Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes.
| Citation | . “Genetic Inactivation Of Angptl4 Improves Glucose Homeostasis And Is Associated With Reduced Risk Of Diabetes.”. Nature Communications, p. 2252. |
| Center | University of Michigan |
| Author | Viktoria Gusarova, Colm O'Dushlaine, Tanya M Teslovich, Peter N Benotti, Tooraj Mirshahi, Omri Gottesman, Cristopher Van Hout V, Michael F Murray, Anubha Mahajan, Jonas B Nielsen, Lars Fritsche, Anders Berg Wulff, Daniel F Gudbjartsson, Marketa Sjögren, Connor A Emdin, Robert A Scott, Wen-Jane Lee, Aeron Small, Lydia C Kwee, Om Prakash Dwivedi, Rashmi B Prasad, Shannon Bruse, Alexander E Lopez, John Penn, Anthony Marcketta, Joseph B Leader, Christopher D Still, Lester Kirchner, Uyenlinh L Mirshahi, Amr H Wardeh, Cassandra M Hartle, Lukas Habegger, Samantha N Fetterolf, Teresa Tusié-Luna, Andrew P Morris, Hilma Holm, Valgerdur Steinthorsdottir, Patrick Sulem, Unnur Thorsteinsdottir, Jerome I Rotter, Lee-Ming Chuang, Scott Damrauer, David Birtwell, Chad M Brummett, Amit Khera V, Pradeep Natarajan, Marju Orho-Melander, Jason Flannick, Luca A Lotta, Cristen J Willer, Oddgeir L Holmen, Marylyn D Ritchie, David H Ledbetter, Andrew J Murphy, Ingrid B Borecki, Jeffrey G Reid, John D Overton, Ola Hansson, Leif Groop, Svati H Shah, William E Kraus, Daniel J Rader, Yii-Der I Chen, Kristian Hveem, Nicholas J Wareham, Sekar Kathiresan, Olle Melander, Kari Stefansson, Børge G Nordestgaard, Anne Tybjærg-Hansen, Goncalo R Abecasis, David Altshuler, Jose C Florez, Michael Boehnke, Mark I McCarthy, George D Yancopoulos, David J Carey, Alan R Shuldiner, Aris Baras, Frederick E Dewey, Jesper Gromada |
| 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), 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. |
| Year of Publication |
2018
|
| Journal |
Nature communications
|
| Volume |
9
|
| Issue |
1
|
| Number of Pages |
2252
|
| Date Published |
12/2018
|
| ISSN Number |
2041-1723
|
| DOI |
10.1038/s41467-018-04611-z
|
| Alternate Journal |
Nat Commun
|
| PMID |
29899519
|
| PMCID |
PMC5997992
|
| Download citation |