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.

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Our SNPwatch posts here at The Spittoon are one of our most exciting features. They give our customers the opportunity to connect their genetic data to the newest discoveries, often within just hours of a study’s publication.

Looking ahead to 2009, we can only begin to imagine the exciting discoveries that will be made in genetics. In the meantime, here are a few of our favorite SNPwatches from 2008:

SNPs That Affect Drug Response
We reported on several studies this year that showed the importance of genetic variations in determining how different people react to certain medications.

• A report in Nature Genetics showed that some women with a particular version of a SNP in the NQO1 are less likely to survive breast cancer after treatment with the commonly used chemotherapeutic epirubicin.
• A study by the SEARCH Collaborative Group found that a version of one SNP is associated with an increased risk for myopathy (muscle pain and/or weakness) in people taking cholesterol-lowering drugs called statins.
• Mayo clinic researchers found that the weight loss drug sibutramine (Meridia) is effective only in people with specific versions of three different genes.
• And just this month we brought you news of three studies that showed that a genetic variant known to affect the metabolism of the anti-clotting drug clopidogrel (Plavix) also affects heart attack patients’ risk of a second major cardiovascular event.

Shared SNPs
Sometimes multiple conditions strike the same person or run in families. Several studies published this year showed that shared genetic risk factors may be part of the reason why.

• Obesity is a known risk factor for many cancers. Researchers found that a variant of adiponectin, a hormone released by fat cells, can increase the risk of developing colorectal cancer.
• Other researchers found variants that affect the risk of developing both type 1 diabetes and celiac disease, two autoimmune diseases that tend to cluster together. One of these shared variants is also associated with HIV resistance.
• Finally, a report published this month in the Proceedings of the National Academy of Sciences showed that a single genetic variant can make a person prone to greater indulgence in both smoking and drinking.

SNPs Associated with Risk Factors for Disease
Several studies this year looked beyond disease itself and instead found associations between SNPs and traits known to be risk factors for disease.

• One study found an association between several SNPs and fasting plasma glucose, a measure of how well a person’s body can control blood sugar levels – a process that goes awry in diabetes.
• Another research group reported SNPs associated with glycated hemoglobin levels, a measure of long-term blood sugar control and another factor associated with the risk of developing diabetes.
• The findings of three papers published in Nature Genetics roughly doubled the number of SNPs associated with blood levels of cholesterol and triglycerides, important risk factors for cardiovascular disease.
• And finally, in a study that looked at behavior instead of metabolic markers, researchers found that a variant in the FTO gene known to increase the risk for obesity affects food choices in children, pushing them towards foods denser in calories.

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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).

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In a recent post on his “Building Confidence” blog, 23andMe scientific advisor Russ Altman recounts an experience that should be familiar to 23andMe customers who regularly read The Spittoon. After reading a recent New England Journal of Medicine paper about a genetic variant associated with the development of side effects among people taking cholesterol-lowering statin drugs, Altman logged into his 23andMe account and checked his own genotype at the SNP in question.

“In about 30 seconds I went from reading an article of potential interest to checking my genotype and drawing a preliminary conclusion,” Altman wrote. “I must say it was quite quick, informative, even fun.”

Russ discovered that his genotype does not put him at elevated risk for statin-induced muscle soreness — not an earth-shattering realization, but one that he said might make him more comfortable with taking cholesterol-lowering drugs should he ever need them.

Now, most of us don’t scour the New England Journal looking for papers that might have relevance to our own health. That’s why The Spittoon publishes SNPWatch posts that announce the latest findings and identify the SNPs that 23andMe customers can use to see how that research might apply to them. In fact, we published a post on the statin-induced myopathy paper when it first came out back in July.

So if you’re a 23andMe customer who is interesting in learning about a particular topic, don’t forget to check The Spittoon as well as your account — because the latest research often appears here first.

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