Even the rarest mutation can change the course of the future. This wordplay on J.R.R. Tolkien’s quintessential quote from The Fellowship of the Ring is very apropos given the new findings from investigators at Boston University School of Public Health (BUSPH), which suggest that a rare, naturally-occurring mutation in the apolipoprotein B (APOB) gene may prevent heart disease. Findings from the new study—published recently in Circulation: Genomic and Precision Medicine through an article titled “Rare Protein-truncating Variants in APOB, Lower LDL-C, and Protection Against Coronary Heart Disease”—show that protein-truncating variants in APOB are linked to lower triglyceride and LDL cholesterol levels, and lower the risk of coronary heart disease by 72%.

Targeting the APOB gene has not been tested in clinical trials for cardiovascular outcomes because of the risk of fatty liver disease, but naturally occurring mutation suggests it may be effective. “An approved drug, Mipomersen, mimics the effects of having one of these variants in APOB, but due to the risk of fatty liver disease, clinical trials for cardiovascular outcomes won’t be done,” stated co-lead study investigator Gina Peloso, PhD, assistant professor of biostatistics at BUSPH. “Using genetics, we provided evidence that targeting this gene could reduce the risk of coronary heart disease.”

Protein-truncating variants in the APOB gene are among the causes of a disorder called familial hypobetalipoproteinemia (FHBL), which causes a person’s body to produce fewer low density lipoproteins (LDL) and triglyceride-rich lipoproteins. People with FHBL generally have very low LDL cholesterol but are at high risk of fatty liver disease

In the current study, the research team sequenced the APOB gene in members of 29 Japanese families with FHBL. Eight of the Japanese families had protein-truncating variants in APOB, and individuals with one of those variants had LDL cholesterol levels 55 mg/DL lower and triglyceride levels 53% lower than individuals who did not have an APOB variant.

“We sequenced the APOB gene in 29 Japanese hypobetalipoproteinemia families as well as 57,973 individuals derived from 12 coronary heart disease (CHD) case-control studies—18,442 with early-onset CHD and 39,531 controls,” the authors wrote. “We defined PTVs as variants that lead to a premature stop, disrupt canonical splice-sites, or lead to insertions/deletions that shift reading frame. We tested the association of rare APOB PTV carrier status with blood lipid levels and CHD.”

Additionally, the researchers also sequenced the APOB gene in 57,973 participants of a dozen coronary heart disease case-control studies of people with African, European, and South Asian ancestries, 18,442 of whom had early-onset coronary heart disease. Again, they found that people with these APOB gene variants had lower LDL cholesterol and triglyceride levels. Only 0.038% of the people with coronary heart disease carried an APOB variant, while 0.092% of those without coronary heart disease did, indicating that carrying gene variants in APOB reduces the risk of coronary heart disease.

“Rare protein-truncating variant mutations in APOB which are associated with lower LDL-C and reduced triglycerides also confer protection against CHD,” the authors concluded.

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