**5. Clinical relevance of the variation in the** *SCLO1B1* **gene**

Clinical relevance of the *SCLO1B* variation is based on biological role of its gene products in hepatic transport of statins. Statins are mainly delivered within hepatocytes to their site of actions by uptake transporters and eliminated into the bile by eflux transporters [41]. Many statins are substrates of hepatic uptake transporters including OATP1B1, OATP2B1 and OATP1B3 [28] with OATB1B1 as the main one. The loss of function the *SLCO1B1*\*5 (Val174Ala, 521 T > C, rs4149056), located in exon 5, downregulates OATB1A1 transporter cell membrane and protein expression [42] which leads to decreased hepatic uptake, greater systemic statin plasma concentrations, and therefore greater muscle statin exposure, all these resulting in adverse effects [20, 36, 43–45].

Importantly, the impact of the rs4149056 variant on statin metabolism appears to differ between distinct statins. The effect of rs4149056 genotypes was much greater for simvastatin, less for atorvastatin and rosuvastatin in healthy volunteers [46, 47]: For simvastatin the area under curve, AUC (0-infinity) was increased by 221% in genotype CC individuals in compared with wild-type TT individuals. For atorvastatin this parameter was increased by 145% and for rosuvastatin by 62%. Individuals carrying C allele also reached maximum concentration (Cmax) earlier, and its value was 200% higher compared with TT individuals of rs4149056 [47]. Further, the rs4149056 polymorphism was significantly associated with simvastatin treatment cases of severe statin induced myopathy, which did not occur after atorvastatin [45] or pravastatin [48] treatment. Similar conclusions regarding simvastatin


**Table 2.** Basic studies that have reported a strong association between the rs4149056 single nucleotide polymorphism and simvastatin induced myopathy.

also been investigated in Europe by the EU Horizon 2020-funded Ubiquitous Pharmacogenomics (U-PGx) Consortium (http://upgx.eu) in seven European countries [55]. Last but not least, recommendations were formulated also on a national level - in France: the French National Network of Pharmacogenetics (RNPGx) [56] is in favour of rs4149056 testing before starting therapy or early after treatment onset in patients with one or more risk factors. If the genotype is not known early, the RNPGx considers that a polymorphism test is potentially useful also in the event of already occurring muscle toxicity in patients treated with statins, in order to rule out or confirm a genetic cause. From the above examples it is clear that pharmacogenetic genotyping for prediction/confirmation of statin intolerance undergoes ongoing development and progress; further updates of the recommendations are expected. It should be noted that there have been opinions as well that the current status of knowledge has not been yet sufficient to allow clinical application of genotyping for risk of statin intolerance [52]. There have been several arguments, however especially those economical ("the tests are too costly") are not substantiated; some "con" opinions have been also "traditionalistic", from conservative point of view on doubting any new test or medical management measure including pharmacogenetics. However, this reluctant or at least "sceptical" attitude about pharmacogenetic contribution to routine statin usage, well known also from other applications of pharmacogenetics, has been gradually changing–it only takes time,

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• Statins are the basis of dyslipidemia treatment in patients with increased cardiovascular risk.

• Guidance for prescribers reflects individual risk for *SLCO1B1* rs4149056 C allele carriers.

• *SCLO1B1* gene variation has strong association with statin-induced myopathy.

• Investigations of clinical relevance of other plausible gene variants are ongoing.

• Genetic factors may predispose to statin intolerance.

systematic information on the evidence and particularly education to overcome it [57].

**7. Future perspectives including economic aspects of genetic test for** 

approaches which utilise alternative parameters for assessing effectiveness (e.g. [62–64]).

Implementation of a genetic test for statin intolerance into routine practice definitely requires analysing its benefits not only for patients but also for health care providers. In this context, pharmacoecomic data on genetic testing statin intolerance have been scarce. The existing literature on cost-effectiveness of pharmacogenetic testing has been either general [58] or described economic savings solely due to hypolipidemic effect of statins [59]. The first specific data for statin intolerance and its genetic testing appeared only very recently [60]–the authors estimated 356 Canadian dollars as the cost limit for economic feasibility and at the same time dominant health effect for cardiovascular prevention. In extension of this very first report [60], this topic should be, therefore, addressed more intensively and also from other angles in the future. This has been the case with other pharmacogenetic applications (e.g. [61]), it will be also innovative to use new

**statin intolerance**

KEY MESSAGE

were obtained in animal model, again for simvastatin however not for pravastatin or atorvastatin [49]. **Table 2** lists main studies investigating effect of simvastatin on statin intolerance/ myopathy in humans.

It is crucial that in agreement with the rules for performing association studies [50] the data obtained in the SEARCH study has been independently replicated within the Heart Protection Study, in 10,000 patients who received 40 mg Simvastatin [21]. The meaningful data obtained in this way provided starting point for reflection of the observations from genetic and pharmacokinetic studies into clinical practice, including formulation of treatment recommendations which will be subject of the next section of our chapter.
