcontrib>Chen, Yue</creatorcontrib><creatorcontrib>Feitosa, Mary F</creatorcontrib><creatorcontrib>Bielak, Lawrence F</creatorcontrib><creatorcontrib>O’Connell, Jeffrey R</creatorcontrib><creatorcontrib>Musani, Solomon K</creatorcontrib><creatorcontrib>Hegde, Yash</creatorcontrib><creatorcontrib>Chen, Yanhua</creatorcontrib><creatorcontrib>Stetson, L C</creatorcontrib><creatorcontrib>Guo, Xiuqing</creatorcontrib><creatorcontrib>Fu, Yi-ping</creatorcontrib><creatorcontrib>Smith, Albert Vernon</creatorcontrib><creatorcontrib>Ryan, Kathleen A</creatorcontrib><creatorcontrib>Eiriksdottir, Gudny</creatorcontrib><creatorcontrib>Cohain, Ariella T</creatorcontrib><creatorcontrib>Allison, Matthew</creatorcontrib><creatorcontrib>Bakshi, Andrew</creatorcontrib><creatorcontrib>Bowden, Donald W</creatorcontrib><creatorcontrib>Budoff, Matthew J</creatorcontrib><creatorcontrib>Carr, J Jeffrey</creatorcontrib><creatorcontrib>Carskadon, Shannon</creatorcontrib><creatorcontrib>Chen, Yii-Der I</creatorcontrib><creatorcontrib>Correa, Adolfo</creatorcontrib><creatorcontrib>Crudup, Breland F</creatorcontrib><creatorcontrib>Du, Xiaomeng</creatorcontrib><creatorcontrib>Harris, Tamara B</creatorcontrib><creatorcontrib>Yang, Jian</creatorcontrib><creatorcontrib>Kardia, Sharon L R</creatorcontrib><creatorcontrib>Launer, Lenore J</creatorcontrib><creatorcontrib>Liu, Jiankang</creatorcontrib><creatorcontrib>Mosley, Thomas H</creatorcontrib><creatorcontrib>Norris, Jill M</creatorcontrib><creatorcontrib>Terry, James G</creatorcontrib><creatorcontrib>Palanisamy, Nallasivam</creatorcontrib><creatorcontrib>Schadt, Eric E</creatorcontrib><creatorcontrib>O’Donnell, Christopher J</creatorcontrib><creatorcontrib>Yerges-Armstrong, Laura M</creatorcontrib><creatorcontrib>Rotter, Jerome I</creatorcontrib><creatorcontrib>Wagenknecht, Lynne E</creatorcontrib><creatorcontrib>Handelman, Samuel K</creatorcontrib><creatorcontrib>Gudnason, Vilmundur</creatorcontrib><creatorcontrib>Province, Michael A</creatorcontrib><creatorcontrib>Peyser, Patricia A</creatorcontrib><creatorcontrib>Halligan, Brian</creatorcontrib><creatorcontrib>Palmer, Nicholette D</creatorcontrib><creatorcontrib>Speliotes, Elizabeth K</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>Web of Science Core Collection</collection><collection>Science Citation Index Expanded</collection><collection>Web of Science - Science Citation Index Expanded - 2021</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The journal of clinical endocrinology and metabolism</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kahali, Bratati</au><au>Chen, Yue</au><au>Feitosa, Mary F</au><au>Bielak, Lawrence F</au><au>O’Connell, Jeffrey R</au><au>Musani, Solomon K</au><au>Hegde, Yash</au><au>Chen, Yanhua</au><au>Stetson, L C</au><au>Guo, Xiuqing</au><au>Fu, Yi-ping</au><au>Smith, Albert Vernon</au><au>Ryan, Kathleen A</au><au>Eiriksdottir, Gudny</au><au>Cohain, Ariella T</au><au>Allison, Matthew</au><au>Bakshi, Andrew</au><au>Bowden, Donald W</au><au>Budoff, Matthew J</au><au>Carr, J Jeffrey</au><au>Carskadon, Shannon</au><au>Chen, Yii-Der I</au><au>Correa, Adolfo</au><au>Crudup, Breland F</au><au>Du, Xiaomeng</au><au>Harris, Tamara B</au><au>Yang, Jian</au><au>Kardia, Sharon L R</au><au>Launer, Lenore