The discovery leveraged sequencing data from more than 360,000 individuals in UK Biobank, and was published in Nature Communications.
The published data shows that rare mutations in the liver-expressed INHBE gene are associated with lower waist-to-hip ratio adjusted for body mass index, (WHRadjBMI), a surrogate for abdominal fat that is causally linked to type 2 diabetes and coronary heart disease.
Findings support the potential of INHBE to be evaluated as a novel therapeutic target for the treatment of cardiometabolic disease, said the RNAi therapeutics developer.
It added that it plans to pursue a development candidate for INHBE and its gene product, Activin E, leveraging its liver IKARIA platform.
Dr Paul Nioi, vice president, discovery and translational research, and the leader of Alnylam’s human genetics group, commented on the development.
“There is a well-established causal link between increased waist-to-hip ratio and a person’s risk of cardiometabolic conditions. By exploring the genetic determinants of waist-to-hip ratio in this study, important insights into the mechanisms that contribute to body fat distribution were uncovered helping identify potential therapeutic targets for abdominal obesity, like INHBE.
“The results of this exome-wide analysis suggest that targeting INHBE is predicted to have broad beneficial effects on all facets of metabolic syndrome with potential reductions in the risk of type 2 diabetes and coronary heart disease. We are currently testing this hypothesis, with the goal of pursuing a development candidate targeting INHBE.”
The findings
Using whole exome-sequencing data from UK Biobank, Alnylam said its team and collaborators mined for gene variants associated with lower WHRadjBMI in more than 360,000 individuals of European ancestry, revealing “loss of function” in INHBE as a novel genetic factor contributing to a healthier fat distribution.
Rare predicted loss of function (pLOF) variants in INHBE, were carried by one in 587 individuals and were associated with lower abdominal fat.
In vitro characterization of the most common INHBE pLOF variant in the study, indicated an approximately 90% reduction in secreted activin E levels. Further analysis of INHBE pLOF carriers revealed a favorable metabolic profile, including decreased triglycerides, increased high-density lipoprotein cholesterol, and decreased fasting glucose.
There were no associations suggesting adverse effects of INHBE pLOF, and carriers of these variants did not show evidence of excess mortality. The study also detected associations with lower WHRadjBMI for variants in ACVR1C, encoding an activin receptor, further highlighting the involvement of activins in regulating fat distribution.
Biobank project
In 2018, Alnylam and partners Regeneron, AbbVie, AstraZeneca, Biogen, and Pfizer, announced an agreement with UK Biobank to form the UK Biobank Exome Sequencing Consortium (UKB-ESC), a pre-competitive consortium that aims to sequence the whole exomes of 500,000 volunteer participants in the biomedical resource.
The goal of the consortium, which represents the largest ever effort to use genome sequencing to map the DNA of a group of people, is to uncover insights that allow researchers to pinpoint new drug targets at the core of human disease in order to develop effective treatments for patients.
To date, the UKB-ESC has made whole-exome sequencing data from 450,000 participants available to the global health community for research purposes and will continue to make all sequenced data available at no cost under the terms of the UKB-ESC charter and the founding principles of UK Biobank.
