Cargando…
Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes
Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investig...
| Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Formato: | Online Artículo Texto |
| Lenguaje: | English |
| Publicado: |
Nature Publishing Group UK
2018
|
| Materias: | |
| Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5997992/ https://www.ncbi.nlm.nih.gov/pubmed/29899519 http://dx.doi.org/10.1038/s41467-018-04611-z |
| _version_ | 1783331161318096896 |
|---|---|
| author | Gusarova, Viktoria O’Dushlaine, Colm Teslovich, Tanya M. Benotti, Peter N. Mirshahi, Tooraj Gottesman, Omri Van Hout, Cristopher V. Murray, Michael F. Mahajan, Anubha Nielsen, Jonas B. Fritsche, Lars Wulff, Anders Berg Gudbjartsson, Daniel F. Sjögren, Marketa Emdin, Connor A. Scott, Robert A. Lee, Wen-Jane Small, Aeron Kwee, Lydia C. Dwivedi, Om Prakash Prasad, Rashmi B. Bruse, Shannon Lopez, Alexander E. Penn, John Marcketta, Anthony Leader, Joseph B. Still, Christopher D. Kirchner, H. Lester Mirshahi, Uyenlinh L. Wardeh, Amr H. Hartle, Cassandra M. Habegger, Lukas Fetterolf, Samantha N. Tusie-Luna, Teresa Morris, Andrew P. Holm, Hilma Steinthorsdottir, Valgerdur Sulem, Patrick Thorsteinsdottir, Unnur Rotter, Jerome I. Chuang, Lee-Ming Damrauer, Scott Birtwell, David Brummett, Chad M. Khera, Amit V. Natarajan, Pradeep Orho-Melander, Marju Flannick, Jason Lotta, Luca A. Willer, Cristen J. Holmen, Oddgeir L. Ritchie, Marylyn D. Ledbetter, David H. Murphy, Andrew J. Borecki, Ingrid B. Reid, Jeffrey G. Overton, John D. Hansson, Ola Groop, Leif Shah, Svati H. Kraus, William E. Rader, Daniel J. Chen, Yii-Der I. Hveem, Kristian Wareham, Nicholas J. Kathiresan, Sekar Melander, Olle Stefansson, Kari Nordestgaard, Børge G. Tybjærg-Hansen, Anne Abecasis, Goncalo R. Altshuler, David Florez, Jose C. Boehnke, Michael McCarthy, Mark I. Yancopoulos, George D. Carey, David J. Shuldiner, Alan R. Baras, Aris Dewey, Frederick E. Gromada, Jesper |
| author_facet | Gusarova, Viktoria O’Dushlaine, Colm Teslovich, Tanya M. Benotti, Peter N. Mirshahi, Tooraj Gottesman, Omri Van Hout, Cristopher V. Murray, Michael F. Mahajan, Anubha Nielsen, Jonas B. Fritsche, Lars Wulff, Anders Berg Gudbjartsson, Daniel F. Sjögren, Marketa Emdin, Connor A. Scott, Robert A. Lee, Wen-Jane Small, Aeron Kwee, Lydia C. Dwivedi, Om Prakash Prasad, Rashmi B. Bruse, Shannon Lopez, Alexander E. Penn, John Marcketta, Anthony Leader, Joseph B. Still, Christopher D. Kirchner, H. Lester Mirshahi, Uyenlinh L. Wardeh, Amr H. Hartle, Cassandra M. Habegger, Lukas Fetterolf, Samantha N. Tusie-Luna, Teresa Morris, Andrew P. Holm, Hilma Steinthorsdottir, Valgerdur Sulem, Patrick Thorsteinsdottir, Unnur Rotter, Jerome I. Chuang, Lee-Ming Damrauer, Scott Birtwell, David Brummett, Chad M. Khera, Amit V. Natarajan, Pradeep Orho-Melander, Marju Flannick, Jason Lotta, Luca A. Willer, Cristen J. Holmen, Oddgeir L. Ritchie, Marylyn D. Ledbetter, David H. Murphy, Andrew J. Borecki, Ingrid B. Reid, Jeffrey G. Overton, John D. Hansson, Ola Groop, Leif Shah, Svati H. Kraus, William E. Rader, Daniel J. Chen, Yii-Der I. Hveem, Kristian Wareham, Nicholas J. Kathiresan, Sekar Melander, Olle Stefansson, Kari Nordestgaard, Børge G. Tybjærg-Hansen, Anne Abecasis, Goncalo R. Altshuler, David Florez, Jose C. Boehnke, Michael McCarthy, Mark I. Yancopoulos, George D. Carey, David J. Shuldiner, Alan R. Baras, Aris Dewey, Frederick E. Gromada, Jesper |
| author_sort | Gusarova, Viktoria |
| collection | PubMed |
| description | Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85–0.92, p = 6.3 × 10(−10)), lower fasting glucose, and greater insulin sensitivity. Predicted loss-of-function variants are associated with lower odds of T2D among 32,015 cases and 84,006 controls (odds ratio 0.71, 95% confidence interval 0.49–0.99, p = 0.041). Functional studies in Angptl4-deficient mice confirm improved insulin sensitivity and glucose homeostasis. In conclusion, genetic inactivation of ANGPTL4 is associated with improved glucose homeostasis and reduced risk of T2D. |
| format | Online Article Text |
| id | pubmed-5997992 |
| institution | National Center for Biotechnology Information |
| language | English |
| publishDate | 2018 |
| publisher | Nature Publishing Group UK |
| record_format | MEDLINE/PubMed |
