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

Publication ,  Journal Article
Gusarova, V; O'Dushlaine, C; Teslovich, TM; Benotti, PN; Mirshahi, T; Gottesman, O; Van Hout, CV; Murray, MF; Mahajan, A; Nielsen, JB; Lee, W-J ...
Published in: Nat Commun
June 13, 2018

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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Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

June 13, 2018

Volume

9

Issue

1

Start / End Page

2252

Location

England

Related Subject Headings

  • Risk Factors
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Lipoprotein Lipase
  • Insulin Resistance
  • Humans
  • Homeostasis
  • Heterozygote
 

Citation

APA
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ICMJE
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Gusarova, V., O’Dushlaine, C., Teslovich, T. M., Benotti, P. N., Mirshahi, T., Gottesman, O., … Gromada, J. (2018). Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes. Nat Commun, 9(1), 2252. https://doi.org/10.1038/s41467-018-04611-z
Gusarova, Viktoria, Colm O’Dushlaine, Tanya M. Teslovich, Peter N. Benotti, Tooraj Mirshahi, Omri Gottesman, Cristopher V. Van Hout, et al. “Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes.Nat Commun 9, no. 1 (June 13, 2018): 2252. https://doi.org/10.1038/s41467-018-04611-z.
Gusarova V, O’Dushlaine C, Teslovich TM, Benotti PN, Mirshahi T, Gottesman O, et al. Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes. Nat Commun. 2018 Jun 13;9(1):2252.
Gusarova, Viktoria, et al. “Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes.Nat Commun, vol. 9, no. 1, June 2018, p. 2252. Pubmed, doi: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 W-J, 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 L-M, 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 Y-DI, 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. Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes. Nat Commun. 2018 Jun 13;9(1):2252.

Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

June 13, 2018

Volume

9

Issue

1

Start / End Page

2252

Location

England

Related Subject Headings

  • Risk Factors
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Lipoprotein Lipase
  • Insulin Resistance
  • Humans
  • Homeostasis
  • Heterozygote