Muscle Pain from Statins? Time for a genetic evalutaion!

In a wonderful demonstration of how successful genetic research on pharmacogenomics needs to be done. The SEARCH Collaborative Group successfully demonstrated the power of GWAS nested in other studies. This will be the hallmark of all great medication studies for the next 50 years. Do I mean GWAS? No!

I mean genetic analysis of the outliers in response to the medication being studied. I only ask myself, why in the hell hasn't pharma been doing this for the last 10 years????? I have my suspicions, but I'll never mention them in public.

So why am I so excited? Well......you know how the DTC companies test you for SNPs that give you odds ratios of 1.3 or less??? Imagine an Odds Ratio of 16 for developing statin induced myopathy!!! I was just talking to the founder of one of those sequencing companies worth billions of dollars about this the other day!!! Odds ratio of 16.9

Uhhhhh...Yeahhhh....that is a pretty good chance of getting the myopathies associated with this super common medication. How is that for immediately clinically relevant. Have the polymorphism?.....Don't take statins...instead take Fenofibrates.

This study was signed sealed and delivered to the door of the makers of Zocor(Merck). I sure hope they license that test!!!! Oh wait...this will likely be sold by deCode. Caraiso just told me that this SNP is on all of the big 3's chips! So who will contact their patients...sorry/customers? If the MD ordered the test....it would be the MD's duty........This is why the government is trying to regulate this testing.....for this type of follow up. This is a great study it needs follow up!

How was it done? From NEJM...

Methods: We carried out a genomewide association study using approximately 300,000 markers (and additional fine-mapping) in 85 subjects with definite or incipient myopathy and 90 controls, all of whom were taking 80 mg of simvastatin daily as part of a trial involving 12,000 participants. Replication was tested in a trial of 40 mg of simvastatin daily involving 20,000 participants.

At first, I balked.....80 mg of Zocor. That's a whopping dose! Who the hell uses that much Zocor? So I tried to dismiss this study....but it was the replication in the 40mg Group that got me.....

So what did they find?

The noncoding rs4363657 SNP was in nearly complete linkage disequilibrium with the nonsynonymous rs4149056 SNP (r2=0.97), which has been linked to statin metabolism. The prevalence of the rs4149056 C allele in the population was 15%. The odds ratio for myopathy was 4.5 (95% confidence interval [CI], 2.6 to 7.7) per copy of the C allele, and 16.9 (95% CI, 4.7 to 61.1) in CC as compared with TT homozygotes. More than 60% of these myopathy cases could be attributed to the C variant. The association of rs4149056 with myopathy was replicated in the trial of 40 mg of simvastatin daily, which also showed an association between rs4149056 and the cholesterol-lowering effects of simvastatin. No SNPs in any other region were clearly associated with myopathy.

Why am I salivating over these results????

1. 16.9 is a huge Odds Ratio in a region where we know there has been lots of literature reporting the issues with Organic Anion Transporters and the bad effects of statins.

2. The replication in a clinically useful cohort.....40 mg of Zocor....there are tons of people on that dose.

3. Statin Myopathy can cause kidney failure from rhabdomyolysis(muscle breakdown). It is a dangerous side effect! Another clinically useful point!

4. There were NO OTHER SNPs associated with anything!!! The odds of that are preposterous! That IMHO means this is a very valid SNP. With everything, I suggest replication and then the marketing of this test to the physician. With the OTC Zocor in the UK....maybe they have an interest in DTC????? Or maybe not

The Sherpa Says:

Pharma are you listening? This is the way to save your medications and save you from lawsuits. The way to stay alive is by developing diagnostics that protect your patients and doctors.....If you don't follow this model, you will perish. When this study is replicated and the test available through a CLIA certified lab, Helix Health of Connecticut will test their patients for this very important genetic polymorphism.....As for the big 3 screens changing medications......Dr Agus should stick to Heme-Onc. The SNPs associated with heart attack in the SNP scan are separate from cholesterol....and statins have not been proven to lower risk via any mechanism other than lipid lowering....Either way, he would be better served testing the organic anion transporter.

Night Owls Unite!!!!

In an interesting "Non medically Related" study....for now
The Telegraph reports of a mutation causing circadian rhythm (activity vs. rest) problems. The gene called F-Box L3 which has been found to be responsible for degradation of proteins responsible for inhibiting or controlling our "internal clock". The effects of the proteins called Cry1 and Cry2 are essential for the oscillatory movement of our cycles. The studies were carried out at New York University and Europe and of course in conjunction with Merck. Heads up Ambien!!
What this study brings to the table is more important than the study itself. Media headline here is: "Gene explains why people are night owls"
No it doesn't! It explains why mice may have altered sleep wake cycles. As my old program director used to say "Mice are NOT humans"

The Gene Sherpa says: Be careful what you read in the press about genetics. Most of it is hype, much of it is not pertinent to humans....yet, and even worse some of it just ain't true. So leave the translation to me :)