| spelling | pubmed-59979922018-06-14 Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes Gusarova, Viktoria O’Dushlaine, Colm Teslovich, Tanya M. Benotti, Peter N. Mirshahi, Tooraj Gottesman, Omri Van Hout, Cristopher V. Murray, Michael F. Mahajan, Anubha Nielsen, Jonas B. Fritsche, Lars Wulff, Anders Berg Gudbjartsson, Daniel F. Sjögren, Marketa Emdin, Connor A. Scott, Robert A. Lee, Wen-Jane Small, Aeron Kwee, Lydia C. Dwivedi, Om Prakash Prasad, Rashmi B. Bruse, Shannon Lopez, Alexander E. Penn, John Marcketta, Anthony Leader, Joseph B. Still, Christopher D. Kirchner, H. Lester Mirshahi, Uyenlinh L. Wardeh, Amr H. Hartle, Cassandra M. Habegger, Lukas Fetterolf, Samantha N. Tusie-Luna, Teresa Morris, Andrew P. Holm, Hilma Steinthorsdottir, Valgerdur Sulem, Patrick Thorsteinsdottir, Unnur Rotter, Jerome I. Chuang, Lee-Ming Damrauer, Scott Birtwell, David Brummett, Chad M. Khera, Amit V. Natarajan, Pradeep Orho-Melander, Marju Flannick, Jason Lotta, Luca A. Willer, Cristen J. Holmen, Oddgeir L. Ritchie, Marylyn D. Ledbetter, David H. Murphy, Andrew J. Borecki, Ingrid B. Reid, Jeffrey G. Overton, John D. Hansson, Ola Groop, Leif Shah, Svati H. Kraus, William E. Rader, Daniel J. Chen, Yii-Der I. Hveem, Kristian Wareham, Nicholas J. Kathiresan, Sekar Melander, Olle Stefansson, Kari Nordestgaard, Børge G. Tybjærg-Hansen, Anne Abecasis, Goncalo R. Altshuler, David Florez, Jose C. Boehnke, Michael McCarthy, Mark I. Yancopoulos, George D. Carey, David J. Shuldiner, Alan R. Baras, Aris Dewey, Frederick E. Gromada, Jesper Nat Commun Article Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85–0.92, p = 6.3 × 10(−10)), lower fasting glucose, and greater insulin sensitivity. Predicted loss-of-function variants are associated with lower odds of T2D among 32,015 cases and 84,006 controls (odds ratio 0.71, 95% confidence interval 0.49–0.99, p = 0.041). Functional studies in Angptl4-deficient mice confirm improved insulin sensitivity and glucose homeostasis. In conclusion, genetic inactivation of ANGPTL4 is associated with improved glucose homeostasis and reduced risk of T2D. Nature Publishing Group UK 2018-06-13 /pmc/articles/PMC5997992/ /pubmed/29899519 http://dx.doi.org/10.1038/s41467-018-04611-z Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
| spellingShingle | Article Gusarova, Viktoria O’Dushlaine, Colm Teslovich, Tanya M. Benotti, Peter N. Mirshahi, Tooraj Gottesman, Omri Van Hout, Cristopher V. Murray, Michael F. Mahajan, Anubha Nielsen, Jonas B. Fritsche, Lars Wulff, Anders Berg Gudbjartsson, Daniel F. Sjögren, Marketa Emdin, Connor A. Scott, Robert A. Lee, Wen-Jane Small, Aeron Kwee, Lydia C. Dwivedi, Om Prakash Prasad, Rashmi B. Bruse, Shannon Lopez, Alexander E. Penn, John Marcketta, Anthony Leader, Joseph B. Still, Christopher D. Kirchner, H. Lester Mirshahi, Uyenlinh L. Wardeh, Amr H. Hartle, Cassandra M. Habegger, Lukas Fetterolf, Samantha N. Tusie-Luna, Teresa Morris, Andrew P. Holm, Hilma Steinthorsdottir, Valgerdur Sulem, Patrick Thorsteinsdottir, Unnur Rotter, Jerome I. Chuang, Lee-Ming Damrauer, Scott Birtwell, David Brummett, Chad M. Khera, Amit V. Natarajan, Pradeep Orho-Melander, Marju Flannick, Jason Lotta, Luca A. Willer, Cristen J. Holmen, Oddgeir L. Ritchie, Marylyn D. Ledbetter, David H. Murphy, Andrew J. Borecki, Ingrid B. Reid, Jeffrey G. Overton, John D. Hansson, Ola Groop, Leif Shah, Svati H. Kraus, William E. Rader, Daniel J. Chen, Yii-Der I. Hveem, Kristian Wareham, Nicholas J. Kathiresan, Sekar Melander, Olle Stefansson, Kari Nordestgaard, Børge G. Tybjærg-Hansen, Anne Abecasis, Goncalo R. Altshuler, David Florez, Jose C. Boehnke, Michael McCarthy, Mark I. Yancopoulos, George D. Carey, David J. Shuldiner, Alan R. Baras, Aris Dewey, Frederick E. Gromada, Jesper Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes |
| title | Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes |
| title_full | Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes |
| title_fullStr | Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes |
| title_full_unstemmed | Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes |
| title_short | Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes |
| title_sort | genetic inactivation of angptl4 improves glucose homeostasis and is associated with reduced risk of diabetes |
| topic | Article |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5997992/ https://www.ncbi.nlm.nih.gov/pubmed/29899519 http://dx.doi.org/10.1038/s41467-018-04611-z |
| work_keys_str_mv | AT gusarovaviktoria geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT odushlainecolm geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT teslovichtanyam geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT benottipetern geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT mirshahitooraj geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT gottesmanomri geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT vanhoutcristopherv geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT murraymichaelf geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT mahajananubha geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT nielsenjonasb geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT fritschelars geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT wulffandersberg geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT gudbjartssondanielf geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT sjogrenmarketa geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT emdinconnora geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT scottroberta geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT leewenjane geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT smallaeron geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT kweelydiac geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT dwivediomprakash geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT prasadrashmib geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT bruseshannon geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT lopezalexandere geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT pennjohn geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT marckettaanthony geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT leaderjosephb geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT stillchristopherd geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT kirchnerhlester geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT mirshahiuyenlinhl geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT wardehamrh geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT hartlecassandram geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT habeggerlukas geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT fetterolfsamanthan geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT tusielunateresa geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT morrisandrewp geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT holmhilma geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT steinthorsdottirvalgerdur geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT sulempatrick geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT thorsteinsdottirunnur geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT rotterjeromei geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT chuangleeming geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT damrauerscott geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT birtwelldavid geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT brummettchadm geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT kheraamitv geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT natarajanpradeep geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT orhomelandermarju geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT flannickjason geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT lottalucaa geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT willercristenj geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT holmenoddgeirl geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT ritchiemarylynd geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT ledbetterdavidh geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT murphyandrewj geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT boreckiingridb geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT reidjeffreyg geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT overtonjohnd geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT hanssonola geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT groopleif geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT shahsvatih geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT krauswilliame geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT raderdanielj geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT chenyiideri geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT hveemkristian geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT warehamnicholasj geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT kathiresansekar geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT melanderolle geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT stefanssonkari geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT nordestgaardbørgeg geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT tybjærghansenanne geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT abecasisgoncalor geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT altshulerdavid geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT florezjosec geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT boehnkemichael geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT mccarthymarki geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT yancopoulosgeorged geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT careydavidj geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT shuldineralanr geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT barasaris geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT deweyfredericke geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes AT gromadajesper geneticinactivationofangptl4improvesglucosehomeostasisandisassociatedwithreducedriskofdiabetes |