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

Viktoria Gusarova; Colm O'Dushlaine; Tanya M. Teslovich; Peter N. Benotti; Tooraj Mirshahi; Omri Gottesman; Cristopher V. Van Hout; 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; H. Lester Kirchner; Uyenlinh L. Mirshahi; Amr H. Wardeh; Cassandra M. Hartle; Lukas Habegger; Samantha N. Fetterolf; Teresa Tusie-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 V. Khera; 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

doi:10.1038/s41467-018-04611-z

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

Viktoria Gusarova, Colm O'Dushlaine, Tanya M. Teslovich, Peter N. Benotti, Tooraj Mirshahi, Omri Gottesman, Cristopher V. Van Hout, 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 DwivediRashmi B. Prasad, Shannon Bruse, Alexander E. Lopez, John Penn, Anthony Marcketta, Joseph B. Leader, Christopher D. Still, H. Lester Kirchner, Uyenlinh L. Mirshahi, Amr H. Wardeh, Cassandra M. Hartle, Lukas Habegger, Samantha N. Fetterolf, Teresa Tusie-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 V. Khera, 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

^*Corresponding author for this work

Department of Clinical Medicine

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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.

Original language	English
Article number	2252
Journal	Nature Communications
Volume	9
Issue number	1
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-018-04611-z
Publication status	Published - 2018

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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), Article 2252. https://doi.org/10.1038/s41467-018-04611-z

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, vol. 9, no. 1, 2252. https://doi.org/10.1038/s41467-018-04611-z

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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",

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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.

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U2 - 10.1038/s41467-018-04611-z

DO - 10.1038/s41467-018-04611-z

M3 - Journal article

C2 - 29899519

AN - SCOPUS:85048556517

SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2252

ER -

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

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