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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 and Nielsen, Jonas B, et al. (2018) In Nature Communications 9. p.1-11
Abstract

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... (More)

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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Nature Communications
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9
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1 - 11
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Nature Publishing Group
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  • scopus:85048556517
ISSN
2041-1723
DOI
10.1038/s41467-018-04611-z
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English
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yes
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58d6e703-044d-4a85-83af-761533f0e1dc
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2018-06-18 11:38:52
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2018-11-11 05:03:02
@article{58d6e703-044d-4a85-83af-761533f0e1dc,
  abstract     = {<p>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.</p>},
  articleno    = {2252},
  author       = {Gusarova, Viktoria and O'Dushlaine, Colm and Teslovich, Tanya M and Benotti, Peter N and Mirshahi, Tooraj and Gottesman, Omri and Van Hout, Cristopher V and Murray, Michael F and Mahajan, Anubha and Nielsen, Jonas B and Fritsche, Lars and Wulff, Anders Berg and Gudbjartsson, Daniel F and Sjögren, Marketa and Emdin, Connor A and Scott, Robert A and Lee, Wen-Jane and Small, Aeron and Kwee, Lydia C and Dwivedi, Om Prakash and Prasad, Rashmi B and Bruse, Shannon and Lopez, Alexander E and Penn, John and Marcketta, Anthony and Leader, Joseph B and Still, Christopher D and Kirchner, H Lester and Mirshahi, Uyenlinh L and Wardeh, Amr H and Hartle, Cassandra M and Habegger, Lukas and Fetterolf, Samantha N and Tusie-Luna, Teresa and Morris, Andrew P and Holm, Hilma and Steinthorsdottir, Valgerdur and Sulem, Patrick and Thorsteinsdottir, Unnur and Rotter, Jerome I and Chuang, Lee-Ming and Damrauer, Scott and Birtwell, David and Brummett, Chad M and Khera, Amit V and Natarajan, Pradeep and Orho-Melander, Marju and Flannick, Jason and Lotta, Luca A. and Willer, Cristen J and Holmen, Oddgeir L. and Ritchie, Marylyn D and Ledbetter, David H. and Murphy, Andrew J and Borecki, Ingrid B and Reid, Jeffrey G. and Overton, John D and Hansson, Ola and Groop, Leif and Shah, Svati and Kraus, William E and Rader, Daniel J and Ida Chen, Yii-Der and Hveem, Kristian and Wareham, Nicolas J and Kathiresan, Sekar and Melander, Olle and Stefansson, Kari and Nordestgaard, Børge G and Tybjaerg-Hansen, Anne and Abecasis, Goncalo R. and Altshuler, David and Florez, Jose C. and Boehnke, Michael and McCarthy, Mark and Yancopoulos, George D and Carey, David J. and Shuldiner, Alan R and Baras, Aris and Dewey, Frederick E and Gromada, Jesper},
  issn         = {2041-1723},
  language     = {eng},
  month        = {06},
  pages        = {1--11},
  publisher    = {Nature Publishing Group},
  series       = {Nature Communications},
  title        = {Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes},
  url          = {http://dx.doi.org/10.1038/s41467-018-04611-z},
  volume       = {9},
  year         = {2018},
}