Genetic polymorphism of the CYP2C19 gene in the Foshan area of Guangdong Province

Background: The CYP2C19 gene is highly polymorphic, and CYP2C19 is involved in the broad interindividual variability of the clinical efficacy of certain clinical medications, such as clopidogrel. However, data on the CYP2C19 genotype in the Chinese population of the Foshan area of Guangdong Province are scarce. The purpose of this study was to determine CYP2C19 genetic polymorphisms in patients in the Foshan area and to compare the CYP2C19 genotype frequencies in different populations to determine the allele distribution pattern to identify the most appropriate prescription. Methods: The CYP2C19 gene was detected in 1231 patients on a gene chip platform, and the genotype frequencies of CYP2C19 in Foshan populations from different populations were compared. Results: The frequencies of CYP2C19*1, *2 and *3 in the Foshan population were 63.89%, 30.46% and 5.65%, respectively. For the three metabolic types, the frequency associated with the rapid metabolism type (*1/*1) was 41.51 [95% confidence interval (CI) 40.11 to 42.91%]; that for the intermediate metabolism type (*1/*2, *1/*3) was 44.76% (95% CI 43.34 to 46.18and that for the slow metabolism type (*2/*2, *2/*3, *3/*3) was 13.73% (95% CI 12.75 to 14.71%). In the Foshan population, the frequencies of the CYP2C19 *2 and *3 alleles were similar to those previously reported for Chinese and other Asian populations. Conclusion: Our study the genetic basis of CYP2C19 polymorphism in the Foshan population. Our results will potentially contribute to the improvement of pharmacotherapy effectiveness by providing personalized medicine for the Foshan population.


Introduction
Coronary heart disease is one of the main causes of disability and death worldwide [1]. Clopidogrel, which blocks the platelet adenosine diphosphate (ADP) receptor pathway to inhibit platelet aggregation, is an antiplatelet drug that is usually used in the treatment of thromboembolic diseases such as coronary artery disease (CAD), ischaemic stroke or peripheral atherosclerotic diseases. [2] However, the pharmacodynamic efficacy of clopidogrel is often reduced because of interindividual variability. According to report, ~ 4-30% of patients appear nonresponsive or show low responsiveness to clopidogrel (clopidogrel resistance), which could increase the risk of major adverse cardiovascular events (MACE) [3].
Cytochrome P450 (CYP450) is an enzyme that is essential for the degradation and biosynthesis of medications, toxins, and endogenous substances [4]. In the last few years, many CYPP450 enzymes that participate in phase I reactions of drug metabolism, including CYP2D6, CYP1A2, CYP2C19, and CYP2C9, have been reported [5,6]. CYP2C19 participates in the metabolism of approximately 10% of commonly prescribed medications, such as antidepressants, antipsychotics, clopidogrel, and proton pump inhibitors [7]. Genetic variations in CYP2C19, which is highly polymorphic, may affect the ability to metabolize the related drugs. Interindividual differences in enzyme activity divide the population into the extensive metabolizer (EM), intermediate metabolizer (IM) and poor metabolizer (PM) phenotypes [8][9]. To date, at least 34 alleles of CYP2C19 have been identified. Among these alleles, CYP2C19*3 and CYP2C19*2 are the most frequent loss-of-function (LOF) alleles and are responsible for the reduced efficacy of clopidogrel and increased rate of cardiovascular events [10][11][12]. In March 2010, the US Food and Drug Administration (FDA) proposed a boxed warning about clopidogrel, which suggests that physicians might consider the use of replacement treatment strategies in individuals with PM genotypes [13]. The polymorphism of CYP2C19 varies greatly among regions and ethnic groups [14]. Multiple studies on the differences in the genotype frequencies of CYP2C19 among different populations have been performed to date.
However, few studies on CYP2C19 genetic polymorphisms and genotype frequencies have been conducted among populations in Guangdong Province. Our study aims to determine the CYP2C19 genetic polymorphisms among patients in Foshan City of Guangdong Province. We also compared the genotype frequencies of CYP2C19 in different populations.

