CYP2A6 polymorphisms in Malays, Chinese and Indians

The genetically polymorphic cytochrome P450 (CYP) 2A6 is the major nicotine-oxidase in humans that may contribute to nicotine dependence and cancer susceptibility. The authors investigated the types and frequencies of CYP2A6 alleles in the three major ethnic groups in Malaysia and CYP2A6*1A, CYP2A6*1B, CYP2A6*1x2, CYP2A6*2, CYP2A6*3, CYP2A6*4, CYP2A6*5, CYP2A6*7, CYP2A6*8 and CYP2A6*10 were determined by allele-specific polymerase chain reaction (PCR) in 270 Malays, 172 Chinese and 174 Indians. Except for CYP2A6*2 and *3 that were not detected in the Malays and Chinese, all the other alleles were detected. Frequencies for the CYP2A6*4 allele were 7, 5 and 2%, respectively, in Malays, Chinese and Indians. A statistically significant high frequency of the duplicated CYP2A6*1x2 allele occurred among Chinese. Among Malays and Chinese, the most common allele was CYP2A6*1B, but it was CYP2A6*1A among Indians. These ethnic difference in frequencies suggested that further studies are required to investigate the implications on diseases such as cancer and smoking behaviour among these major ethnic groups in Malaysia.     

Ethnic variation in CYP2A6 and association of genetically slow nicotine metabolism and smoking in adult Caucasians

Genetically variable CYP2A6 is the primary enzyme that inactivates nicotine to cotinine. Our objective was to investigate allele frequencies among five ethnic groups and to investigate the relationship between genetically slow nicotine metabolic inactivation and smoking status, cigarette consumption, age of first smoking and duration of smoking. Chinese, Japanese, Canadian Native Indian, African-North American and Caucasian DNA samples were assessed for CYP2A6 allelic frequencies (CYP2A6*1B-*12,*1x2). Adult Caucasian non-smokers (n = 224) (1-99 cigarettes/lifetime) and smokers (n = 375) (> or = 100 cigarettes/lifetime) were assessed for demographics, tobacco/drug use history and DSM-IV dependence and genotyped for CYP2A6 alleles associated with decreased nicotine metabolism (CYP2A6*2, CYP2A6*4, CYP2A6*9, CYP2A6*12). CYP2A6 allele frequencies varied substantially among the ethnic groups. The proportion of Caucasian slow nicotine inactivators was significantly lower in current, DSM-IV dependent smokers compared to non-smokers [7.0% and 12.5%, respectively, P = 0.03, odds ratio (OR) = 0.52; 95% confidence interval (CI) 0.29-0.95]; non-dependent smokers showed similar results. Daily cigarette consumption (cigarettes/day) was significantly (P = 0.003) lower for slow (21.3; 95% CI 17.4-25.2) compared to normal inactivators (28.2; 95% CI 26.4-29.9); this was observed only in DSM-IV dependent smokers. Slow inactivators had a significantly (P = 0.03) lower age of first smoking compared to normal inactivators (13.0 years of age; 95% CI 12.1-14.0 versus 14.2; 95% CI 13.8-14.6), and a trend towards smoking for a shorter duration. This study demonstrates that slow nicotine inactivators are less likely to be adult smokers (dependent or non-dependent). Slow inactivators also smoked fewer cigarettes per day and had an earlier age of first smoking (only dependent smokers).     

CYP2A6 polymorphisms in Malays,Chinese and Indians

The genetically polymorphic cytochrome P450 (CYP) 2A6 is the major nicotine-oxidase in humans that may contribute to nicotine dependence and cancer susceptibility. The authors investigated the types and frequencies of CYP2A6 alleles in the three major ethnic groups in Malaysia and CYP2A6*1A, CYP2A6*1B, CYP2A6*1x2, CYP2A6*2, CYP2A6*3, CYP2A6*4, CYP2A6*5, CYP2A6*7, CYP2A6*8 and CYP2A6*10 were determined by allele-specific polymerase chain reaction (PCR) in 270 Malays, 172 Chinese and 174 Indians. Except for CYP2A6*2 and *3 that were not detected in the Malays and Chinese, all the other alleles were detected. Frequencies for the CYP2A6*4 allele were 7, 5 and 2%, respectively, in Malays, Chinese and Indians. A statistically significant high frequency of the duplicated CYP2A6*1x2 allele occurred among Chinese. Among Malays and Chinese, the most common allele was CYP2A6*1B, but it was CYP2A6*1A among Indians. These ethnic difference in frequencies suggested that further studies are required to investigate the implications on diseases such as cancer and smoking behaviour among these major ethnic groups in Malaysia.     

