Study of Common Variants Finds Rare Mutation With Implications For Heart Disease Prevention

Genome-wide association studies, the research projects that connect SNPs to different traits and conditions (and fuel much of the 23andMe Health and Traits feature), focus on fairly common genetic variations that generally have small effects on risk.

But critics of this type of research charge that studying common variation is of little value because it misses important information hiding in the genome in the form of rare mutations with large effects.

The results of a new genome-wide association study in the Old Order Amish of Lancaster, PA, may have bridged some of the gap between these two camps. In current issue of Science, researchers looking for SNPs associated with elevated triglycerides, a risk factor for heart disease, report finding a rare mutation in the Amish that could have important implications for preventing the condition in everyone.

About 5% of the isolated Amish community was found to carry one copy of a mutation that completely prevents a protein called apoC-III, encoded by the APOC3 gene, from being produced. ApoC-III prevents the breakdown of triglycerides in the bloodstream.

Mutation carriers had about 50% of the normal levels of apoC-III in their blood along with lower triglyceride levels, less “bad” LDL cholesterol and more “good” HDL cholesterol.

Carriers of the mutation were also much less likely to have coronary artery calcification (CAC), a measure of atherosclerosis. The mutation reduced the odds of having detectable CAC by 65%.

There is already a class of lipid-lowering drugs called fibrates that indirectly decrease the amount of protein made by APOC3. Other cholesterol drugs such as statins and niacin have also been associated with decreases in apoC-III levels. But the authors of the current study suggest that their discovery could mean that therapies aimed at directly reducing apoC-III levels will be useful in fighting heart disease.

Although 5% of the Amish carried the APOC3 mutation, it is thought to be rare or even entirely absent in the general population. Researchers believe the mutation was first introduced into the Amish community by a person who was born in the mid-1700’s.

The Amish are often used in genetic studies because they are an isolated and homogenous community with good genealogical records that date back to the time when they first migrated to North America.






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