**3. Genes responsible for statin intolerance**

The following section characterises the gene variants that have been implicated in mechanisms of statin intolerance represented by statin-induced myopathy. These are listed in the **Table 1**.

#### **3.1.** *SLCO1B1* **gene**

By analogy to individual nature of patients´ response to treatment [8–10] there are also interindividual differences in occurrence and extent of statin intolerance and its symptoms. The knowledge of the risk factors predisposing for intolerance development including characteristic genetic background is crucial for its understanding and prevention. In this chapter we will review the polymorphic gene variants implicated in development of statin intolerance,

Statin intolerance is the inability to tolerate sufficient dose of statin needed to reduce cardiovascular risk due to side effects or intolerance to treatment [11]. The most frequent are muscle

Statin-induced muscle symptoms range from myalgia to mild or severe myopathy and even to rare rhabdomyolysis [12]. The symptoms appear in about 75% in the first 10–12 weeks and in 90% of cases in the first 6 months after treatment initiation or dose up titration [13]. The true frequency muscle related side effects has been widely debated: while an observational study reported as much as about 20% of patients on statins [14], clinical trial data suggests frequencies to be equal or lower than 5% [15], however there was a study reporting that clinical trials did not use a standard definition for statin myalgia [16], which may result in underestimated occurrence of statin-induced muscle symptoms. In any case, given very high usage of statins (the third most frequently prescribed drug), even lower relative frequency numbers would

The available data shows that the side effects of statin therapy are group-dependent, timedependent and dose-dependent; their frequency is greater at a higher statin dose [17].

Endogenous factors known to increase occurrence of side effects are as follows: another lipid-lowering therapy, alcohol abuse, surgery, heavy exercise. Importantly, interactions with medication may be serious [18]; particularly drug interactions likely contribute the suscepti-

Further factors predisposing to statin intolerance are: advanced age (>70 year), female sex, race/ethnicity, family history of muscle disorders, vitamin D deficiency, history of creatine

Besides the above characterised factors, genetic "make-up" of a given patient is important component in susceptibility to statin intolerance. Indeed, genetic variation represents the major factor responsible for inter-individual differences in patient responsiveness and their

elevation, hepatic and renal impartment, hypothyroidism, low body mass index [20].

briefly describe their biological plausibility and characterise clinical relevance.

**2. Statin intolerance**

128 Genetic Diversity and Disease Susceptibility

symptoms characterised bellow.

**2.2. Clinical-related risk factors**

**2.3. Genetic factors**

bility to statin related muscle symptoms [19].

inclination towards undesirable side effects of statins.

**2.1. Statin-associated muscle symptoms**

mean substantial absolute number of symptomatic patients.

*SLCO1B1* gene encodes the OATP1B1 (organic anion transporting polypeptide), which has been reported to regulate the hepatic uptakes of statins [27, 28]. Strong support for its nomination as a risk factor for statin intolerance came from the GWAS study which investigated genetic variation in 85 subject with myopathy and 90 controls, all taking 80 mg of simvastatin [21]: strong association was identified between statin-induced myopathy and single nucleotide polymorphism (SNP) rs4363657 located within the *SLCO1B1* gene. This noncoding SNP was in nearly complete linkage disequilibrium with the nonsynonymous rs4149056 SNP variant, which has been linked to statin metabolism: the odds ratio for myopathy was 4.5% per one copy of the C allele and 16.9% in CC homozygotes compared with homozygotes for standard allele (TT). More than 60% of observed myopathy cases could be attributed to this particular genetic variation, [21], which is also due to its relatively high population prevalence - rs4149056 C allele frequency is 15%.

#### **3.2.** *LILRB5* **gene**

A potential role for immune system genetic variation in development of statin-induced myopathy has been recently reported for a variant in leukocyte immunoglobulin-like receptor subfamily-B, *LILRB5* gene (rs12975366:T > C:Asp247Gly) [25]. The missense variant Asp247Gly has been associated with serum creatine kinase (CK) levels; the mean levels of this enzyme were elevated in Asp247 homozygotes (TT). The *LILRB5* Asp247 homozygous genotype has, therefore, been associated with increased risk of statin intolerance [25]. No independent replication data on this plausible new variant has been available so far.


Note: rs, reference sequence; ≠ denotes haplotype (not allele) designation, see Section 4, second paragraph.

