| Title: | Rare loss of function variants in the hepatokine gene INHBE protect from abdominal obesity |
| Journal: | Nature Communications |
| Published: | 27 Jul 2022 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/35896531/ |
| DOI: | https://doi.org/10.1038/s41467-022-31757-8 |
| URL: | https://www.nature.com/articles/s41467-022-31757-8.pdf |
| Citations: | 21 (19 in last 2 years) as of 8 Aug 2024 |
Publication 7369
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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.17 Authors
- 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
- Paul Nioi
2 Applications
| Application ID | Title |
|---|---|
| 26041 | Large-Scale Sequencing in the UK Biobank to Facilitate Gene Discovery, Genome Sciences, and Precision Medicine |
| 65851 | Large-scale proteomic profiling to facilitate genetics-guided drug discovery and precision medicine: The UK Biobank - Pharma Proteomics Project (UKB-PPP) |
Enabling scientific discoveries that improve human health