4.3.1. Genomic Variation in CYP450

CYP450 genomics examine how modifications in the genes encoding the CYP450 complex affect enzyme function in metabolism and downstream drug therapeutic response. This has direct clinical applicability. This can be illustrated by examining two CYP450 enzymes relevant to Cardio-Oncology—CYP2C19 and CYP2D6 [7,16,68].

#### 4.3.2. Genomic Variation in CYP2C19

Over 50 CYP2C19 genomic variants have been identified [7]. The CYP2C19 gene is located on chromosome 10q24.1q24.3, is composed of nine exons and produces a medium-sized protein (55.93 kDa) from 490 amino acids [7]. Homozygosity for loss-of-function alleles confers poor metabolism, heterozygosity for loss-of-function (LOF) alleles confers intermediate metabolism, wild type alleles (\*1/\*1) confer what may be considered 'normal' metabolism and homozygosity for a gain-of-function (GOF) allele confers ultra-rapid metabolism [7]. The four major phenotypes listed above correspond to selected permutations of the most common CYP2C19 genetic variants (\*1, \*2, \*3, \*17) in the dose-response relationship (Table 3). The frequency of these phenotypes seems to differ with ethnicity. Approximately 2% of Europeans (the most widely studied population) are poor CYP2C19 metabolizers, while up to 20% of Asians are poor metabolizers [1,2,69], underscoring the need for further study in all populations. Poor or intermediate metabolism of clopidogrel may lead to persistently elevated platelet function in spite of treatment (i.e., high on-treatment platelet reactivity or HTPR) in individuals treated for acute coronary syndromes (ACS) [7]. These individuals remain at high-risk for ischemia, limited post-PCI myocardial flow and adverse cardiovascular outcomes (e.g., stent thrombosis, myocardial infarction, stroke and death) [7]. The most common SNPs responsible for the poor metabolizer phenotype result from premature stop codons due to the presence of Adenine in lieu of Guanine on nucleotide 681 of exon 5 (CYP2C19\*2) and on nucleotide 636 of exon 3 (CYP2C19\*2). While there are other alleles associated with CYP2C19 LOF (CYP2C19\*4, \*5, \*6, \*7, \*8), they comprise less than one percent of the known CYP2C19 alleles [7]. Only one GOF variant (CYP2C19\*17) has been identified.


**Table 3.** Anticipated CYP2C19 phenotypes corresponding to genotypes. Used with permission of Creative Commons [7], copyright 2019; and adapted from Reference [70], used with permission of John Wiley and Sons; copyright 2013.

#### 4.3.3. Genomic Variation in CYP2D6

CYP2D6 phenotypes can also be categorized into 4 different groups based on enzyme activity: poor metabolizer, intermediate metabolizer, extensive metabolizer and ultra-rapid metabolizer [16,71–75]. The poor metabolizer phenotype is in part explained by genetic alterations, namely frame-shift mutations or splicing defects, yielding minimal expression of the CYP2D6 protein or a nonfunctional CYP2D6 protein [16]. There are over 100 CYP2D6 genomic variants, of which nearly half—through either decreased (CYP2D6\*9, \*17, \*41, etc.) or no functional enzyme (CYP2D6 \*4, \*6, \*15, etc.)—are

phenotypically poor metabolizers [68]. The remaining known variants are phenotypically normal or as of yet undetermined. Less than 10% of the population possesses the 2D6 poor metabolizer phenotype and CYP2D6 metabolizes up to 20% of medications currently in use in the general population [16]. More research is needed to similarly characterize mechanisms behind the extensive and ultra-rapid CYP2D6 metabolizer phenotypes [16]. Further, translational and post-translational modifications may complement the contribution of genomics to interindividual variability. Among individuals with confirmed wild type ('normal') gene copies of CYP2D6, a remarkable extent of interindividual variability of phenotypic CYP2D6 activity was noted [16,76].
