Scientists from the Broad Institute, Massachusetts General Hospital, and other biomedical research institutions have pinpointed rare mutations in the APOA5 gene that increase a person's risk of having a heart attack early in life. These mutations disable the APOA5 gene and also raise the levels in the blood of triglyceride-rich lipoproteins, a type of fat.
The researchers' findings, together with other recent genetic discoveries (specifically, the identification of protective mutations in the APOC3 gene that lower triglyceride levels and the risk of heart attack), refocus attention on abnormal triglyceride metabolism as an important risk factor for heart attack at any age. The work (“Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction”) appears in Nature.
“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,” said Sekar Kathiresan, M.D., a senior author of the study, Broad associate member, and director of preventive cardiology at Massachusetts General Hospital. “This gives us an important window into the biology of the disease and also suggests potential new avenues for therapeutic development.”
In addition to underscoring the role of high triglycerides in heart attack risk, Dr. Kathiresan and his colleagues also found that harmful LDL receptor mutations are more prevalent than previously believed.
Using an exome-based approach, the researchers zeroed in on two genes, LDLR and APOA5. Their findings implicating a role for multiple rare mutations in the LDL receptor gene (LDLR) in early heart attack confirms what is already well-known from decades of research: that high levels of LDL, the so-called “bad” cholesterol, is a key risk factor that raises the risk of heart attack.
The second major finding (evidence linking rare mutations in the APOA5 gene, encoding an apolipoprotein, and early heart attack) highlights the role of triglyceride levels in heart attack. Dr. Kathiresan and his colleagues discovered that people carrying APOA5 mutations have higher levels of blood triglycerides and a roughly two-fold increased risk of a heart attack.
Although APOA5 had been previously implicated in the condition, it required the resolution of large-scale DNA sequencing to definitively make the connection between APOA5 and heart attack risk.
“We simply wouldn't have made this critical connection without our careful and disciplined approach to whole exome sequencing and subsequent data analysis,” said Stacey Gabriel, Ph.D., a co-author of the Nature study and director of the Broad Institute's Genomics Platform.
This work points to several features being key to successful sequencing studies focused on finding rare variants in the genome. These include the importance of large sample sizes to help distinguish harmful from benign genetic variants (typically thousands of cases and controls), as well as precise statistical analyses, including so-called “aggregation tests” that enable the combined analysis of multiple distinct rare variants within the same gene.
Together with his recent discovery of another apolipoprotein gene, APOC3, that also influences triglyceride levels and heart disease, Dr. Kathiresan's findings point to an important role for triglycerides in influencing heart attack risk—something that had been largely disregarded until recently. In addition to casting new light on disease biology, the work also suggests a potential path for future therapeutic development in heart disease.
