Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes
Journal
Nature Communications
Journal Volume
9
Journal Issue
1
Pages
2252
Date Issued
2018
Author(s)
Gusarova V.
O'Dushlaine C.
Teslovich T.M.
Benotti P.N.
Mirshahi T.
Gottesman O.
Van Hout C.V.
Murray M.F.
Mahajan A.
Nielsen J.B.
Fritsche L.
Wulff A.B.
Gudbjartsson D.F.
Sjögren M.
Emdin C.A.
Scott R.A.
Lee W.-J.
Small A.
Kwee L.C.
Dwivedi O.P.
Prasad R.B.
Bruse S.
Lopez A.E.
Penn J.
Marcketta A.
Leader J.B.
Still C.D.
Kirchner H.L.
Mirshahi U.L.
Wardeh A.H.
Hartle C.M.
Habegger L.
Fetterolf S.N.
Tusie-Luna T.
Morris A.P.
Holm H.
Steinthorsdottir V.
Sulem P.
Thorsteinsdottir U.
Rotter J.I.
Damrauer S.
Birtwell D.
Brummett C.M.
Khera A.V.
Natarajan P.
Orho-Melander M.
Flannick J.
Lotta L.A.
Willer C.J.
Holmen O.L.
Ritchie M.D.
Ledbetter D.H.
Murphy A.J.
Borecki I.B.
Reid J.G.
Overton J.D.
Hansson O.
Groop L.
Shah S.H.
Kraus W.E.
Rader D.J.
Chen Y.-D.I.
Hveem K.
Wareham N.J.
Kathiresan S.
Melander O.
Stefansson K.
Nordestgaard B.G.
Tybjærg-Hansen A.
Abecasis G.R.
Altshuler D.
Florez J.C.
Boehnke M.
McCarthy M.I.
Yancopoulos G.D.
Carey D.J.
Shuldiner A.R.
Baras A.
Dewey F.E.
Gromada J.
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 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. ? 2018 The Author(s).
SDGs
Other Subjects
angiopoietin related protein 4; glucose; insulin; triacylglycerol; angiopoietin related protein 4; ANGPTL4 protein, human; Angptl4 protein, mouse; lipoprotein lipase; confidence interval; diabetes; enzyme; enzyme activity; genetics; glucose; homeostasis; inhibitor; lipid; protein; Article; body composition; body mass; body weight change; cholesterol blood level; diabetes mellitus; energy expenditure; fat intake; food intake; gene frequency; gene inactivation; genetic variability; glucose homeostasis; glucose tolerance; heterozygote; homozygosity; homozygote; human; insulin sensitivity; lipid diet; lipid storage; loss of function mutation; lymphadenopathy; non insulin dependent diabetes mellitus; nonhuman; open reading frame; risk reduction; triacylglycerol blood level; triacylglycerol level; whole exome sequencing; amino acid substitution; animal; C57BL mouse; case control study; deficiency; female; gene silencing; genetic association study; genetic variation; genetics; glucose blood level; homeostasis; insulin resistance; knockout mouse; male; metabolism; mouse; non insulin dependent diabetes mellitus; risk factor; Mus; Amino Acid Substitution; Angiopoietin-like 4 Protein; Animals; Blood Glucose; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Gene Silencing; Genetic Association Studies; Genetic Variation; Heterozygote; Homeostasis; Humans; Insulin Resistance; Lipoprotein Lipase; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Risk Factors; Whole Exome Sequencing
Publisher
Nature Publishing Group
Type
journal article