Rare Genetic Variation Associated with Lower-Than-Average Risk of Heart Disease

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Researchers from Amgen Inc.’s (Thousand Oaks CA) deCode genetics unit said they have discovered a rare genetic variation that is associated with a 34% lower-than-average risk of heart disease, potentially opening up a new front in the battle against the world’s leading killer.

Carriers of the variant, in a gene called ASGR1, had substantially lower levels of harmful cholesterol, which researchers said likely accounted for a portion of the lower heart risk. Amgen is now working on several potential agents designed to mimic the effect of this genetic trait in hopes of converting discovery of a rare mutation into a drug that could have broad impact against a common disease.

It expects to begin testing one of the candidates in people within two years. The variant was found in one out of about 120 people in the study and was associated with an additional year of life. A second much rarer variant of the same gene was also linked to lower harmful cholesterol.

Despite its link with lower cholesterol, the gene isn’t associated with other known cholesterol-related mechanisms, fueling hope that an effective drug might further reduce risk of heart disease beyond reductions achieved with cholesterol-lowering drugs called statins.

“We have a mutation in a gene that is in a different pathway than the one people usually look at in cardiovascular disease,” said Kari Stefansson, deCode’s CEO.

He is senior author of a report on the discovery published online by the New England Journal of Medicine. DeCode, based in Reykjavik, Iceland, has accumulated a huge database of genomic and health data of Icelanders.

Researchers discovered the role of the genetic anomaly by analyzing the data and then replicating the results by extending the analysis to 300,000 people in the U.S., United Kingdom and other countries. The finding underscores the power of a new, big data approach to drug discovery: using computers to analyze huge genomic databases to identify potential drug targets.

Amgen is among several drug companies betting that big data can help make sense of the flood of data from genetic sequencing and electronic health records in a high-tech effort to find the molecular roots of disease. Discovery of a potential drug target like ASGR1 “is exactly what we had in mind” when the company acquired deCode in 2012, said Sean Harper, Amgen’s chief of research and development.

Monday, May 23, 2016 / Vol. 24 / No. 20