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

Nat Commun. 2018 Jun 13;9(1):2252. doi: 10.1038/s41467-018-04611-z.

Authors

Viktoria Gusarova¹, Colm O'Dushlaine², Tanya M Teslovich², Peter N Benotti³, Tooraj Mirshahi³, Omri Gottesman², Cristopher V Van Hout², Michael F Murray³, Anubha Mahajan⁴, Jonas B Nielsen^{5

6}, Lars Fritsche⁷, Anders Berg Wulff⁸, Daniel F Gudbjartsson⁹, Marketa Sjögren¹⁰, Connor A Emdin¹¹, Robert A Scott¹², Wen-Jane Lee^{13

14}, Aeron Small^{15

16}, Lydia C Kwee¹⁷, Om Prakash Dwivedi¹⁸, Rashmi B Prasad¹⁹, Shannon Bruse², Alexander E Lopez², John Penn², Anthony Marcketta², Joseph B Leader³, Christopher D Still³, H Lester Kirchner³, Uyenlinh L Mirshahi³, Amr H Wardeh³, Cassandra M Hartle³, Lukas Habegger², Samantha N Fetterolf³, Teresa Tusie-Luna^{20

21}, Andrew P Morris^{4

22

23}, Hilma Holm⁹, Valgerdur Steinthorsdottir⁹, Patrick Sulem⁹, Unnur Thorsteinsdottir⁹, Jerome I Rotter²⁴, Lee-Ming Chuang^{25

26}, Scott Damrauer^{27

28}, David Birtwell^{15

16}, Chad M Brummett²⁹, Amit V Khera^{11

30}, Pradeep Natarajan^{11

30}, Marju Orho-Melander¹⁰, Jason Flannick^{11

31}, Luca A Lotta¹², Cristen J Willer^{5

6

32}, Oddgeir L Holmen³³, Marylyn D Ritchie³, David H Ledbetter³, Andrew J Murphy¹, Ingrid B Borecki², Jeffrey G Reid², John D Overton², Ola Hansson^{18

19}, Leif Groop^{18

19}, Svati H Shah¹⁷, William E Kraus¹⁷, Daniel J Rader^{15

16}, Yii-Der I Chen²⁴, Kristian Hveem^{33

34

35}, Nicholas J Wareham¹², Sekar Kathiresan³⁰, Olle Melander¹⁰, Kari Stefansson⁹, Børge G Nordestgaard^{36

37

38

39}, Anne Tybjærg-Hansen^{8

36

38

39}, Goncalo R Abecasis⁷, David Altshuler^{11

40

41

42}, Jose C Florez^{43

44

45}, Michael Boehnke⁷, Mark I McCarthy^{4

46

47}, George D Yancopoulos¹, David J Carey³, Alan R Shuldiner², Aris Baras⁴⁸, Frederick E Dewey⁴⁹, Jesper Gromada⁵⁰

