SLCO1B1 gene encodes transporter protein for statins

[eml256]

Could SNPs in the SLCO1B1 gene account for the adverse effects of statins? The gene encodes the transport protein responsible for uptake of statins into the hepatocytes of the liver to be detoxified. WIth decreased uptake of statins for detoxification, plasma levels of the drug build up to toxic levels. It is predicted 20 to 36% of the caucasian population possess this mutation, exposing a large # of people to problems detoxifying statins.

(If one wishes to find out if he/she has this mutation, the souce we used was the genomic profiling offerred by 23andme foundation (i think the cost is now $99.00) This is just a partial profiling, though interestingly, the results include mutations in SLCO family of transporter proteins. There are other sources for getting one's genetic profiling done. I am not familiar with any but 23andme. )

Research reports:
1) Having one of the mutations was associated with an increased cholesterol synthesis rate, thus increased total cholesterol levels. This transport protein family is responsible for movement of bile acids across membranes. Interference with this function leads to interruption of the feedback mechanism which helps in regulating cholesterol genesis. ( ANd of course, increased cholesterol levels require---statins.)
2)Having either of 2 mutations resulted in greatly increased statin plasma levels for those on statin therapy (results ranged from 122% to 400% increases in statin plasma levels)
3) One of the mutations is found in 15 to 32% of the caucasian population; a second mutation is found in 5 to 6% of the caucasian population. Thus 20 to 38% of the caucasian population possess one of these 2 mutations, resulting in decreased uptake of statins by the liver for detoxification and resultant increased statin levels. In Addition, having one of the mutations results in increased total cholesterol levels, leading to statin therapy.

SNPs in this gene:
reports note that having one of these variants (having one "C" at rs4149056) occurs in 15% to 32% of the caucasian population (much lower in African American and Asian population), and having 2 "C's" occurs in 5 to 6 % of the population. Thus, roughly 20 to 38% of the Caucasian population possess either of these SNPs.

Individuals with SNPs in the SLCO1B1 gene showed an increase in statin plasma levels reported in studies ranging from 122% to 400% above "normal statin plasma levels". Conclusion from one study noted that (stating the obvious)"...SLCO1B1 polymorphism is likely to play a major role in interindividual variability in the pharmacokinetics of simvastatin and possibly in its efficacy and tixicity at the population level."
http://www.ncbi.nlm.nih.gov/pubmed/17108811
http://www.nature.com/clpt/journal/v79/ ... 6348a.html

Additionally, at least one of the SNPs is directly involved in "basal cholesterol homeostasis" Translation: the SLCO1B1 polymorphism (521CC variant) was associated with an increased cholesterol synthesis rate:
http://www.ihop-net.org/UniPub/iHOP/pm/ ... d=18794729

Following study looked at myopathy associated with 2 polymoprphisms of the SLCO1B1 gene. I am unable to find any studies involving SLCO1B1 variants looking at adverse effects from statins other than myopathies. My opinion is that those who sufferred just myopathy prompting discontinuance of statins are indeed lucky.



Reports of a major study: 12,000 patients who were taking 80 mgm simvastatin/day following a heart attack. The authors found that having one C at rs4149056, a SNP in the SLCO1B1 gene, increased a person's odds of having myopathy 4.5 times compared to the TT genotype. Having two C copies of the SNP increased a person's odds of myopathy by about 17 times.
SEARCH Collaborative Group et al. (2008) . “SLCO1B1 variants and statin-induced myopathy--a genomewide study.â€Â

[eml256]

I am unable to unearth the study to which this artilce refers, though think it must directly relate to genetic testing for SLCO1B1 transporter gene.

http://dailyexpress.co.uk/posts/view/138489/Test-to-avoid-pain-of-statins

TEST TO AVOID PAIN OF STATINS

Statins can have painful side effects
Friday November 6,2009
By Victoria Fletcher
PIONEERING British research could save hundreds of thousands of patients from the agonising side-effects of taking statins.

The discovery means that within five years doctors could offer patients a simple test to reveal if the cholesterol-lowering drug would trigger muscle pain.

Researchers, funded by the Department of Health, have found a genetic variation which means many of the drug’s four million users are more prone to suffering muscle-aches than others.

[eml256]

If someone with better computer skills than I unearths the study to which the above article refers, would you please post a link to that? thanks

[eml256]

In addition, the study may refer to the findings that a defect in the atrogin-1 gene which results in increased muscle wasting.