**1. Introduction**

Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase) inhibitors are highly effective drugs lowering plasmatic concentration of LDL-C cholesterol by 30–50% [1]. Despite the fact that they are usually considered safe and very well tolerated, a significant proportion of the treated patients does not tolerate the drug: they suffer from side effects, which may result in non-compliance of patients, drug dose-lowering and even discontinuation of therapy [2–4]. Undesirable effects of statins restrict their administration or reaching LDL-C cholesterol target values and limits effective treatment of patients at risk. Non-adherence or discontinuation of therapy is associated with an increased risk of cardiovascular events [5–7].

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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, briefly describe their biological plausibility and characterise clinical relevance.

**3. Genes responsible for statin intolerance**

**Table 1**.

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

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

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

Pharmacogenetics of Cardiovascular Disease: Genetic Variation and Statin Intolerance

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

129

*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%.

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 rep-

**Gene Chromosome Allele rs number Coding variation Study** *SLCO1B1* 12p12.2 \*5 ≠ rs4149056 521 T > C [21] *CYP2D6* 22q13.1 \*3 rs35742686 2549delA [22]

*CYP3A4* 7q21.1 \*1B rs2740574 -392A > G transition [23] *GATM* 15q15.3 — rs9806699 G > A, cis-e QTL [24] *LILRB5* 19q13.4 — rs12975366 T > C: Asp247Gly [25] *COQ2* 4q21.22-q21.23 — rs6335454 synonymous [26]

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.

\*4 rs3892097 splicing defect, G > A

\*5 gene deletion

— rs4693075 non-coding

lication data on this plausible new variant has been available so far.
