Mutations Counteract Abdominal Obesity and Metabolic Syndrome

RNA interface (RNAi) therapeutics company Alnylam Pharmaceuticals has made public its discovery of mutations in the INHBE gene associated with mitigating a condition that affects more than 20% of adults the world over: abdominal obesity and metabolic syndrome. Sequencing data derived from more than 360,00 individuals in U.K. Biobank provided the information that led to their discovery. Rarely seen mutations in the liver-expressive INHBE gene are linked with lower average waist-to-hip ratios adjusted for body mass index (WHRadjBMI), which when higher is an indication of risk for developing type 2 diabetes and coronary heart disease. Now, backed by the findings, INHBE is a prime candidate for a novel therapeutic target for treatment of cardiometabolic disease.

Alnylam has plans to this end; its liver IKARIA platform will be a fundamental building block for the candidate. “We are thrilled that our investment in genetic databases like U.K. Biobank is proving to be fruitful in identifying novel targets in highly prevalent diseases with continued unmet need,” said Dr. Paul Nioi, the Vice President of Discovery and Translational Research as well as the leader of Alnylam’s Human Genetics Group. 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 in the near future.”

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“Loss of function” in INHBE was an uncovered novel genetic factor resulting in healthier distribution of body fat. The variant, which signals a roughly 90% reduction in secreted activin E levels, was found in one in 587 individuals. Additional analysis of those carrying INHBE pLOF has a preferable metabolic profile that also boasted decreased triglycerides, increased high-density lipoprotein cholesterol, and decreased fasting glucose.