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Genetic Mutations That Protect Against Cardiovascular Disease

Study of 10,503 adults in Pakistan identifies gene-inactivating mutations that may lead to new heart disease drugs. 

Rachele Hendricks-Sturrup
Tue, 07/11/2017


Unidentified children in a village in the south of Skardu, Pakistan are learning in the classroom of the village school on April 18, 2015.



People with inactive versions of certain genes may be at lower risk of cardiovascular disease, according to a new clinical study called the Pakistan Risk of Myocardial Infarction Study (PROMIS).

In the study, which involved 10,503 adults in Pakistan, researchers from the Broad Institute of Harvard and MIT, the University of Pennsylvania, Punjab Institute of Cardiology in Pakistan and other organizations sought to learn about genes involved in cardiovascular health by identifying people with nonfunctional versions of particular genes.

They examined the phenotypic outcomes and effects of “consanguineous unions”—marriages between people who are family members, second cousins or closer—in Pakistan, where such unions are relatively common. Because blood relatives share many of the same mutations, individuals who marry relatives are more likely to carry or bear children with two copies of the same recessive loss-of-function mutation. While one copy of such a mutation doesn't destroy gene function, two copies result in inactivation of the gene.

The researchers specifically investigated the phenotypic outcomes associated with consanguineous union-derived homozygous predicted loss-of-function mutations in their study population, which consisted of mostly men (83 percent) of an average age of 52. The researchers hypothesized that certain predicted loss-of-function mutations would serve as potential determinants of human metabolic and cardiovascular disease outcomes, such as diabetes, familial chylomicronemia syndrome, coronary artery disease and lung disease.

The study revealed cardiovascular-protective effects of homozygous predicted loss-of-function mutations in several genes:

  • APOC3 (implicated in familial chylomicronemia syndrome);
  • PLA2G (implicated in coronary artery disease); and
  • A3GALT2 (which could be implicated in diabetes and/or insulin regulation).

These findings pave the way for exploring potential new drug targets to treat cardiovascular and metabolic diseases.

“In 2014, we published an earlier paper showing that losing one copy of APOC3 led to lower blood triglycerides and protection against coronary heart disease. This established APOC3 as a therapeutic target," said Sekar Kathiresan, a corresponding author on the paper. "Now, we have found humans who lack both copies, and this suggests that inhibition of APOC3 is likely to be safe.”

The study provides a proof-of- concept substantiating the goals of the Human Knockout Project, a larger project that aims to identify and understand the genotypic profiles of people with nonfunctional versions of genes, Kathiresan said.

“The human genome project gave us a parts-list of genes," Kathiresan said. "We are now in a position to examine what missing a part means."