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

Nat Commun

Authors	Viktoria Gusarova Colm O'Dushlaine Tanya Teslovich Peter Benotti Tooraj Mirshahi Omri Gottesman Cristopher Van Hout Michael Murray Anubha Mahajan Jonas Nielsen Lars Fritsche Anders Wulff Daniel Gudbjartsson Marketa Sjögren Connor Emdin Robert Scott Wen-Jane Lee Aeron Small Lydia Kwee Om Dwivedi Rashmi Prasad Shannon Bruse Alexander Lopez John Penn Anthony Marcketta Joseph Leader Christopher Still H Lester Kirchner Uyenlinh Mirshahi Amr Wardeh Cassandra Hartle Lukas Habegger Samantha Fetterolf Teresa Tusié-Luna Andrew Morris Hilma Holm Valgerdur Steinthorsdottir Patrick Sulem Unnur Thorsteinsdottir Jerome Rotter Lee-Ming Chuang Scott Damrauer David Birtwell Chad Brummett Amit Khera Pradeep Natarajan Marju Orho-Melander Jason Flannick Luca Lotta Cristen Willer Oddgeir Holmen Marylyn Ritchie David Ledbetter Andrew Murphy Ingrid Borecki Jeffrey Reid John Overton Ola Hansson Leif Groop Svati Shah William Kraus Daniel Rader Yii-Der Chen Kristian Hveem Nicholas Wareham Sekar Kathiresan Olle Melander Kari Stefansson Børge Nordestgaard Anne Tybjærg-Hansen Gonçalo Abecasis David Altshuler Jose Florez Michael Boehnke Mark McCarthy George Yancopoulos David Carey Alan Shuldiner Aris Baras Frederick Dewey Jesper Gromada
Keywords	Animals Female Humans Male Mice Gene Silencing Risk Factors Heterozygote Genetic Variation Mice, Inbred C57BL Homeostasis Mice, Knockout Case-Control Studies Genetic Association Studies Blood Glucose Diabetes Mellitus, Type 2 Insulin Resistance Lipoprotein Lipase Amino Acid Substitution Whole Exome Sequencing Angiopoietin-Like Protein 4
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	Nat Commun
Volume	9
Issue	1
Pages	2252
Date Published	2018 06 13
ISSN	2041-1723
DOI	10.1038/s41467-018-04611-z
PubMed ID	29899519
PubMed Central ID	PMC5997992
Links	Google Scholar PubMed DOI
Grant list	KL2 TR001100 / TR / NCATS NIH HHS / United States R35 HL135824 / HL / NHLBI NIH HHS / United States MC_UU_12015/1 / Medical Research Council / United Kingdom K08 HL140203 / HL / NHLBI NIH HHS / United States U01 DK062370 / DK / NIDDK NIH HHS / United States P30 DK020572 / DK / NIDDK NIH HHS / United States

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