Rare Genetic Mutations in LDLR and APOA5 Associated With Early-Onset MI in Men and Women

December 17, 2014

BOSTON, MA — Rare variants in two genes—low-density-lipoprotein receptor (LDLR) and apolipoprotein A-V (APOA5)—are associated with a significantly increased risk of early-onset myocardial infarction, according to a large exome-sequencing study[1].

In sequencing the protein-coding regions of 9793 genomes in individuals with early-onset MI (<50 years in men and <60 years in women) and healthy controls, the rare coding-sequence mutations in both genes were more frequent in MI cases than in healthy individuals, according to the report published December 11, 2014 in Nature.

"Of all genes in the genome, low-density-lipoprotein receptor is the most important at the population level, accounting for about 2% of all heart attacks before the age of 50 in men and 60 in women," senior investigator Dr Sekar Kathiresan (Massachusetts General Hospital/Broad Institute, Boston) told heartwire . "Remarkably, about one in 200 individuals carry a mutation in LDLR and have very high LDL cholesterol (LDL >190 mg/dL). These people are at fourfold-higher risk for heart attack."

The LDL receptor is encoded by LDLR, and mutations in this gene are responsible for familial hypercholesterolemia (FH). Kathiresan said that heterozygous FH has been estimated to occur in approximately one in 500 individuals based on a classic study by Nobel laureate Dr Joseph Goldstein (University of Texas Southwestern Medical Center, Dallas) using total-cholesterol levels. In directly sequencing the genes, the estimate appears to be much closer to one in 200 individuals.

"Finding every one of these individuals with LDLR mutations and high LDL and offering treatment may dramatically reduce early heart attack in the population," noted Kathiresan.

In addition to LDL cholesterol, the exomewide sequencing study suggests that some triglyceride-rich lipoprotein (TRL) pathways might be responsible for causing MI. For APOA5, carriers of the rare mutations had a 2.2-fold increased risk of MI.

APOA5, Kathiresan told heartwire , is functionally related to two other TRL genes, LPL and APOC3, and mutations in all three genes affect the TRL pathway and MI risk. Targeting the TRL pathway in the future might reduce the risk of MI, he noted.

Funding for the exome-sequencing project was provided by National Heart, Lung, and Blood Institute grants. Kathiresan is supported by a research scholar award from the Massachusetts General Hospital, the Howard Goodman Fellowship, the Donovan Family Foundation, and a grant from Fondation Leducq. Disclosures for the coauthors are listed in the article.


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