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Exome Sequencing Leads to Rare Heart Attack Risk Variants in Two Genes

NEW YORK (GenomeWeb) – An international team led by investigators at Massachusetts General Hospital, Harvard Medical School, and the Broad Institute has identified rare variants in two genes that seem to dial up heart attack risk.

As they reported online today in Nature, researchers did exome sequencing on nearly 10,000 individuals with or without early-onset myocardial infarction — a search that ultimately led to rare heart attack risk variants in genes called LDLR and APOA5 that are involved in low-density lipoprotein (LDL) cholesterol levels and triglyceride lipoprotein levels, respectively.

"Our APOA5 result tells us that beyond LDL levels, which are well-known to contribute to heart attack risk, abnormalities in triglyceride metabolism also play an important role," corresponding author Sekar Kathiresan said in statement.

Kathiresan is director of preventive cardiology at Massachusetts General Hospital. He is also affiliated with Harvard Medical School and the Broad Institute.

Past studies have pointed to a few dozen common variants associated with elevated heart attack risk, he and his co-authors noted, while studies on families prone to myocardial infarction highlighted rare mutations in genes involved in LDL cholesterol levels.

Because heart attack heritability appears to be higher in individuals who experience myocardial infarction at younger-than-usual ages, the researchers decided to focus on early-onset cases: men with a history of myocardial infarction prior to their 50th birthdays and women with myocardial infarction before the age of 60.

To that end, the team started by evaluating protein-coding sequences in the genomes of 1,027 individuals with early-onset myocardial infarction who'd been enrolled through the US National Heart, Lung, and Blood Institute's exome sequencing study.

For the discovery stage of the study, researchers compared these exomes to those generated for 946 elderly control individuals (men over the age of 60 and women over the age of 70) who had not experienced myocardial infarction.

The team did not detect significant associations between myocardial infarction and individual SNPs in the discovery data set. Nor where there clear ties to heart attack risk in its original gene-based association analysis.

But that changed when researchers broadened their search to include additional samples assessed by imputation, array-based genotyping, targeted sequencing, or exome sequencing.

In these follow-up stages of the study, they found clues that rare mutations in the apolipoprotein A-V gene APOA5, which are related to elevated blood triglyceride levels, are more common in individuals with early-onset heart attack than in those without.

Meanwhile, data from the full collection of 9,793 case and control exomes considered for the discovery and follow-up phases of the investigation led the team to rare mutations in LDLR, which were linked to elevated levels of LDL cholesterol.

The researchers estimated that rare mutations in APOA5 or LDLR bump up heart attack risk to varying degrees depending on the severity of these mutations. For instance, rare deleterious glitches in APOA5 appeared to more-than-double heart attack risk, while mutations that disrupt the gene were associated with a roughly 4.5-fold increase in risk.

The estimated heart attack risk rose by roughly 4.2-fold given rare, deleterious mutations in LDLR gene, whereas apparently disruptive changes in that gene were associated with a 13-fold higher risk.

Though triglyceride ties to heart disease have traditionally been more tenuous than LDL cholesterol levels, the findings do fit with results described in the early 1970s that linked heart attack risk with higher-than-usual levels of cholesterol or triglycerides in the blood.

"Now, after sequencing all of the genes in the genome, we can directly point to the specific genes that are most important," Kathiresan said. "There is remarkable consistency between the observations from 40 years ago and today."