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Heart Disease: An Inherited Quirk

Studying a family with miniscule levels of low-density lipoproteins may help develop gene therapies for people predisposed to heart disease.

By Lauren Ware // The MGH Research Issue 2011
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genetics case study

Justin Gabbard

“People with a strong family history of heart disease have two to three times the normal risk of heart attack,” says Sekar Kathiresan, director of preventive cardiology at MGH. Seeking to discover the genetic underpinnings of that heightened vulnerability, Kathiresan and his colleagues looked at 38 members of one family across three generations. But this particular clan didn’t have an elevated risk of heart disease. On the contrary, family members shared a quirk that reduced their risk—abnormally scant levels of low-density lipoproteins (LDL).

When LDL is high, so is the risk of heart disease. By looking for a gene that might explain this family’s unusually low levels, Kathiresan hoped to uncover a way to push down LDL in other people. For each family member, the researchers sequenced the exome, the portion of the genome that provides the genetic code for forming proteins. They discovered “nonsense mutations”—changes in the normal DNA sequence that hindered production of the angiopoietin-like 3 (ANGPTL3) protein. Family members who had one copy of the mutated gene had lower than normal levels of ANGPTL3, but those who had two copies made virtually none of the protein—and had the lowest levels of LDL.

Knowing that ANGPTL3 raises LDL levels in humans will help lead scientists to a very specific avenue for reducing LDL in people at risk of heart disease, says Kathiresan. “We’re now in a position to systematically apply a genomic approach to find out why some people are protected from heart disease.”

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