Another Cholesterol-Lowering Variant that Reduces Heart Disease Risk, but This One Has Unfortunate Side Effects

In recent years, researchers have discovered a number of human gene variants or mutations that significantly lower blood cholesterol, and this also the risk of heart disease, such as DSCAML1, ANGPTL4, and ASGR1. Why does this work? Oxidized cholesterol contributes to the development of atherosclerosis with advancing age, by causing macrophages to falter in their work of removing cholesterol from blood vessel walls, become inflammatory, transform into foam cells, and die, leaving debris that grows the lesions the cells are trying to repair. Reducing overall cholesterol works because it reduces oxidized cholesterol as well.

Yet this business of reducing blood cholesterol is unfortunately far from the most efficient way to tackle atherosclerosis. It can only slow it down, and not produce significant reversal of existing fatty lesions in blood vessel walls. Nonetheless, when lowered cholesterol levels are in place for the entire lifespan rather than just as a result of statin drugs in later life, and there is a considerable prevention effect, then effect sizes can be quite large. Sadly, the mutation in APOB noted here has unpleasant side-effects that make this gene and its protein a less desirable target for therapy than the others mentioned above.

A new study finds that protein-truncating variants in the apolipoprotein B (APOB) gene are linked to lower triglyceride and LDL cholesterol levels, and lower the risk of coronary heart disease by 72 percent. 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 less 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.

"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. Using genetics, we provided evidence that targeting this gene could reduce the risk of coronary heart disease."

The researchers 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 percent lower than individuals who did not have an APOB variant. 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 percent of the people with coronary heart disease carried an APOB variant, while 0.092 percent of those without coronary heart disease did, indicating that carrying gene variants in APOB reduces the risk of coronary heart disease.

Link: https://www.eurekalert.org/pub_releases/2019-05/buso-bfr051319.php

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