CAMBRIDGE, Mass.—While recent research has already elucidated the existence of protective mutations within the APOC3 gene (for more information, check out 'Rare mutations may highlight promising heart disease target'), a new study has found that rare mutations of a nearby neighbor, APOA5, could lead to an increased risk of heart attack early in life.
The mutations in question disable the APOA5 gene, while also raising the blood levels of triglyceride-rich lipoproteins, a type of fat.
The team included researchers from the Broad Institute of MIT and Harvard, Massachusetts General Hospital and other leading biomedical research institutions, and was led by Sekar Kathiresan, a senior author of the study, Broad associate member and director of preventive cardiology at Massachusetts General Hospital. This work represents the largest exome sequencing study published for any disease to date.
The team conducted a large-scale, DNA sequencing-based study focused exclusively on the exomes of approximately 10,000 people, half of whom had suffered from an early heart attack and half who had not. (Only about 5 percent of heart attacks occur at what is considered a relatively young age: before 50 for men and before 60 for women.)
This approach led Kathiresan and his colleagues to narrow their focus to two genes: LDLR and APOA5. They found that multiple rare mutations in the LDL receptor gene (LDLR) seem to play a role in early heart attack, and that there is evidence linking rare mutations of the APOA5 gene, which encodes an apoliopoprotein, and early heart attack. Both of these findings are supported by and confirm, respectively, existing research that link triglyceride levels and high levels of LDL in heart attack. Individuals with APOA5 mutations were found to have higher levels of blood triglycerides, and, consequently, roughly a twofold increased risk of a heart attack. The researchers also found that harmful LDL receptor mutations are more prevalent than what was previously believed.
“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,” Kathiresan said in a press release. “This gives us an important window into the biology of the disease and also suggests potential new avenues for therapeutic development.”
This builds off of a similar study led by Joseph Goldstein and colleagues published in 1973 in which the researchers examined several hundred people who had suffered heart attacks before the age of 60. The team studied the participants' lipid levels and identified high total cholesterol levels as the major abnormality associated with early-onset heart attack, with elevated blood triglycerides emerging as the second most common abnormality.
“In 1973, Goldstein’s work taught us what types of lipids in the blood are most important for early heart attack risk,” said Kathiresan. “Now, after sequencing all of the genes in the genome, we can directly point to the specific genes that are most important. There is remarkable consistency between the observations from 40 years ago and today.”
This exome study, along with Kathiresan's recent work linking the APOC3 gene to triglyceride levels and heart disease, adds new light to the role triglycerides play in mediating one's risk of heart attack.
“We simply wouldn’t have made this critical connection without our careful and disciplined approach to whole exome sequencing and subsequent data analysis,” noted Stacey Gabriel, a co-author of the Nature study and director of the Broad Institute’s Genomics Platform.
The study received support from the National Heart, Lung, and Blood Institute, the National Human Genome Research Institute, Massachusetts General Hospital (MGH), the Howard Goodman Fellowship from MGH, the Donovan Family Foundation, Fondation Leducq, Canadian Institutes of Health Research and RFPS. The study, titled “Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction,” appeared online in Nature Dec. 10.
SOURCE: Broad Institute press release