Lower abdominal fat and cardiovascular risk? Alnylam thinks it found a gene for that

Who doesn’t want reduced abdominal fat and a lower risk of cardiovascular disease? Well, Alnylam Pharmaceuticals thinks it’s identified the gene mutation that makes this fitness instructor’s dream a reality.

The drugmaker leveraged gene sequencing data from over 360,000 individuals held in the UK Biobank, a large-scale biomedical database. In its findings, published July 27 in the journal Nature Communications, Alnylam showed that rare mutations in the INHBE gene expressed by the liver are tied to a lower waist-to-hip ratio adjusted for body mass index, which is used as a surrogate measure of abdominal fat and has been linked to type 2 diabetes and coronary heart disease.

The researchers looked to animals to confirm their thesis, where they noted a higher expression of INHBE in the livers of obese monkeys compared to lean monkeys.

“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,” Paul Nioi, Ph.D., Vice President of Discovery and Translational Research at Alnylam and leader of the company’s Human Genetics Group, said in a statement.

 “We are currently testing this hypothesis, with the goal of pursuing a development candidate targeting INHBE in the near future.”

To make their discovery, Alnylam and its collaborators searched the database for gene variants associated with a lower waist-to-hip ratio adjusted for body mass index. This analysis revealed that a faulty INHBE gene, seen in one in every 587 individuals on the database, was a factor that contributed to a healthier distribution of fat around the body.

In vitro tests showed that the most common variant causing a loss of INHBE function was linked to around a 90% reduction in levels of a secreted protein called activin E. Further analysis of individuals with this gene variant then revealed they had a favorable metabolic profile, including lower levels of triglycerides—a type of fat found in the blood—increased high-density lipoprotein cholesterol, and decreased fasting glucose.

What’s more, scanning the database suggested there are no adverse effects to losing the function of the INHBE gene, and individuals who carried the variant did not appear to die any earlier on average.

Armed with these results, the Cambridge, Mass.-based company plans to leverage its Ikaria RNAi platform to develop a candidate that targets INHBE and Activin E.

“Importantly, by reducing abdominal fat, drugs targeting INHBE would have a distinct biological mechanism to existing drugs for coronary heart disease and type 2 diabetes and may complement current therapies,” Alnylam concluded in its study results.