Guangzhao Qi

Purpose: Pharmacogenetic testing is recognized as the major method for the individualized pharmacotherapy in clinical pharmacy practice, but information about the clinical implementation of pharmacogenetic testing in China is limited. The present study aimed to determine the situation of clinical implementation for pharmacogenetic testing in central China. Methods: The study is conducted in the department of clinical pharmacy in The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. We collected and analyzed pharmacogenetic testing results from November 1, 2013 to November 2, 2018 in our hospital, which were checked in the electronic medical record system. The main outcome measures were the number and type of pharmacogenetic testing across five years. Results: A total of 47,265 (56.9% male, mean age = 51.5 years) pharmacogenetic testing results were obtained with an average annual rate of growth of 63.0% across five years. A 50.2% (23,748/47,265) of all the pharmacogenetic testing results were for the determination of cytochrome P450 2C19 (CYP2C19) *2, *3 genotypes, and 41.7% were for the methylene tetrahydrofolate reductase (MTHFR) C677T genotype. The number of departments performing the pharmacogenetic testing was 35, 63, 55, 52, 52 and 39 for 2013– 2018, respectively, and the main top five departments were cardiology, psychiatry, ICU, cardiac surgery and intervention. Conclusion: Clinical implementation of pharmacogenetic testing in China is growing rapidly, but the types and implementing departments of pharmacogenetic testing were limited. Our present study reported the real-world implementation modality of pharmacogenomic tests in China. It will help us to understand the testing of pharmacogenetics in China in order to promote the rational development of pharmacogenetics.

Over 50% prescribed drugs are metabolised by cytochrome P450 3A (CYP3A) and glutathione S‐transferase pi (GSTP1) adds a glutathione to the oxidative products by CYP3A, which increases the hydrophilic property of metabolites and facilitates the excretion. Single nucleotide polymorphisms (SNPs) of CYP3A and GSTP1 show a diverse allele and genotype frequencies distribution among the world populations. The present study aimed to investigate the genotype and allele frequency distribution patterns of CYP3A4, CYP3A5, CYP3A7 and GSTP1 polymorphisms among healthy participants in mainland Tibetan, Mongolian, Uyghur, and Han Chinese populations. Blood samples were collected from 842 unrelated healthy subjects (323 Tibetan, 134 Mongolian, 162 Uyghur, and 223 Han) for genotyping analysis. Variant allele frequencies of CYP3A4 rs2242480, CYP3A5 rs776746, CYP3A7 rs2257401, and GSTP1 Ile105Val were observed in Han (0.253, 0.686, 0.312 and 0.188), Tibetan (0.186, 0.819, 0.192 and 0.173), Mongolian (0.198, 0.784, 0.228 and 0.235) and Uyghur (0.179, 0.858, 0.182 and 0.250) respectively. The allele frequency of CYP3A7*1C in Uyghur (0.019) was higher than that in Tibetan (0.002, p < 0.01). There was a strong linkage disequilibrium between CYP3A4 rs2242480, CYP3A5 rs776746, and CYP3A7 rs2257401 among the four ethnic groups. The results might be useful for the precise medication in the Chinese populations.

Inter-individual differences of drug responses could be attributed to genetic variants of pharmacogenes such as cytochrome P450 (CYP), phase 2 enzymes, and transporters. In contrast to extensive studies on the genetic polymorphisms of CYP gene, genetic mutation spectrum of other pharmacogenes was under-representative in the pharmacogenetics investigations. Here we studied the genetic variations of 125 pharmacogenes including drug transporters, non-CYP phase 1 enzymes, phase 2 enzymes, nuclear receptors and others in Chinese from the Chinese Millionome Database (CMDB), of which 38,188 variants were identified. Computational analyses of the 2554 exonic variants found 617 deleterious missense variants, 91.1% of which were rare, and of the 54 loss-of-function (splice acceptor, splice donor, start lost, and stop gained) variants, 53 (98.1%) were rare. These results suggested an enrichment of rare variants in functional ones for pharmacogenes. Certain common functional variants including NUDT15 13:48611934 G/A (rs186364861), UGT1A1 2:234676872 C/T (rs34946978), and ALDH2 12:112241766 G/A (rs671) were population-specific for CMDB Chinese because they were absent (with a zero of variant allele frequency) or very rare in other gnomAD populations. These findings might be useful for the further pharmacogenomics research and clinical application in Chinese.

Genetic variations of cytochrome P450 (CYP) influence the inter‐individual differences in drug response. Here, we collected 8682 variants of 57 CYP genes and cytochrome P450 oxidoreductase (POR) from a large‐scale sequencing project in Chinese, Chinese Millionome Database (CMDB). In addition, 52 294 variants from the Genome Aggregation Database (gnomAD) had been simultaneously identified and analysed. Rare variants with a variant allele frequency (VAF) < 0.01 comprised 41.4% (3594/8682) of identified variations in the CMDB, while 98.1% (51 320/52 294) in the gnomAD were rare. Out of 8682 variants in the CMDB, 66.9% (5808/8682) were in introns and only 4.3% (377/8682) were missense variants. In contrast, 36.2% (18 929/52 294) variants in the gnomAD were missense. The common alleles with a VAF over 0.1 were found in CYP1A2*1C, CYP1A2*1F, CYP2C19*2, CYP2D6*2, CYP2D6*10, CYP3A5*3 and CYP4F2*3, with a VAF of 0.161, 0.6, 0.27, 0.274, 0.678, 0.92 and 0.233, respectively. The growing number of genetic variations in CYP genes as more genomes are sequenced would increase the power to predict drug metabolism and response based on the genotype of the particular individual.

