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

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

130 Genetic Diversity and Disease Susceptibility

**3.4. Family of cytochrome P450 genes**

damage if they express two copies of *CYP3A5*\*3.

**3.5. Other plausible gene variants**

has been subsequently replicated [31].

group (41.4%).

be replicated.

response to statin therapy.

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

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

*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

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

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

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

required before a possible role for this variation in statin tolerance is clarified.

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, Middle East, Oceania and the Americas (Amerindians).

*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 exposure.
