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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; Nielsen, Jonas B.; Fritsche, Lars; Wulff, Anders Berg; Gudbjartsson, Daniel F.; Sjögren, Marketa; Emdin, Connor A.; Scott, Robert A.; Lee, Wen Jane; Small, Aeron; Kwee, Lydia C.; Dwivedi, Om Prakash; Prasad, Rashmi B.; Bruse, Shannon; Lopez, Alexander E.; Penn, John; Marcketta, Anthony; Leader, Joseph B.; Still, Christopher D.; Kirchner, H. Lester; Mirshahi, Uyenlinh L.; Wardeh, Amr H.; Hartle, Cassandra M.; Habegger, Lukas; Fetterolf, Samantha N.; Tusie-Luna, Teresa; Morris, Andrew P.; Holm, Hilma; Steinthorsdottir, Valgerdur; Sulem, Patrick; Thorsteinsdottir, Unnur; Rotter, Jerome I.; Chuang, Lee Ming; Damrauer, Scott; Birtwell, David; Brummett, Chad M.; Khera, Amit V.; Natarajan, Pradeep; Orho-Melander, Marju; Flannick, Jason; Lotta, Luca A.; Willer, Cristen J.; Holmen, Oddgeir L.; Ritchie, Marylyn D.; Ledbetter, David H.; Murphy, Andrew J.; Borecki, Ingrid B.; Reid, Jeffrey G.; Overton, John D.; Hansson, Ola; Groop, Leif; Shah, Svati H.; Kraus, William E.; Rader, Daniel J.; Chen, Yii Der I.; Hveem, Kristian; Wareham, Nicholas J.; Kathiresan, Sekar; Melander, Olle; Stefansson, Kari; Nordestgaard, Børge G.; Tybjærg-Hansen, Anne; Abecasis, Goncalo R.; Altshuler, David; Florez, Jose C.; Boehnke, Michael; McCarthy, Mark I.; Yancopoulos, George D.; Carey, David J.; Shuldiner, Alan R.; Baras, Aris; Dewey, Frederick E.; Gromada, Jesper.
I:
Nature Communications, Bind 9, Nr. 1, 2252, 2018.
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Harvard
Gusarova, V, O'Dushlaine, C, Teslovich, TM, Benotti, PN, Mirshahi, T, Gottesman, O, Van Hout, CV, Murray, MF, Mahajan, A, Nielsen, JB, Fritsche, L, Wulff, AB, Gudbjartsson, DF, Sjögren, M, Emdin, CA, Scott, RA, Lee, WJ, Small, A, Kwee, LC, Dwivedi, OP, Prasad, RB, Bruse, S, Lopez, AE, Penn, J, Marcketta, A, Leader, JB, Still, CD, Kirchner, HL, Mirshahi, UL, Wardeh, AH, Hartle, CM, Habegger, L, Fetterolf, SN, Tusie-Luna, T, Morris, AP, Holm, H, Steinthorsdottir, V, Sulem, P, Thorsteinsdottir, U, Rotter, JI, Chuang, LM, Damrauer, S, Birtwell, D, Brummett, CM, Khera, AV, Natarajan, P, Orho-Melander, M, Flannick, J, Lotta, LA, Willer, CJ, Holmen, OL, Ritchie, MD, Ledbetter, DH, Murphy, AJ, Borecki, IB, Reid, JG, Overton, JD, Hansson, O, Groop, L, Shah, SH, Kraus, WE, Rader, DJ, Chen, YDI, Hveem, K, Wareham, NJ, Kathiresan, S, Melander, O, Stefansson, K
, Nordestgaard, BG, Tybjærg-Hansen, A, Abecasis, GR, Altshuler, D, Florez, JC, Boehnke, M, McCarthy, MI, Yancopoulos, GD, Carey, DJ, Shuldiner, AR, Baras, A, Dewey, FE & Gromada, J 2018, '
Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes',
Nature Communications, bind 9, nr. 1, 2252.
https://doi.org/10.1038/s41467-018-04611-zAPA
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., ... Gromada, J. (2018).
Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes.
Nature Communications,
9(1), [2252].
https://doi.org/10.1038/s41467-018-04611-zVancouver
Gusarova V, O'Dushlaine C, Teslovich TM, Benotti PN, Mirshahi T, Gottesman O o.a.
Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes.
Nature Communications. 2018;9(1). 2252.
https://doi.org/10.1038/s41467-018-04611-zAuthor
Gusarova, Viktoria ; O'Dushlaine, Colm ; Teslovich, Tanya M. ; Benotti, Peter N. ; Mirshahi, Tooraj ; Gottesman, Omri ; Van Hout, Cristopher V. ; Murray, Michael F. ; Mahajan, Anubha ; Nielsen, Jonas B. ; Fritsche, Lars ; Wulff, Anders Berg ; Gudbjartsson, Daniel F. ; Sjögren, Marketa ; Emdin, Connor A. ; Scott, Robert A. ; Lee, Wen Jane ; Small, Aeron ; Kwee, Lydia C. ; Dwivedi, Om Prakash ; Prasad, Rashmi B. ; Bruse, Shannon ; Lopez, Alexander E. ; Penn, John ; Marcketta, Anthony ; Leader, Joseph B. ; Still, Christopher D. ; Kirchner, H. Lester ; Mirshahi, Uyenlinh L. ; Wardeh, Amr H. ; Hartle, Cassandra M. ; Habegger, Lukas ; Fetterolf, Samantha N. ; Tusie-Luna, Teresa ; Morris, Andrew P. ; Holm, Hilma ; Steinthorsdottir, Valgerdur ; Sulem, Patrick ; Thorsteinsdottir, Unnur ; Rotter, Jerome I. ; Chuang, Lee Ming ; Damrauer, Scott ; Birtwell, David ; Brummett, Chad M. ; Khera, Amit V. ; Natarajan, Pradeep ; Orho-Melander, Marju ; Flannick, Jason ; Lotta, Luca A. ; Willer, Cristen J. ; Holmen, Oddgeir L. ; Ritchie, Marylyn D. ; Ledbetter, David H. ; Murphy, Andrew J. ; Borecki, Ingrid B. ; Reid, Jeffrey G. ; Overton, John D. ; Hansson, Ola ; Groop, Leif ; Shah, Svati H. ; Kraus, William E. ; Rader, Daniel J. ; Chen, Yii Der I. ; Hveem, Kristian ; Wareham, Nicholas J. ; Kathiresan, Sekar ; Melander, Olle ; Stefansson, Kari ; Nordestgaard, Børge G. ; Tybjærg-Hansen, Anne ; Abecasis, Goncalo R. ; Altshuler, David ; Florez, Jose C. ; Boehnke, Michael ; McCarthy, Mark I. ; Yancopoulos, George D. ; Carey, David J. ; Shuldiner, Alan R. ; Baras, Aris ; Dewey, Frederick E. ; Gromada, Jesper. / Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes. I: Nature Communications. 2018 ; Bind 9, Nr. 1.
Bibtex
@article{d25ff1f7455a4c1187ededec55141ef1,
title = "Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes",
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. ",
author = "Viktoria Gusarova and Colm O'Dushlaine and Teslovich, {Tanya M.} and Benotti, {Peter N.} and Tooraj Mirshahi and Omri Gottesman and {Van Hout}, {Cristopher V.} and Murray, {Michael F.} and Anubha Mahajan and Nielsen, {Jonas B.} and Lars Fritsche and Wulff, {Anders Berg} and Gudbjartsson, {Daniel F.} and Marketa Sj{\"o}gren and Emdin, {Connor A.} and Scott, {Robert A.} and Lee, {Wen Jane} and Aeron Small and Kwee, {Lydia C.} and Dwivedi, {Om Prakash} and Prasad, {Rashmi B.} and Shannon Bruse and Lopez, {Alexander E.} and John Penn and Anthony Marcketta 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 Lukas Habegger and Fetterolf, {Samantha N.} and Teresa Tusie-Luna and Morris, {Andrew P.} and Hilma Holm and Valgerdur Steinthorsdottir and Patrick Sulem and Unnur Thorsteinsdottir and Rotter, {Jerome I.} and Chuang, {Lee Ming} and Scott Damrauer and David Birtwell and Brummett, {Chad M.} and Khera, {Amit V.} and Pradeep Natarajan and Marju Orho-Melander and Jason Flannick 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 Ola Hansson and Leif Groop and Shah, {Svati H.} and Kraus, {William E.} and Rader, {Daniel J.} and Chen, {Yii Der I.} and Kristian Hveem and Wareham, {Nicholas J.} and Sekar Kathiresan and Olle Melander and Kari Stefansson and Nordestgaard, {B{\o}rge G.} and Anne Tybj{\ae}rg-Hansen and Abecasis, {Goncalo R.} and David Altshuler and Florez, {Jose C.} and Michael Boehnke and McCarthy, {Mark I.} and Yancopoulos, {George D.} and Carey, {David J.} and Shuldiner, {Alan R.} and Aris Baras and Dewey, {Frederick E.} and Jesper Gromada",
year = "2018",
doi = "10.1038/s41467-018-04611-z",
language = "English",
volume = "9",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "nature publishing group",
number = "1",
}
RIS
TY - JOUR
T1 - Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes
AU - Gusarova, Viktoria
AU - O'Dushlaine, Colm
AU - Teslovich, Tanya M.
