Rare loss of function variants in the hepatokine gene INHBE protect from abdominal obesity.
Aimee M DeatonAditi DubeyLucas D WardPeter DornbosJason Flannicknull nullElaine YeeSimina TicauLeila NoetzliMargaret M ParkerRachel A HoffingCarissa WillisMollie E PlekanAaron M HollemanGregory HinkleKevin FitzgeraldAkshay K VaishnawPaul NioiPublished in: Nature communications (2022)
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.
Keyphrases
- copy number
- type diabetes
- insulin resistance
- body mass index
- weight gain
- genome wide
- metabolic syndrome
- weight loss
- adipose tissue
- high fat diet induced
- glycemic control
- dna methylation
- body weight
- cardiovascular disease
- protein protein
- binding protein
- total hip arthroplasty
- genome wide identification
- protein kinase
- amino acid
- physical activity
- gene expression
- big data
- transcription factor