An interethnic comparison of polymorphisms of the genes encoding drug-metabolizing enzymes and drug transporters: experience in Singapore

Much of the interindividual variability in drug response is attributable to the presence of single nucleotide polymorphisms (SNPs) in genes encoding drug-metabolizing enzymes and drug transporters. In recent years, we have investigated the polymorphisms in a number of genes encoding phase I and II drug-metabolizing enzymes including CYPIA1, CYP3A4, CYP3A5, GSTM1, NAT2, UGT1A1, and TPMT and drug transporter (MDR1) in three distinct Asian populations in Singapore, namely the Chinese, Malays, and Indians. Significant differences in the frequencies of common alleles encoding these proteins have been observed among these three ethnic groups. For example, the frequency of the variant A2455G polymorphism of CYP1A1 was 28% in Chinese and 31% in Malays, but only 18% in Indians. CYP3A4*4 was detected in two of 110 Chinese subjects, but absent in Indians and Malays. Many Chinese and Malays (61-63%) were homozygous for the GSTM1*0 null genotype compared with 33% of Indians. The frequency of the UGTIA1*28 allele was highest in the Indian population (35%) compared to similar frequencies that were found in the Chinese (16%) and Malay (19%) populations. More importantly, our experience over the years has shown that the pharmacogenetics of these drug-metabolizing enzymes and MDR1 in the Asian populations are different from these in the Caucasian and African populations. For example, the CYP3A4*1B allele, which contains an A-290G substitution in the promoter region of CYP3A4, is absent in all three Asian populations of Singapore studied, but occurs in more than 54% of Africans and 5% of Caucasians. There were no difference in genotype and allelic variant frequencies in exon 12 of MDR1 between the Chinese, Malay, and Indian populations. When compared with other ethnic groups, the distribution of the wild-type C allele in exon 12 in the Malays (34.2%) and Indians (32.8%) was relatively high and similar to the Japanese (38.55%) and Caucasians (41%) but different from African-Americans (15%). The frequency of wild-type TT genotype in Asians (43.5% to 52.1%) and Japanese (61.5%) was much higher than those found in Caucasians (13.3%). All the proteins we studied represent the primary hepatic or extrahepatic enzymes, and their polymorphic expression may be implicated in disease risk and the disposition of drugs or endogenous substances. As such, dose requirements of certain drugs may not be optimal for Asian populations, and a second look at the factors responsible for this difference is necessary.     

CYP3A5*3 and *6 single nucleotide polymorphisms in three distinct Asian populations

OBJECTIVE: To determine the frequencies of two functional single nucleotide polymorphisms, CYP3A5*3 and CYP3A5*6, in the CYP3A5 gene in three distinct Asian ethnic groups, namely, the Chinese, Malays and Indians. METHODS: Single nucleotide polymorphism analyses of CYP3A5*1, *3 and *6 were performed in 296 healthy subjects (108 Chinese, 98 Malays and 90 Indians) using the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: The *1 allele frequency was 25% in Chinese compared with 40% in Malays and Indians ( P=0.001). The *3 allele frequency was also higher in the Chinese population, being 76% versus 60% in the Malays and Indians ( P=0.001). The Malays and Indians also had allele frequencies significantly different from Caucasian, Japanese and African-American populations (each P相似文献   

CYP2D6 genetic polymorphism in South Indian populations

This study aimed to determine the prevalence of genetic polymorphism in the CYP2D6 gene, which codes for the polymorphically expressed CYP2D6 drug-metabolizing enzyme. The common variants CYP2D6 *2, *3, *4, *5, *10, *14, and *17 were studied in the populations (n=447) of the four South Indian states namely Tamilnadu (TN), Kerala (Ker), Karnataka (Kar) and Andhra Pradesh (AP). Genetic polymorphisms were identified using polymerase chain reaction (PCR) and PCR-Restriction Fragment Length Polymorphism (PCR-RFLP) based methods. Differences in frequencies of CYP2D6 polymorphism between each South Indian state were statistically compared, and also the frequency of South Indian population as a whole in relation to other major populations. The CYP2D6*2 allele was the most frequent variant (34.8%), followed by the *10 allele (10.2%). The *4 and *5 alleles occurred at 7.3% and 1.9% respectively. The *3, *14 and *17 alleles were not detected in the study. The *1/*2, *1/*1 and *2/*2 genotypes were the most common CYP2D6 genotypes, representing 32.7%, 19.4% and 11.8% of the South Indian population. Genotypes that predict poor metabolizer phenotype i.e. *4/*4 and *4/*5 were found at 0.6% in South Indian population. The genetic composition at the CYP2D6 locus in South Indians is distinct from Caucasian, African and even other Asian (Chinese and Japanese) populations.     

CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants

Over 40 cytochrome P450 (CYP) 2D6 allelic variants have been discovered thus far. The alleles may be classified on the basis of the level of activity for which they encode CYP2D6 enzymes, into functional, non-functional and reduced function groups. CYP2D6 allele frequency is known to vary amongst racial/ethnic groups. Generally, for European Caucasians and their descendants, the functional group of alleles are predominant, with a frequency of 71%. Non-functional alleles represent 26% of the variability, mainly CYP2D6*4. In Asians and their close descendants, functional alleles represent only ~ 50% of the frequency of CYP2D6 alleles. Asians and Pacific Islanders have a high frequency (median = 41%) of a reduced function allele, CYP2D6*10, contributing to the population shift to the right of metabolic rates indicating slower metabolism. Information concerning Amerindians from North (Canada), Central and South America indicate comparatively low frequencies of CYP2D6*10, perhaps a "founders" effect. The frequency of functional alleles in Africans and African Americans is also about 50%. Both Africans and African Americans have reduced function alleles representing 35% of allele variation, mainly CYP2D6*17. African Americans, however, have more than twice the median frequency of nonfunctional alleles compared with Africans (14.5% vs 6.3%). Non-functional and reduced function alleles represent about 50% of allele frequency in Black populations but a much greater variety than carried in Asians. Since alleles which encode for no or reduced functioning clearly affect metabolic activity of drugs mediated by CYP2D6, studies are needed in populations in which these alleles play a major role in order to assure optimal dosing recommendations are based on empirical pharmacogenetics.     

