Mutations are bad, right?

Not always.  Some DNA changes are completely neutral. That’s how the human genome came to have so many variations. And some mutations are actually advantageous.

A case in point is the PCSK9 gene. So-called “loss-of-function” mutations that prevent the protein encoded by this gene from functioning properly actually lead to lower cholesterol levels.

Researchers at several pharmaceutical companies have taken inspiration from these PCSK9 mutations. They are now developing drugs that would block its function in people with non-mutated forms of the gene.  These drugs, though still in the early stages of testing, may offer a new way for the tens of millions of Americans with high cholesterol to get their levels under control.

The PCSK9 protein binds to LDL cholesterol receptors on the surface of cells.  Once cholesterol binds to the receptor too, the whole complex is internalized into the cell, and the receptor is degraded.  When PCSK9 function is missing, the LDL receptor is able to recycle back to the cell’s surface after dropping off its cholesterol cargo in the cells, allowing it to sop up more “bad” cholesterol from the bloodstream.  There doesn’t seem to be any downside to the cholesterol-lowering PCSK9 mutations, suggesting that targeting the protein with drugs could be safe and effective way of reducing cholesterol.

One company, Amgen, is tackling the problem with antibodies that attach to the PCSK9 protein outside of cells, targeting it for destruction by the immune system.  Two others, Isis and Alnylam, are using small pieces of RNA designed to go inside cells and keep the PCSK9 protein from being made in the first place.  All three companies have shown reductions of LDL cholesterol in early animal experiments.  A review of their findings appeared recently in Nature Publishing Group’s Science-Business eXchange.

People who need to lower their cholesterol but can’t tolerate statins stand to benefit most from any PCSK9 inhibitors that are developed.  But these drugs might be good for those taking statins too.  High doses of statins can actually increase the amount of PCSK9 in the body.  Taking a PCSK9 inhibitor along with a statin could help cut off this potentially backtracking side effect.  Unfortunately, unlike statins, none of the PCSK9 inhibitors under development can be taken orally.  They all need to be delivered through an injection.

Many years of clinical trials are ahead for each of these drugs.  Researchers will need to assess both their safety and efficacy.  But it’s exciting to see a genetics discovery be so quickly translated into an idea that could help millions of people.

What This Means For You
23andMe customers can check their data for two (there are others) PCSK9 loss-of-function mutations:

• The T version of rs11591147 and the A version of rs28362286 have both been associated with decreased LDL levels.  Each copy of these variants leads to lower LDL cholesterol.

ShareThis

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.

ShareThis

The online publication of three papers by Nature Genetics this week has roughly doubled the number of genetic locations associated with levels of cholesterol and triglycerides in the blood.

With the addition of so many new SNPs, researchers have a wealth of opportunities to better understand how the body regulates cholesterol and triglyceride levels, find new targets for drugs to control them and identify people who are at increased risk of cardiovascular disease.

Two of the Nature Genetics papers combined data from a number of previous studies to increase their statistical power to detect SNPs associated with cholesterol and triglyceride levels. One looked at between 17,798 and 22,562 European subjects (depending on the specific measurement being examined), and found six genes or locations on five chromosomes that were significantly associated with total cholesterol, HDL, LDL or triglycerides. The other studied 20,623 people from Europe and the United States, and identified 11 genetic regions that were not previously known to be associated with cholesterol or triglyceride levels.

The third paper found five genetic regions associated with cholesterol or triglycerides in a cohort of 4,763 people born in northern Finland in 1966.

A number of the new associations were located near places in the genome where rare mutations are already known to completely disable cholesterol-regulating genes, causing serious disruptions in cholesterol metabolism. The newly discovered SNPs apparently cause much subtler effects, however; in most cases they appear to modulate the activity of the genes they affect.

The authors of one study (Kathiresan et al.) also provided evidence that seven of their new SNPs modulate the expression of genes in the liver, where cholesterol is produced.

In spite of their success in both discovering new genetic locations associated with cholesterol and triglyceride levels — the papers also replicated virtually all previously known associations as well — the value of all this information for personal genomics is somewhat limited. After all, blood levels of cholesterol and trigylcerides are themselves indicators of cardiovascular disease risk. Knowing a person’s genetic risk on top of their actual cholesterol levels provides only an “incremental” amount of additional information, Kathiresan et al. wrote.

Even so, Kathiresan et al. developed an “allelic dosage score” that consisted of a person’s number of elevated-risk genotypes out of 32 previously known and newly discovered SNPs. Study subjects with scores in the top tenth of the distribution were more than twice as likely to have LDL cholesterol about 160 mg/dl, HDL cholesterol below 40 mg/dl and trigylcerides above 200 mg/dl.

Researchers still have captured only a small fraction of the gene variation that explains why one person’s cholesterol level is higher or lower than the next person’s. The authors of the Finnish study, who found one cholesterol-increasing version of the AR gene that was present in less than 2% of subjects, suggest that much of that unknown risk may lie in similarly rare variants.

23andMe customers can use our Browse Raw Data feature to check their genotypes at most of the newly reported SNPs. The following table indicates which version of each SNP is less common among Europeans, and whether that version causes an increase or decrease in LDL cholesterol, triglycerides or HDL cholesterol (lower HDL raises a person’s risk of cardiovascular disease).

ShareThis