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

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.

Empowering rare variant burden-based gene-trait association studies via optimized computational predictor choice

“…Burden scans have shown great promise for identifying disease mechanisms and therapeutic targets [39, 61]. Through an independent assessment of 20 computational variant effect predictors, this study identified two predictors, VARITY and REVEL, as corresponding most closely with human traits in a large prospective cohort, suggesting that they might also enhance the power of rare-variant burden scans for detecting gene-trait associations.…”

The GDF3-ALK7 signaling axis in adipose tissue: a possible therapeutic target for obesity and associated diabetes?

“…It remains unknown from which cells activin B or C is derived to act on ALK7 in adipocytes. On the other hand, mutations of genes encoding hepatokine, activin E, and ALK7 are commonly associated with fat distribution and diabetes risk in humans [31,32], although there is no direct biochemical evidence for their ligand-receptor relationship.…”

“…A recent work using inhibitors of Smad Activin AB, B, and C can activate ALK7 signaling both in heterologous cells and in adipocytes [5,23,30], although it is unknown from which cells these activins are derived to act on ALK7 in vivo. Variants in activin E produced from liver and ALK7 are associated with a lower waist-to-hip ratio in humans [31,32], although there is no direct evidence for the ligand-receptor relationship between them. GDF3 can also activate ALK7 signaling both in heterologous cells and in adipocytes [11,25].…”

The Sexual Dimorphism of Human Adipose Depots

“…Expression quantitative trait loci (eQTLs) analysis in relevant tissues together with exome sequencing further highlighted enrichment in the brain- or peripheral-tissue-related pathways as a determinant for BMI or WHRadjBMI, respectively. For example, the predictive loss of function (pLoF) of adipocyte-expressed PLIN1 , INSR , ACVR1C and PDE3B and liver-expressed INHBE variants are associated with increased gfSAT and healthy metabolic phenotypes [ 61 , 70 , 71 ]. Importantly, WHRadjBMI-associated loci exhibit heritability and effect size stronger in women than men with one-third of all signals sexually dimorphic [ 72 ].…”

“…The GWAS highlight several peripheral tissue- and cell-enriched pathways as determinants for WHRadjBMI suggesting that WAT intrinsic cell composition, function and remodeling are key contributors in fat depot repartition [ 61 , 70 , 71 ]. Recent single-cell atlas of human and mouse WAT provides a transcriptional basis of the heterogeneity in subsets of resident progenitors and adipocytes with fat depot-specific prevalence and functions [ 82 ].…”