J</au><au>Liu, Jiankang</au><au>Mosley, Thomas H</au><au>Norris, Jill M</au><au>Terry, James G</au><au>Palanisamy, Nallasivam</au><au>Schadt, Eric E</au><au>O’Donnell, Christopher J</au><au>Yerges-Armstrong, Laura M</au><au>Rotter, Jerome I</au><au>Wagenknecht, Lynne E</au><au>Handelman, Samuel K</au><au>Gudnason, Vilmundur</au><au>Province, Michael A</au><au>Peyser, Patricia A</au><au>Halligan, Brian</au><au>Palmer, Nicholette D</au><au>Speliotes, Elizabeth K</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Noncoding Variant Near PPP1R3B Promotes Liver Glycogen Storage and MetS, but Protects Against Myocardial Infarction</atitle><jtitle>The journal of clinical endocrinology and metabolism</jtitle><stitle>J CLIN ENDOCR METAB</stitle><addtitle>J Clin Endocrinol Metab</addtitle><date>2021-02-01</date><risdate>2021</risdate><volume>106</volume><issue>2</issue><spage>372</spage><epage>387</epage><pages>372-387</pages><issn>0021-972X</issn><eissn>1945-7197</eissn><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.</abstract><cop>US</cop><pub>Oxford University Press</pub><pmid>33231259</pmid><doi>10.1210/clinem/dgaa855</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0002-8197-0652</orcidid><orcidid>https://orcid.org/0000-0001-8883-2511</orcidid><orcidid>https://orcid.org/0000-0001-6659-3441</orcidid><orcidid>https://orcid.org/0000-0001-5696-0084</orcidid><orcidid>https://orcid.org/0000-0003-2001-2474</orcidid><orcidid>https://orcid.org/0000-0002-0633-9772</orcidid><orcidid>https://orcid.org/0000-0003-1942-5845</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0021-972X |
| ispartof | The journal of clinical endocrinology and metabolism, 2021-02, Vol.106 (2), p.372-387 |
| issn | 0021-972X 1945-7197 |
| language | eng |
| recordid | cdi_gale_infotracmisc_A702287704 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Oxford University Press Journals All Titles (1996-Current); Web of Science - Science Citation Index Expanded - 2021<img src="https://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" />; Alma/SFX Local Collection |
| subjects | Adult Aged Antisense RNA Biomarkers - analysis Cholesterol Clinical s Computed tomography CRISPR Electronic health records Electronic medical records Endocrinology & Metabolism Fatty liver Female Follow-Up Studies Gene deletion Glycogen Glycogen Storage Disease - etiology Glycogen Storage Disease - metabolism Glycogen Storage Disease - pathology Glycogenosis Heart attack Heart attacks Hepatocellular carcinoma Humans Life Sciences & Biomedicine Liver diseases Liver Glycogen - metabolism Low density lipoproteins Male Medical records Metabolic syndrome Metabolic Syndrome - etiology Metabolic Syndrome - metabolism Metabolic Syndrome - pathology Metabolism Middle Aged Myocardial infarction Myocardial Infarction - genetics Myocardial Infarction - pathology Myocardial Infarction - prevention & control Polymorphism, Single Nucleotide Prognosis Prospective Studies Protein Phosphatase 1 - genetics Science & Technology Scientific equipment and supplies industry Steatosis Storage diseases Trans fatty acids Triglycerides |
| title | A Noncoding Variant Near PPP1R3B Promotes Liver Glycogen Storage and MetS, but Protects Against Myocardial Infarction |
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