Affiliations

¹ Regeneron Pharmaceuticals, Tarrytown, 10591, NY, USA.
² Regeneron Genetics Center, Tarrytown, 10591, NY, USA.
³ Geisinger, Danville, 17822, PA, USA.
⁴ Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.
⁵ Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, University of Michigan, Ann Arbor, 48109, MI, USA.
⁶ Department of Human Genetics, University of Michigan, University of Michigan, Ann Arbor, 48109, MI, USA.
⁷ Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, 48109, MI, USA.
⁸ Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, 2100, Denmark.
⁹ deCODE Genetics/Amgen, Inc., Reykjavik, 101, Iceland.
¹⁰ Department of Clinical Sciences, Malmö, Lund University, Malmö, 221, Sweden.
¹¹ Program in Medical and Population Genetics, Broad Institute, Cambridge, 02142, MA, USA.
¹² MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
¹³ Department of Medical Research, Taichung Veterans General Hospital, Taichung, 40705, Taiwan.
¹⁴ Department of Social Work, Tunghai University, Taichung, 40704, Taiwan.
¹⁵ Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, 19104, PA, USA.
¹⁶ Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, 19104, USA.
¹⁷ Division of Cardiology, Department of Medicine; Molecular Physiology Institute, School of Medicine, Duke University, Durham, 27710, NC, USA.
¹⁸ Finnish Institute of Molecular Medicine (FIMM), Helsinki University, Helsinki, 00170, Finland.
¹⁹ Department of Clinical Sciences, Clinical Research Centre, Lund University, Malmö, 221, Sweden.
²⁰ Instituto de Investigaciones Biomédicas, UNAM, Coyoacán, 04510, Mexico City, Mexico.
²¹ Unidad de Biología Molecular y Medicina Genómica, UNAM/INCMNSZ Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, 14080, Mexico.
²² Department of Biostatistics, University of Liverpool, Liverpool, L69 7ZX, UK.
²³ Estonian Genome Center, University of Tartu, Tartu, 50090, Estonia.
²⁴ Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, LABioMed at Harbor-UCLA Medical Center, Torrance, 90502, CA, USA.
²⁵ Division of Endocrinology & Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, 10617, Taiwan.
²⁶ Institute of Preventive Medicine, School of Public Health, National Taiwan University, Taipei, 10617, Taiwan.
²⁷ Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, 19104, PA, USA.
²⁸ Department of Surgery, Corporal Michael Crescenz VA Medical Center, Philadelphia, 19104, PA, USA.
²⁹ Department of Anesthesiology, University of Michigan, Ann Arbor, 48109, MI, USA.
³⁰ Center for Human Genetic Research, Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, 02114, MA, USA.
³¹ Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, 02114, MA, USA.
³² Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, 48109, MI, USA.
³³ HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, 7601, Norway.
³⁴ K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health, Norwegian University of Science and Technology, Trondheim, 7491, Norway.
³⁵ Department of Medicine, Levanger Hospital, Nord-Trøndelag Health Trust, Levanger, 7601, Norway.
³⁶ The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, 2730, Denmark.
³⁷ Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, 2730, Denmark.
³⁸ The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, 2400, Denmark.
³⁹ Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark.
⁴⁰ Department of Molecular Biology, Diabetes Unit, and Center for Human Genetic Research, Massachusetts General Hospital, Boston, 02114, MA, USA.
⁴¹ Departments of Genetics and Medicine, Harvard Medical School, Boston, 02115, MA, USA.
⁴² Department of Biology, Massachusetts Institute of Technology, Cambridge, 02139, MA, USA.
⁴³ Diabetes Unit and Center for Human Genetic Research, Massachusetts General Hospital, Boston, 02115, MA, USA.
⁴⁴ Programs in Metabolism and Medical & Population Genetics, Broad Institute, Cambridge, 02142, MA, USA.
⁴⁵ Department of Medicine, Harvard Medical School, Boston, 02115, MA, USA.
⁴⁶ Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, OX3 7LE, UK.
⁴⁷ Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, OX4 2PG, UK.
⁴⁸ Regeneron Genetics Center, Tarrytown, 10591, NY, USA. aris.baras@regeneron.com.
⁴⁹ Regeneron Genetics Center, Tarrytown, 10591, NY, USA. rickdewey@gmail.com.
⁵⁰ Regeneron Pharmaceuticals, Tarrytown, 10591, NY, USA. jesper.gromada@regeneron.com.

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.

MeSH terms

Amino Acid Substitution
Angiopoietin-Like Protein 4 / deficiency*
Angiopoietin-Like Protein 4 / genetics*
Angiopoietin-Like Protein 4 / metabolism
Animals
Blood Glucose / metabolism
Case-Control Studies
Diabetes Mellitus, Type 2 / etiology
Diabetes Mellitus, Type 2 / genetics*
Diabetes Mellitus, Type 2 / metabolism*
Exome Sequencing
Female
Gene Silencing
Genetic Association Studies
Genetic Variation
Heterozygote
Homeostasis
Humans
Insulin Resistance / genetics
Lipoprotein Lipase / metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Risk Factors

Substances

ANGPTL4 protein, human
Angiopoietin-Like Protein 4
Angptl4 protein, mouse
Blood Glucose
Lipoprotein Lipase

Abstract

MeSH terms

Substances

Grants and funding