Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes

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Gusarova, ViktoriaRegeneron Pharmaceuticals, Inc. (author)

Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes

Article/chapterEnglish2018

Publisher, publication year, extent ...

2018-06-13
Springer Science and Business Media LLC,2018

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LIBRIS-ID:oai:lup.lub.lu.se:58d6e703-044d-4a85-83af-761533f0e1dc
https://lup.lub.lu.se/record/58d6e703-044d-4a85-83af-761533f0e1dcURI
https://doi.org/10.1038/s41467-018-04611-zDOI

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Language:English
Summary in:English

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SwePubSwePub

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Subject category:art swepub-publicationtype
Subject category:ref swepub-contenttype

Notes

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.

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O'Dushlaine, ColmRegeneron Pharmaceuticals, Inc. (author)
Teslovich, Tanya MRegeneron Pharmaceuticals, Inc. (author)
Benotti, Peter NGeisinger Health System (author)
Mirshahi, ToorajGeisinger Health System (author)
Gottesman, OmriRegeneron Pharmaceuticals, Inc. (author)
Van Hout, Cristopher VRegeneron Pharmaceuticals, Inc. (author)
Murray, Michael FGeisinger Health System (author)
Mahajan, AnubhaUniversity of Oxford (author)
Nielsen, Jonas BUniversity of Michigan (author)
Fritsche, LarsUniversity of Michigan (author)
Wulff, Anders BergCopenhagen University Hospital (author)
Gudbjartsson, Daniel F (author)
Sjögren, MarketaLund University,Lunds universitet,Kardiovaskulär forskning - hypertoni,Forskargrupper vid Lunds universitet,Cardiovascular Research - Hypertension,Lund University Research Groups(Swepub:lu)endo-msj (author)
Emdin, Connor ABroad Institute (author)
Scott, Robert A (author)
Lee, Wen-JaneTunghai University (author)
Small, AeronUniversity of Pennsylvania (author)
Kwee, Lydia CDuke University (author)
Dwivedi, Om Prakash (author)
Prasad, Rashmi BLund University,Lunds universitet,Translationell muskelforskning,Forskargrupper vid Lunds universitet,Translational Muscle Research,Lund University Research Groups(Swepub:lu)med-rpa (author)
Bruse, Shannon (author)
Lopez, Alexander E (author)
Penn, John (author)
Marcketta, Anthony (author)
Leader, Joseph B (author)
Still, Christopher D (author)
Kirchner, H Lester (author)
Mirshahi, Uyenlinh L (author)
Wardeh, Amr H (author)
Hartle, Cassandra M (author)
Habegger, Lukas (author)
Fetterolf, Samantha N (author)
Tusie-Luna, Teresa (author)
Morris, Andrew PUniversity of Tartu (author)
Holm, HilmadeCODE Genetics (author)
Steinthorsdottir, ValgerdurdeCODE Genetics (author)
Sulem, PatrickdeCODE Genetics (author)
Thorsteinsdottir, Unnur (author)
Rotter, Jerome I (author)
Chuang, Lee-MingNational Taiwan University (author)
Damrauer, Scott (author)
Birtwell, DavidUniversity of Pennsylvania (author)
Brummett, Chad M (author)
Khera, Amit VHarvard Medical School (author)
Natarajan, PradeepMassachusetts General Hospital (author)
Orho-Melander, MarjuLund University,Lunds universitet,Diabetes - kardiovaskulär sjukdom,Forskargrupper vid Lunds universitet,Diabetes - Cardiovascular Disease,Lund University Research Groups(Swepub:lu)endo-mor (author)
Flannick, JasonBroad Institute (author)
Lotta, Luca A.University of Cambridge (author)
Willer, Cristen JUniversity of Michigan (author)
Holmen, Oddgeir L.Norwegian University of Science and Technology (author)
Ritchie, Marylyn D (author)
Ledbetter, David H. (author)
Murphy, Andrew J (author)
Borecki, Ingrid B (author)
Reid, Jeffrey G. (author)
Overton, John D (author)
Hansson, OlaLund University,Lunds universitet,Translationell muskelforskning,Forskargrupper vid Lunds universitet,Translational Muscle Research,Lund University Research Groups,University of Helsinki(Swepub:lu)medk-oha (author)
Groop, LeifLund University,Lunds universitet,Translationell muskelforskning,Forskargrupper vid Lunds universitet,Translational Muscle Research,Lund University Research Groups,University of Helsinki(Swepub:lu)endo-lgr (author)
Shah, SvatiDuke University (author)
Kraus, William EDuke University (author)
Rader, Daniel J (author)
Ida Chen, Yii-Der (author)
Hveem, KristianNorwegian University of Science and Technology,Nord-Trøndelag Health Trust (author)
Wareham, Nicolas J (author)
Kathiresan, SekarMassachusetts General Hospital (author)
Melander, OlleLund University,Lunds universitet,Institutionen för kliniska vetenskaper, Malmö,Medicinska fakulteten,Kardiovaskulär forskning - hypertoni,Forskargrupper vid Lunds universitet,Department of Clinical Sciences, Malmö,Faculty of Medicine,Cardiovascular Research - Hypertension,Lund University Research Groups(Swepub:lu)endo-ome (author)
Stefansson, KarideCODE Genetics (author)
Nordestgaard, Børge GCopenhagen University Hospital,University of Copenhagen (author)
Tybjaerg-Hansen, AnneCopenhagen University Hospital (author)
Abecasis, Goncalo R. (author)
Altshuler, DavidMassachusetts General Hospital,Harvard Medical School,Broad Institute (author)
Florez, Jose C.Massachusetts General Hospital,Harvard Medical School,Broad Institute (author)
Boehnke, MichaelUniversity of Michigan (author)
McCarthy, Mark (author)
Yancopoulos, George D (author)
Carey, David J. (author)
Shuldiner, Alan R (author)
Baras, ArisRegeneron Pharmaceuticals, Inc. (author)
Dewey, Frederick ERegeneron Pharmaceuticals, Inc. (author)
Gromada, JesperRegeneron Pharmaceuticals, Inc. (author)
Regeneron Pharmaceuticals, Inc.Geisinger Health System (creator_code:org_t)

