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

Author

Listed:
  • 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
    Division of Genetics and Genomics, Boston Children’s Hospital
    Harvard Medical School)

  • Jason Flannick

    (Programs in Metabolism and Medical & Population Genetics, Broad Institute
    Division of Genetics and Genomics, Boston Children’s Hospital
    Harvard Medical School)

  • 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)

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.

Suggested Citation

  • 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 , 2022. "Rare loss of function variants in the hepatokine gene INHBE protect from abdominal obesity," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31757-8
    DOI: 10.1038/s41467-022-31757-8
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