Polymorphisms of cytochrome P450 are potential candidates that could potentially help clinicians on the treatment of cardiovascular diseases among Asian populations.

There are significant ethnic differences in the metabolism of some drugs that can be explained by cytochrome P450 polymorphisms and, in particular, the CYP2D6 isozyme. In addition, among patients who are not carriers of the CYP2C19 loss-of-function alleles, there is a reduced risk of stroke when clopidogrel is taken with aspirin compared to aspirin alone. These findings demonstrate that there is inter-ethnic variability in the metabolism of some drugs, which results in different responses to cardiovascular drugs in Asian versus non-Asian populations.

Using a 2-by-2 quasi-factorial open-label design, Craig S. Anderson et al. reported that there was no heterogeneity in the effect of Alteplase dose on the risk of symptomatic intracerebral haemorrhage (ICH) between Asians and non-Asian patients. However, the results suggested that low doses of Alteplase had a protective effect on ICH in Asian subjects compared with the standard dose. Furthermore, this effect is observed using several different criteria [Symptomatic intracerebral haemorrhage by SITS-MOST criteria: low dose = 17 (1.0%) versus standard dose = 35 (2.1%); OR = 0.48, Confidence Interval (CI) of 95% = 0.27 to 0.86 0.01, p-value = 0.01; symptomatic intracerebral haemorrhage by NINDS criteria: low dose = 98 (5.9%) versus standard dose = 131 (8.0%); OR = 0.73, CI 95% = 0.55 to 0.95, p-value = 0.02]. The trend of a reduced risk of ICH in patients treated with a low dose of this drug versus those administered a higher dose is evident. Similar results were found by Wang et al. in a Chinese population (In a randomized, double-blind, placebo-controlled trial conducted at 114 centres in China). They reported that among patients with transient ischaemic attack (TIA) or minor stroke, the combination of clopidogrel and aspirin had a greater effect than aspirin alone in reducing the risk of stroke in the first 90 days while not increasing the risk of haemorrhage. Clopidogrel (alone or in combination with aspirin) is used to prevent vascular complications in atherothrombotic patients and stent thrombosis in patients undergoing percutaneous coronary intervention, and it is also used as a long-term preventative measure for cardiovascular and cerebrovascular events. Unfortunately, approximately 20% (of more than 40 million patients in the world) of the patients are poor responders or show no response at all. This drug is regulated and metabolized by cytochromes CYP2C19, CYP2C9, CYP2B6, CYP1A2, CYP3A4, and CYP3A5, in addition to the glycoprotein paraoxonase-1. Wong et al. reported that among patients with minor ischaemic stroke or TIA, the use of clopidogrel with aspirin compared to aspirin alone reduced the risk of a new stroke only in the subgroup of patients who were not carriers of the CYP2C19 loss-of-function alleles. Additionally, other studies indicated that the polymorphism CYP2C19*17 increases the metabolism of clopidogrel and as a result clopidogrel-induced platelet inhibition. These findings demonstrated that the inter-ethnic variability can be explained by genetic polymorphisms. There are significant ethnic differences in the metabolism of some drugs that are caused by cytochrome P450 (CYP) polymorphisms, particularly the CYP2D6 isozyme. It is well-established that there are 57 active CYP genes in the human genome (categorized into 18 families), and the variation in these genes results in several phenotypes defined as ultrarapid, extensive, intermediate and poor metabolizers. In general, an ultrarapid metabolizer carries duplicated or multi-duplicated gene copies of the same allele, whereas intermediate and poor metabolizers carry one and two defective alleles (by gene inactivation or deletion), respectively. The extensive metabolizer carries two normal activity alleles of the CYP enzyme (also called the *1 or consensus allele). On the other hand, the first three families (CYP1-3) are generally involved in the metabolism of drugs. CYP enzymes are responsible for approximately 65–70% of the clearance of prescribed drugs, while the CYP2D6 isoenzyme metabolizes 25–30% of these drugs. Asian and African-American populations have reduced CYP2D6 activity compared to Caucasians who have a lower occurrence of non-functional alleles (e.g., *3, *4, *5,*6), but a higher frequency of alleles associated with reduced activity (e.g., *10, *17).8, 9 Therefore, due to the high frequency of an allele with reduced function in the form of CYP2D6*10 among Asian populations that contributes to reduced enzymatic activity and a potentially increased dose of circulating drugs, this isozyme is another potential candidate for explaining the different effects of Alteplase dose on the risk of symptomatic ICH in Asian patients. Consequently, for Asian populations, this finding may be important to improve pharmacotherapy. Considering the patients' genotype with available clinical practice guidelines as a tool to complement algorithms could potentially help clinicians with this assessment and support evidence-based decision making. This focus may help clinicians to personalize treatment decisions based on risk stratification. However, the performance of the suggested practical approach must be rigorously assessed or validated in clinical studies, and the clinician’s judgement remains paramount when making decisions.5, 6, 10 The polymorphic nature of the cytochrome P450 gene affects an individual’s drug response and adverse reactions to said drug to a great extent. This variation includes copy number variants, missense mutations, insertions and deletions, and mutations affecting gene expression and activity of CYP2A6, CYP2B6, CYP2C9, CYP2C19 and CYP2D6. Therefore, the pharmacogenetic effect of CYP2D6*10 may only be evident against a specific haplotype background. In the context of this hypothesis, if the clinical genotyping identifies a patient as a poor metabolizer for a candidate gene associated with Alteplase therapy, current evidence suggests that a low-dose treatment with Alteplase could reduce the risk of symptomatic ICH in Asian populations.

Similarly, in patients with minor ischaemic stroke or TIA who are not carriers of the CYP2C19 loss-of-function alleles, the use of clopidogrel with aspirin reduces the risk of a new stroke.1, 2, 6 However, the therapy recommendations based on the cytochrome CYP2D6 phenotype (haplotypes) require the identification of the haplotypes of clinical relevance for each population and each medication. Therefore, the scientific evidence suggests that gene polymorphisms may explain differences in outcome after drug administration and that pharmacogenomics-guided treatments may be possible, but controlled clinical trials are necessary to support this statement.