Rare loss of function variants in the hepatokine gene INHBE protect from abdominal obesity.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
27 07 2022
27 07 2022
Historique:
received:
20
12
2021
accepted:
01
07
2022
entrez:
27
7
2022
pubmed:
28
7
2022
medline:
30
7
2022
Statut:
epublish
Résumé
Identifying genetic variants associated with lower waist-to-hip ratio can reveal new therapeutic targets for abdominal obesity. We use exome sequences from 362,679 individuals to identify genes associated with waist-to-hip ratio adjusted for BMI (WHRadjBMI), a surrogate for abdominal fat that is causally linked to type 2 diabetes and coronary heart disease. Predicted loss of function (pLOF) variants in INHBE associate with lower WHRadjBMI and this association replicates in data from AMP-T2D-GENES. INHBE encodes a secreted protein, the hepatokine activin E. In vitro characterization of the most common INHBE pLOF variant in our study, indicates an in-frame deletion resulting in a 90% reduction in secreted protein levels. We detect associations with lower WHRadjBMI for variants in ACVR1C, encoding an activin receptor, further highlighting the involvement of activins in regulating fat distribution. These findings highlight activin E as a potential therapeutic target for abdominal obesity, a phenotype linked to cardiometabolic disease.
Identifiants
pubmed: 35896531
doi: 10.1038/s41467-022-31757-8
pii: 10.1038/s41467-022-31757-8
pmc: PMC9329324
doi:
Substances chimiques
INHBE protein, human
0
Inhibin-beta Subunits
93443-12-0
ACVR1C protein, human
EC 2.7.11.30
Activin Receptors, Type I
EC 2.7.11.30
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
4319Subventions
Organisme : Medical Research Council
ID : MC_PC_17228
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_QA137853
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : R01 DK125490
Pays : United States
Informations de copyright
© 2022. The Author(s).
Références
N Engl J Med. 2017 Jul 20;377(3):211-221
pubmed: 28538136
Gigascience. 2015 Feb 25;4:7
pubmed: 25722852
Cell Rep. 2018 Oct 30;25(5):1193-1203
pubmed: 30380411
Biometrics. 2020 Dec;76(4):1262-1272
pubmed: 31883270
Nature. 2020 Oct;586(7831):749-756
pubmed: 33087929
Nat Genet. 2021 Dec;53(12):1712-1721
pubmed: 34857953
PLoS Genet. 2019 Dec 12;15(12):e1008489
pubmed: 31830040
Am J Hum Genet. 2022 Jan 6;109(1):81-96
pubmed: 34932938
Nature. 2015 Feb 12;518(7538):187-196
pubmed: 25673412
Bioinformatics. 2009 Jul 15;25(14):1754-60
pubmed: 19451168
Science. 2021 Jul 2;373(6550):
pubmed: 34210852
JAMA. 2017 Feb 14;317(6):626-634
pubmed: 28196256
Circulation. 2017 Jun 13;135(24):2373-2388
pubmed: 28500271
Lancet. 1993 Oct 9;342(8876):924
pubmed: 8105179
Nature. 2019 Jun;570(7759):71-76
pubmed: 31118516
Science. 1988 May 6;240(4853):787-90
pubmed: 2834824
Genome Biol. 2016 Jun 06;17(1):122
pubmed: 27268795
N Engl J Med. 2006 Mar 23;354(12):1264-72
pubmed: 16554528
Nature. 2016 Aug 4;536(7614):41-47
pubmed: 27398621
Am J Hum Genet. 2013 Dec 5;93(6):1072-86
pubmed: 24290377
PLoS One. 2018 Mar 29;13(3):e0194798
pubmed: 29596463
J Hepatol. 2020 Dec;73(6):1594-1595
pubmed: 32951912
Nature. 2020 May;581(7809):434-443
pubmed: 32461654
Am J Hum Genet. 2014 Nov 6;95(5):553-64
pubmed: 25439724
Nature. 2006 Dec 14;444(7121):881-7
pubmed: 17167477
Nat Rev Drug Discov. 2013 Aug;12(8):581-94
pubmed: 23868113
N Engl J Med. 1993 Jul 22;329(4):241-5
pubmed: 8316268
Nature. 2021 Nov;599(7886):628-634
pubmed: 34662886
Diabetes. 2019 Jan;68(1):226-234
pubmed: 30389748
Can J Cardiol. 2014 Dec;30(12):1649-54
pubmed: 25475467
Mol Metab. 2021 Nov;53:101295
pubmed: 34271221
Nat Commun. 2022 Jun 30;13(1):3771
pubmed: 35773277
Nature. 2022 Jul;607(7920):732-740
pubmed: 35859178
Bioinformatics. 2016 Apr 15;32(8):1220-2
pubmed: 26647377
Nat Commun. 2019 Nov 27;10(1):5402
pubmed: 31776332
J Clin Endocrinol Metab. 2022 Mar 24;107(4):1065-1077
pubmed: 34875679
N Engl J Med. 2011 Feb 24;364(8):740-8
pubmed: 21345103
Nature. 2017 Oct 11;550(7675):204-213
pubmed: 29022597
J Clin Invest. 2011 Feb;121(2):769-83
pubmed: 21293061
Eur J Hum Genet. 2016 Aug;24(8):1181-7
pubmed: 26757982
J Biol Chem. 2003 Sep 26;278(39):37713-21
pubmed: 12840023
N Engl J Med. 2008 Nov 13;359(20):2105-20
pubmed: 19005195
JMIR Med Inform. 2019 Nov 29;7(4):e14325
pubmed: 31553307
Nat Genet. 2021 Jul;53(7):1097-1103
pubmed: 34017140
Bioinformatics. 2010 Sep 1;26(17):2190-1
pubmed: 20616382
Sci Rep. 2021 May 21;11(1):10688
pubmed: 34021172
Nature. 2014 Feb 6;506(7486):97-101
pubmed: 24390345
Nucleic Acids Res. 2019 Jan 8;47(D1):D886-D894
pubmed: 30371827
Cold Spring Harb Perspect Biol. 2016 Jul 01;8(7):
pubmed: 27328872
Nat Genet. 1999 Aug;22(4):336-45
pubmed: 10431236
Nat Genet. 2018 Apr;50(4):559-571
pubmed: 29632382
Sci Rep. 2021 Nov 3;11(1):21565
pubmed: 34732801
Lancet Diabetes Endocrinol. 2019 Sep;7(9):715-725
pubmed: 31301983
Bioinformatics. 2016 Jan 1;32(1):133-5
pubmed: 26382196
Elife. 2021 Apr 15;10:
pubmed: 33856341
J Biol Chem. 1990 Sep 5;265(25):14979-85
pubmed: 2168397
Lancet. 2005 Nov 5;366(9497):1640-9
pubmed: 16271645
JAMA. 2001 May 16;285(19):2486-97
pubmed: 11368702
Nat Genet. 2019 Mar;51(3):452-469
pubmed: 30778226
J Allergy Clin Immunol. 2020 Feb;145(2):537-549
pubmed: 31669095
Nat Genet. 2015 Aug;47(8):856-60
pubmed: 26121088
Am J Hum Genet. 2014 Feb 6;94(2):233-45
pubmed: 24507775
Elife. 2022 Jun 23;11:
pubmed: 35736809
Nature. 2013 Jan 10;493(7431):216-20
pubmed: 23201682
Hum Mol Genet. 2019 Jan 1;28(1):166-174
pubmed: 30239722
J Neurol Sci. 1999 Jun 1;165(2):121-5
pubmed: 10450796