Rare loss of function variants in the hepatokine gene INHBE protect from abdominal obesity

Aimee M. Deaton (), Aditi Dubey, Lucas D. Ward, Peter Dornbos, Jason Flannick, Elaine Yee, Simina Ticau, Leila Noetzli, Margaret M. Parker, Rachel A. Hoffing, Carissa Willis, Mollie E. Plekan, Aaron M. Holleman, Gregory Hinkle, Kevin Fitzgerald, Akshay K. Vaishnaw and Paul Nioi
Additional contact information
Aimee M. Deaton: Alnylam Pharmaceuticals
Aditi Dubey: Alnylam Pharmaceuticals
Lucas D. Ward: Alnylam Pharmaceuticals
Peter Dornbos: Programs in Metabolism and Medical & Population Genetics, Broad Institute
Jason Flannick: Programs in Metabolism and Medical & Population Genetics, Broad Institute
Elaine Yee: Alnylam Pharmaceuticals
Simina Ticau: Alnylam Pharmaceuticals
Leila Noetzli: Alnylam Pharmaceuticals
Margaret M. Parker: Alnylam Pharmaceuticals
Rachel A. Hoffing: Alnylam Pharmaceuticals
Carissa Willis: Alnylam Pharmaceuticals
Mollie E. Plekan: Alnylam Pharmaceuticals
Aaron M. Holleman: Alnylam Pharmaceuticals
Gregory Hinkle: Alnylam Pharmaceuticals
Kevin Fitzgerald: Alnylam Pharmaceuticals
Akshay K. Vaishnaw: Alnylam Pharmaceuticals
Paul Nioi: Alnylam Pharmaceuticals

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-31757-8

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