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

Autor: Teresa Tusié-Luna, Svati H. Shah, Wen-Jane Lee, Amit Khera, Gonçalo R. Abecasis, Olle Melander, Alan R. Shuldiner, Connor A. Emdin, Kari Stefansson, Jesper Gromada, Andrew P. Morris, Lee-Ming Chuang, Omri Gottesman, Lars G. Fritsche, Pradeep Natarajan, Marju Orho-Melander, Daniel F. Gudbjartsson, Anubha Mahajan, Marylyn D. Ritchie, William E. Kraus, Tooraj Mirshahi, Colm O'Dushlaine, Jason Flannick, Nicholas J. Wareham, Anne Tybjærg-Hansen, Anders Berg Wulff, Rashmi B. Prasad, Aris Baras, Jonas B. Nielsen, Valgerdur Steinthorsdottir, Yii-Der Ida Chen, Jerome I. Rotter, Lukas Habegger, Samantha N. Fetterolf, David Altshuler, Om Prakash Dwivedi, Tanya M. Teslovich, Cristen J. Willer, Luca A. Lotta, Andrew J. Murphy, Joseph B. Leader, Cristopher V. Van Hout, Christopher D. Still, Ola Hansson, David Birtwell, Alexander Lopez, Daniel J. Rader, John D. Overton, Anthony Marcketta, Patrick Sulem, Peter N. Benotti, Jose C. Florez, Lydia Coulter Kwee, David J. Carey, Oddgeir L. Holmen, Kristian Hveem, Leif Groop, Sekar Kathiresan, Viktoria Gusarova, Unnur Thorsteinsdottir, Cassandra M. Hartle, Uyenlinh L. Mirshahi, H. Lester Kirchner, Shannon Bruse, Robert A. Scott, Michael F. Murray, Marketa Sjögren, Jeffrey G. Reid, Aeron Small, Børge G. Nordestgaard, Amr H. Wardeh, Chad M. Brummett, Mark I. McCarthy, Frederick E. Dewey, David H. Ledbetter, John Penn, Ingrid B. Borecki, Scott M. Damrauer, Hilma Holm, Michael Boehnke, George D. Yancopoulos
Přispěvatelé: Institute for Molecular Medicine Finland, University of Helsinki, Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Blood Glucose
Male
0301 basic medicine
Insulin Resistance/genetics
General Physics and Astronomy
Type 2 diabetes
030204 cardiovascular system & hematology
Inbred C57BL
Cardiovascular
HAN CHINESE
Whole Exome Sequencing
Mice
0302 clinical medicine
Risk Factors
ANGPTL4
Homeostasis
Glucose homeostasis
lcsh:Science
Mice
Knockout
Lipoprotein lipase
Multidisciplinary
Diabetes
Lipoprotein Lipase/metabolism
REMNANT CHOLESTEROL
ADIPOSE-TISSUE
Female
Type 2
Heterozygote
medicine.medical_specialty
Knockout
Science
LIPOPROTEIN-LIPASE
HEART-DISEASE
Diabetes Mellitus
Type 2/etiology
Article
General Biochemistry
Genetics and Molecular Biology
Angiopoietin-like 4 Protein/deficiency
03 medical and health sciences
Internal medicine
Diabetes mellitus
Exome Sequencing
Diabetes Mellitus
Genetics
medicine
Angiopoietin-Like Protein 4
Animals
Humans
Gene Silencing
GENOME-WIDE ASSOCIATION
Metabolic and endocrine
Genetic Association Studies
CHINESE POPULATION
Blood Glucose/metabolism
PLASMA-LIPIDS
business.industry
Case-control study
Genetic Variation
General Chemistry
Odds ratio
Atherosclerosis
medicine.disease
Mice
Inbred C57BL
Lipoprotein Lipase
030104 developmental biology
Endocrinology
Diabetes Mellitus
Type 2
Amino Acid Substitution
Case-Control Studies
lcsh:Q
3111 Biomedicine
ANGIOPOIETIN-LIKE PROTEIN-4
Insulin Resistance
business
Zdroj: Nature Communications, Vol 9, Iss 1, Pp 1-11 (2018)
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, Chuang, L-M, 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 2018, ' Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes ', Nature Communications, vol. 9, no. 1, pp. 2252 . https://doi.org/10.1038/s41467-018-04611-z
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, Chuang, L M, 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 2018, ' Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes ', Nature Communications, vol. 9, no. 1, 2252 . https://doi.org/10.1038/s41467-018-04611-z
Nature Communications
Nature communications, vol 9, iss 1
ISSN: 2041-1723
DOI: 10.1038/s41467-018-04611-z
Popis: 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.
Genetic variation in ANGPTL4 is associated with lipid traits. Here, the authors find that predicted loss-of-function variants in ANGPTL4 are associated with glucose homeostasis and reduced risk of type 2 diabetes and that Angptl4−/− mice on a high-fat diet show improved insulin sensitivity.
Databáze: OpenAIRE
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