AU - Benotti, Peter N.
AU - Mirshahi, Tooraj
AU - Gottesman, Omri
AU - Van Hout, Cristopher V.
AU - Murray, Michael F.
AU - Mahajan, Anubha
AU - Nielsen, Jonas B.
AU - Fritsche, Lars
AU - Wulff, Anders Berg
AU - Gudbjartsson, Daniel F.
AU - Sjögren, Marketa
AU - Emdin, Connor A.
AU - Scott, Robert A.
AU - Lee, Wen Jane
AU - Small, Aeron
AU - Kwee, Lydia C.
AU - Dwivedi, Om Prakash
AU - Prasad, Rashmi B.
AU - Bruse, Shannon
AU - Lopez, Alexander E.
AU - Penn, John
AU - Marcketta, Anthony
AU - Leader, Joseph B.
AU - Still, Christopher D.
AU - Kirchner, H. Lester
AU - Mirshahi, Uyenlinh L.
AU - Wardeh, Amr H.
AU - Hartle, Cassandra M.
AU - Habegger, Lukas
AU - Fetterolf, Samantha N.
AU - Tusie-Luna, Teresa
AU - Morris, Andrew P.
AU - Holm, Hilma
AU - Steinthorsdottir, Valgerdur
AU - Sulem, Patrick
AU - Thorsteinsdottir, Unnur
AU - Rotter, Jerome I.
AU - Chuang, Lee Ming
AU - Damrauer, Scott
AU - Birtwell, David
AU - Brummett, Chad M.
AU - Khera, Amit V.
AU - Natarajan, Pradeep
AU - Orho-Melander, Marju
AU - Flannick, Jason
AU - Lotta, Luca A.
AU - Willer, Cristen J.
AU - Holmen, Oddgeir L.
AU - Ritchie, Marylyn D.
AU - Ledbetter, David H.
AU - Murphy, Andrew J.
AU - Borecki, Ingrid B.
AU - Reid, Jeffrey G.
AU - Overton, John D.
AU - Hansson, Ola
AU - Groop, Leif
AU - Shah, Svati H.
AU - Kraus, William E.
AU - Rader, Daniel J.
AU - Chen, Yii Der I.
AU - Hveem, Kristian
AU - Wareham, Nicholas J.
AU - Kathiresan, Sekar
AU - Melander, Olle
AU - Stefansson, Kari
AU - Nordestgaard, Børge G.
AU - Tybjærg-Hansen, Anne
AU - Abecasis, Goncalo R.
AU - Altshuler, David
AU - Florez, Jose C.
AU - Boehnke, Michael
AU - McCarthy, Mark I.
AU - Yancopoulos, George D.
AU - Carey, David J.
AU - Shuldiner, Alan R.
AU - Baras, Aris
AU - Dewey, Frederick E.
AU - Gromada, Jesper
PY - 2018
Y1 - 2018
N2 -
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.
AB -
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.
UR - http://www.scopus.com/inward/record.url?scp=85048556517&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-04611-z
DO - 10.1038/s41467-018-04611-z
M3 - Journal article
C2 - 29899519
AN - SCOPUS:85048556517
VL - 9
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 2252
ER -