**Table 1.** Gene and their variants implicated in development of statin intolerance presented as statin myopathy.

#### **3.3.** *GATM* **gene**

Glycine amidinotransferase, *GATM* gene encodes a mitochondrial enzyme, which is involved in creatine biosynthesis. SNP rs9806699 within the *GATM* gene has been associated with statin induced myopathy, specifically minor allele A conferring a protective effect and reduced risk of myopathy [24]. However, as this result was not replicated [29], further investigations are required before a possible role for this variation in statin tolerance is clarified.

**4. Genetic variability and population distribution of** *SLCO1B1*

Middle East, Oceania and the Americas (Amerindians).

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

exposure.

adverse effects [20, 36, 43–45].

More than 45 nonsynonymous variants in *SLCO1B1* gene have been identified [34]. Some of the variants have altered function [35]. Genotypic frequencies of *SLCO1B1* variants depend on ethnicity, and genetic difference between populations correlated with the geographical distances [34, 36, 37]. In particular, single nucleotide polymorphism the 521 T > C (rs4149056) appeared more commonly in European-Americans while it was less frequent in African-Americans. In opposite, single nucleotide polymorphism the 388A > G (rs2306283) was detected predominantly in African-Americans. Pasanen et al. [38] investigated the frequencies of 12 SNPs in *SLCO1B1* in 941 persons from 52 populations across Europe, Asia, Africa,

Pharmacogenetics of Cardiovascular Disease: Genetic Variation and Statin Intolerance

http://dx.doi.org/10.5772/intechopen.79518

131

*SLCO1B1* single nucleotide polymorphisms 521 T > C and 388A > G form four haplotypes: \*1A (388A/521 T), \*1B (388G/521 T), \*5 (388A/521 T) and \*15 (388G/521C) [38, 39]. The low activity haplotypes–\*5 (388A/521C) and \*15 (388G/521C) occur with combined haplotype frequency of approximately 15–20% in Europeans, 10–15% in Asians, 2% in sub-Saharian Africans. The \*1B (388G/521 T) haplotype occurs in approximately 26% Europeans, in 39–63% Asians and in 77% sub-Saharian Africans. The haplotypes \*5 and \*15 are associated with significant reductions of statin hepatic uptake [40], resulting in increase of systemic substrates

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

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

#### **3.4. Family of cytochrome P450 genes**

The cytochrome P450 family is a group of izoenzymes important for catalysing oxidation of xenobiotics. There is a wide spectrum of polymorphic variants affecting various pharmacogenetics aspects. Regarding cardiovascular setting, CYP gene variation plays role in warfarin and clopidogrel metabolism with clear clinical relevance (e.g. [30]). In context of statin adverse drug reaction, Mulder et al. [22] reported higher incidence of statin intolerance in the group of patients who carried two of the less effective *CYP2D6* \*3,\*4,\*5 alleles. Regarding another gene within cytochrome P450 system, namely *CYP3A5*, an association was observed between nonfunctional *CYP3A5*\*3 allele and the magnitude of CK elevation in case of patients experiencing myalgia during atorvastatin treatment [23]. Importantly, patients who develop myalgia while taking atorvastatin were more likely to experience a greater degree of muscle damage if they express two copies of *CYP3A5*\*3.

#### **3.5. Other plausible gene variants**

*COQ2* gene encodes Coenzyme Q2, involved in synthesis of ubiquinon (Coenzyme Q10, CoQ10), a redox carrier in the mitochondrial respiratory chain and a lipid-soluble antioxidant. Two variants within the *COQ2* gene (**Table 1**) have been associated with increased odds of statin intolerance, defined primarily through muscle symptomatology [26]. This observation has been subsequently replicated [31].

From other molecules functioning as drug transporters, *ABCB1* gene variation may also participate in development of statin muscle symptoms. This gene encodes the P-glycoprotein, an independent efflux pump. From its variants, the 1236 T, 2677non-G, and 3435 T alleles were less frequent in cases undergoing statin therapy than in the control group [32]. The authors also demonstrated a reduced T-non-G-T haplotype frequency (20.0%) in patients in whom myalgia developed during simvastatin treatment, as compared with the control, non-myalgia group (41.4%).

Most recently, a variant of a *UGT1* gene coding for uridine diphosphate glucuronosyltransferase, specifically *UGT1A1*\*28 variant allele (rs8175347), was reported to possess plausible protective effect in development of statin intolerance [33], however again this finding must be replicated.

In the following text we will concentrate on the *SLCO1B1* gene variation and describe its population distribution and clinical relevance. The reason for our focus is that to date, the rs4149056 *SLCO1B1* variant has been repeatedly evidenced to possess the strongest effect in response to statin therapy.
