The Statin Damage Gene?

by Duane Graveline, MD, MPH

With the advent of increasingly sophisticated and available genetic screening, much has been learned in these past few years directly bearing on statin toxicity.

It appears that some of us are born with various genetic combinations that greatly increase sensitivity to statin drugs. The question now is just how great this genetic factor is. A massive study out of Finland comparing Finns with the rest of the world provided insight, chilling in its implications.

This all has to do with a genetic combination known to geneticists as the SLCO1B1 polymorphism, specifically the variant c.521CC genotype – affectionately known as “SNIPS” to workers in the field – special genetic combinations having very special effects.

This particular variant form has some rather remarkable effects on the pharmacokinetics (the action of drugs in the body) of different statins. Its greatest effect was on the plasma concentrations of simvastatin (Zocor). It also had increased the plasma concentrations of atorvastatin (Lipitor), pravastatin (Pravachol) and rosuvastatin (Crestor).

Large differences in frequency of these genetic combinations exist between different populations. The highest frequencies of these variant genotypes were found in the U.S.A. (24% average, 18–32% range) with similar but slightly smaller figures for Europe (18% average, 14–23% range). The smallest frequency of this variant genotype was Sub-Saharan Africa (1.9%average, 0.7–4.8% range).

So those in the United States are dealing with the presumed fact that 24% of the population are born with a super-sensitivity to statins. Simply following the usual doses of statin prescribed by doctors, they are yielding blood levels far higher than anyone expected them to be.

I have written before about the genetic complications secondary to statin use, but always with reference to mitochondrial DNA damage and mutations. Because of the programmed inhibition of the mevalonate pathway by statins, this will inevitably inhibit CoQ10 allowing excess free radical oxidation of mitochondrial DNA causing damage and mutations.

Until I read this, I had no idea that one quarter of the population of the United States would be inadvertently super-dosed by statins because of a genetically programmed predisposition.

One would have thought that this doctorate thesis, PHARMACOGENETICS OF SLCO1B1: POPULATION GENETICS AND EFFECT ON STATINS by Marja Pasanen on 19 December 2008 (1), would have been picked up by now by the pharmaceutical industry.

One would think they would be clamoring for confirmation and clarification of the apparent fact that for one-quarter of the U.S. population and a similar number in Europe, they have not the slightest idea what the effective dose really has been in their statin users.

One would think they would not let a moment go by before coming up with a test for statin sensitivity. Instead they are trying to promote greater and greater use for statins for primary as well as secondary prevention. Not a word about grossly adverse population genetics. 

Although statins appear to be quite well tolerated, the myopathy incidence is now much closer to 20 percent than it is to the 2 percent predicted 20 years ago and of that number, a high percentage could be permanent.

Two hundred rhabdomyolysis deaths still occur annually, long after Baycol was removed from the market. Peripheral neuropathy incidence is nearly as common as myopathy and mostly appears to be permanent. Additionally, over 500 cases of statin associated atypical ALS occur each year. This toxicity of statins is a dose and concentration dependent phenomenon. The risk of toxicity increases as the plasma concentrations are increased.

The SLCO1B1 genetic polymorphism is associated with an increased cholesterol synthesis rate implying falsely elevated cholesterol values provoking that greater and greater doses of the statin be used – a catch-22 if ever there was one.

Of five statins in general use, there are wide variations in the degree to which the SLCO1B1 gene is carried. Fluvastatin (Lescol) is the only statin not significantly involved with this gene. Pravastatin (pravachol), simvastatin (Zocor), rosuvastatin (Crestor) and atorvastatin (Lipitor) are all described as significantly involved in this study.

Since these are far more commonly prescribed than Lescol, it is safe to say that genetic predisposition to overdose is a major problem with statin use today. No doubt it underlies much of the myopathies and rhabdomyopathies and adverse reactions in general.

No doctor can feel comfortable prescribing statins in accordance with drug company guidelines until we have a quick and inexpensive means of determining each potential user's sensitivity to it. Only then will the proper dose be able to be determined.

Duane Graveline MD MPH
Former USAF Flight Surgeon
Former NASA Astronaut
Retired Family Doctor

Reference:1. https://helda.helsinki.fi/bitstream/handle/10138/22995/pharmaco.pdf?sequence=2

Updated June 2016

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