Cytochrome P450 2D6 (CYP2D6) and endothelial nitric oxide synthase (eNOS) are important in the cardiovascular disease susceptibility and drug response. The methylation of cytosine in the promoter of genes could influence expression. The interindividual differences of drug response could only be explained partly by the polymorphisms of drug disposition genes. This study was aimed to investigate the genetic and epigenetic polymorphisms of CYP2D6 and eNOS in Chinese Tibetan, Mongolian, Uygur, and Han volunteers. Blood samples were collected from 842 unrelated Chinese healthy subjects (323 Tibetan, 134 Mongolian, 162 Uygur, and 223 Han) for genotyping and part of the DNA samples were subjected to cytosine methylation analysis. Significant genetic and epigenetic interethnic polymorphisms of eNOS and CYP2D6 were found in the four Chinese groups. The 4b-G-T wild-type haplotype of eNOS was the most common in Chinese Tibetan (87.1%), Mongolian (79.9%), Uygur (76.4%), and Han (79.5%), respectively. eNOS T-786C creates a new CpG site and a significantly higher methylation level was found in −786CC than that in −786TC in Chinese Han (P = 0.0485) and total Chinese (P = 0.0104). CYP2D6 A-678 (rs28633410) makes the symmetrical CpG site changed to be an asymmetrical CpA site, and the methylation level of cytosine in the CpG context of G-678A was significantly higher than that in the CpA. The results of the present study could be useful for understanding the interindividual disparity of cardiovascular disease susceptibility and drug response among different Chinese ethnic groups and would provide more evidences for the precise medication of Chinese.

Walnuts kernels ( Juglans regia L. ) have rich antioxidants content and have been used in both cosmetic and pharmaceutical industry. This study dealt with the protective role of walnut kernels extracts (WK) on isoproterenol (ISO)-induced myocardial infarction (MI) in rats. Rats were pretreated with WK extracts (300 mg/kg) daily for 35 days. Then, ISO (100 mg/kg) was injected subcutaneously into rats to induce MI. Cardiac diagnostic markers (LDH and CPK), cardiac troponin, heart lipid peroxidation (TBARS and hydroperoxide), antioxidant system (CAT, SOD, GPx, GST, GSH, and GSSG) and the levels of lipid profile were evaluated in rats, and the results revealed WK significantly prevented myocardial injury induced by ISO ( p < 0.05). WK significantly alleviated the oxidative damage and dyslipidemia in ISO-induced MI rats ( p < 0.05). The effect produced by WK was compared with α-tocopherol. The mechanisms for the protective effects of WK could be attributed to its antilipid peroxidative, antioxidant, and antilipidemic properties. In conclusion, we demonstrated that WK has a significant protective effect against ISO-induced MI.

Background and objectives Pioglitazone is a thiazolidinedione antihyperglycemic drug with insulin-sensitizing properties. We investigated whether the variant genotypes of cytochrome P450 2C8 (CYP2C8), CYP2C9, CYP3A5 and transporter ABCB1 influence the pharmacokinetic phenotype of the substrate pioglitazone in Chinese individuals. Participants and methods Single-nucleotide polymorphisms were determined by the PCR-restriction fragment length polymorphism method in 244 (CYP2C8 and CYP2C9) healthy Chinese Han individuals. After a single oral dose of 30 mg pioglitazone, the plasma concentrations of the parent drug and of two major active metabolites M-III and M-IV were measured using a validated LC-MS/MS in 21 (genotyping CYP3A5 and ABCB1) of these 244 volunteers. Results The results confirmed that the unique frequencies of CYP2C8*2 (0.0%), CYP2C8*3 (0.0%), and CYP2C9*2 (0.0%) alleles were significantly different from those reported in Whites and Africans, and there were only 10 variant CYP2C9*1/*3 heterozygous (CYP2C9*3 carriers) among 244 Chinese individuals. These results were similar to those reported in Asian ethnic populations, including the Chinese. Unexpectedly, the pioglitazone AUC_0–48 in CYP2C9*3 carriers was lower (50.8%), whereas the AUC_0–48 ratios of metabolites M-III/pioglitazone and M-IV/pioglitazone increased to 134.3 and 155.8%, respectively, compared with the wild-type CYP2C9*1/*1 homozygous. Moreover, this phenomenon was not observed in individuals with genetic variants of CYP3A5*3 and ABCB1 (C1236T). Conclusion The present research suggests that the CYP2C8, CYP3A5, and ABCB1 genes play no significant role in the interindividual variation of pioglitazone pharmacokinetics, whereas CYP2C9*3 carriers are likely to accelerate the metabolism of this antidiabetic drug in the Chinese Han ethnic population.