Subjects
Our study was retrospective. The study was approved by the ethics committee of Nan Hai Hospital affiliated with Southern Medical University, and written informed consent was obtained from all participants (number: 20160106). We selected 1231 patients (ages 19-92 years) who visited Nan Hai Hospital affiliated with Southern Medical University between January 2016 and May 2018 for inclusion in this study. All subjects were Han Chinese individuals residing in the Foshan area of Guangdong Province with more than three generations of paternal ancestry of their ethnicity. Subjects with liver diseases or severe heart failure or kidney disease was excluded. All of the chosen subjects had undergone clopidogrel therapy and were unrelated. Positive and negative controls were included in each experiment.

Statistical analysis
Statistical analyses were performed with Excel and SPSS 19.0.
The gene counting method was used to calculate allele frequencies and genotype frequencies. A chisquare test was used to analyse the differences in the allele frequencies between our population and other populations. P values < 0.05 were considered significant. Hardy-Weinberg equilibrium was calculated for each allele using the chi-square test.

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CYP2C19 genotype and allele frequencies of all subjects A total of 1231 individuals (range, 19-92 years old) were included in the study.
The CYP2C19 allele and genotype frequencies in all subjects were in Hardy-Weinberg equilibrium (χ2 = 8.00, P > 0.05). We further compared the CYP2C19 allele frequencies between our data and previously published studies from different countries and ethnic groups ( Table 2). Our results showed that the CYP2C19*1 allele frequency in our population was lower than those in other Caucasian and Asian populations. In addition, the CYP2C19*2 and CYP2C19*3 allele frequencies in the subjects of our study were higher than those in studies of Caucasians. Discussion CYP2C19 participates in the metabolization of approximately 10% of commonly prescribed medications, such as antidepressants, antipsychotics, clopidogrel, and proton pump inhibitors [7]. The genetic polymorphism of CYP2C19 plays an important role in related drug metabolism and may lead to inter-individual and inter-ethnic variation in patient responsiveness and adverse drug reactions [15]. Currently, at least 34 alleles of CYP2C19 have been identified. Among these alleles, the CYP2C19*2 and CYP2C19*3 alleles are responsible for the reduced activation of metabolized drugs and an increased rate of serious adverse effects that undermine clinical therapeutics [16][17]. Several In our current study, a total of three different alleles and six genotypes were detected. The CYP2C19*1 allele (wild-type) frequency in the Foshan population was lower than that in Caucasian populations and Asian populations [25][26][27][28][29][30][31][32]. According to previous studies, the highest CYP2C9*2 allele frequency was found in Asians (21.0-49.39%) [18][19][20][21][22][23][24]; however, the lowest frequency was found in Caucasians (2.9-14%) [25][26][27][28][29]. The CYP2C19*2 allele frequency in the subjects of our study was higher than that reported for Caucasians. Interestingly, the CYP2C19*2 allele frequency in our group (30.46%) was closer to those of Hakka (31.06%) and Chinese-Dai (30%) populations [18][19]. As shown in Table 2, the CYP2C19*2 allele frequency in our group was closer to that reported for other Asian populations.
Recent reports have provided evidence that the polymorphisms of CYP2C19 might affect its activity in the metabolization of related drugs. Interindividual differences in enzyme activity divide the population into EM, IM and PM phenotypes [8][9]. In our current study, the proportion of the IM phenotype (44.76%) was slightly higher than that of the EM phenotype (41.51%). The proportion of the PM phenotype was 13.73%, which is closer to that recorded in other Asian populations. Similar to findings in the Hakka population, the CYP2C19*2 allele was the most important variation in our group and was chiefly responsible for the PM phenotype, accounting for 80.48% of the study population.

Conclusions
In summary, our study provides the CYP2C19 genetic polymorphisms present in the Foshan

Consent for publication
Not applicable.

Availability of data and materials
The datasets generated and/or analysed during the current study are not publicly available due to protecting the participants' anonymity but are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests.

Funding
Not applicable.