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In:Nature Communications: Springer Science and Business Media LLC9, s. 1-112041-1723

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By the author/editor: Gusarova, Viktor ...; O'Dushlaine, Col ...; Teslovich, Tanya ...; Benotti, Peter N; Mirshahi, Tooraj; Gottesman, Omri; show more...; Van Hout, Cristo ...; Murray, Michael ...; Mahajan, Anubha; Nielsen, Jonas B; Fritsche, Lars; Wulff, Anders Be ...; Gudbjartsson, Da ...; Sjögren, Marketa; Emdin, Connor A; Scott, Robert A; Lee, Wen-Jane; Small, Aeron; Kwee, Lydia C; Dwivedi, Om Prak ...; Prasad, Rashmi B; Bruse, Shannon; Lopez, Alexander ...; Penn, John; Marcketta, Antho ...; Leader, Joseph B; Still, Christoph ...; Kirchner, H Lest ...; Mirshahi, Uyenli ...; Wardeh, Amr H; Hartle, Cassandr ...; Habegger, Lukas; Fetterolf, Saman ...; Tusie-Luna, Tere ...; Morris, Andrew P; Holm, Hilma; Steinthorsdottir ...; Sulem, Patrick; Thorsteinsdottir ...; Rotter, Jerome I; Chuang, Lee-Ming; Damrauer, Scott; Birtwell, David; Brummett, Chad M; Khera, Amit V; Natarajan, Prade ...; Orho-Melander, M ...; Flannick, Jason; Lotta, Luca A.; Willer, Cristen ...; Holmen, Oddgeir ...; Ritchie, Marylyn ...; Ledbetter, David ...; Murphy, Andrew J; Borecki, Ingrid ...; Reid, Jeffrey G.; Overton, John D; Hansson, Ola; Groop, Leif; Shah, Svati; Kraus, William E; Rader, Daniel J; Ida Chen, Yii-De ...; Hveem, Kristian; Wareham, Nicolas ...; Kathiresan, Seka ...; Melander, Olle; Stefansson, Kari; Nordestgaard, Bø ...; Tybjaerg-Hansen, ...; Abecasis, Goncal ...; Altshuler, David; Florez, Jose C.; Boehnke, Michael; McCarthy, Mark; Yancopoulos, Geo ...; Carey, David J.; Shuldiner, Alan ...; Baras, Aris; Dewey, Frederick ...; Gromada, Jesper; show less...

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