Nicotine metabolism and CYP2A6 allele frequencies in Koreans.

CYP2A6 is a major catalyst of nicotine metabolism to cotinine. Previously, we demonstrated that the interindividual difference in nicotine metabolism is related to a genetic polymorphism of the CYP2A6 gene in Japanese. To clarify the ethnic differences in nicotine metabolism and frequencies of CYP2A6 alleles, we studied nicotine metabolism and the CYP2A6 genotype in 209 Koreans. The cotinine/nicotine ratio of the plasma concentration 2 h after chewing one piece of nicotine gum was calculated as an index of nicotine metabolism. The genotypes of CYP2A6 gene (CYP2A6*1A, CYP2A6*1B, CYP2A6*2, CYP2A6*3, CYP2A6*4 and CYP2A6*5) were determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism or allele specific (AS)-PCR. There were ethnic differences in the allele frequencies of CYP2A6*1A, CYP2A6*1B, CYP2A6*4 and CYP2A6*5 between Koreans (45.7%, 42.8%, 11.0% and 0.5%, respectively) and Japanese (42.4%, 37.5%, 20.1% and 0%, respectively, our previous data). Similar to the Japanese, no CYP2A6*2 and CYP2A6*3 alleles were found in Koreans. The homozygotes of the CYP2A6*4 allele (four subjects) were completely deficient in cotinine formation, being consistent with the data among Japanese. The heterozygotes of CYP2A6*4 tended to possess a lower metabolic ratio (CYP2A6*1A/CYP2A6*4, 4.79 +/- 3.17; CYP2A6*1B/CYP2A6*4, 7.43 +/- 4.97) than that in subjects without the allele (CYP2A6*1A/CYP2A6*1A, 7.42 +/- 6.56; CYP2A6*1A/CYP2A6*1B, 9.85 +/- 16.12; CYP2A6*1B/CYP2A6*1B, 11.33 +/- 9.33). The subjects who possess the CYP2A6*1B allele appeared to show higher capabilities of cotinine formation. It was confirmed that the interindividual difference in nicotine metabolism was closely related to the genetic polymorphism of CYP2A6. The probit plot of the metabolic ratios in Koreans (8.73 +/- 11.88) was shifted to a higher ratio than that in the Japanese (3.78 +/- 3.09). In each genotype group, the Korean subjects revealed significantly higher metabolic ratios than the Japanese subjects. The ethnic difference in cotinine formation might be due to environmental and/or diet factors as well as genetic factors.     

In vivo evaluation of coumarin and nicotine as probe drugs to predict the metabolic capacity of CYP2A6 due to genetic polymorphism in Thais

The association between the distribution characteristics of CYP2A6 catalytic activities toward nicotine and coumarin, and the frequency distribution of CYP2A6 variant alleles reported was estimated in 120 healthy Thais. The distributions of the subjects as classified by the amounts of 7-hydroxycoumarin (7-OHC) excreted in the urine and by cotinine/nicotine ratio in the plasma were clearly bimodal. However, the numbers of apparently poor metabolizers for coumarin and nicotine were different. The inter-individual variability in the in vivo dispositions of coumarin and nicotine closely related to the CYP2A6 genetic polymorphism. There was a close correlation between the rate of 7-OHC excretion in the urine and cotinine/nicotine ratio in the plasma among subjects (R=0.92, p<0.001). The frequency of CYP2A6 allele found in the present study was: CYP2A6*1A=32% (95% CI, 22.1-39.4%), CYP2A6*1B=27% (95% CI, 19.4-33.5%), CYP2A6*9=20% (95% CI, 17.6-23.3%), CYP2A6*4=14% (95% CI, 9.6-17.8%), CYP2A6*7=5% (95% CI, 3.7-9.4%), CYP2A6*10=2% (95% CI, 0.8-5.1%). Subjects having CYP2A6*1A/*1B were found to have a higher rate of 7-OHC excretion, as well as a higher cotinine/nicotine ratio in the plasma compared with those of the other genotypes. In contrast, subjects with CYP2A6*4/*7 and CYP2A6*7/*7 almost lacked any cotinine formation, whereas urinary 7-OHC was still detectable. CYP2A6*9 allele clearly resulted in reduced enzyme activities. Despite the absence of the homozygote for CYP2A6*10 allele, the presence of CYP2A6*10 allele significantly decreased the enzyme activities. The results of the present study demonstrate that in vivo phenotyping of CYP2A6 using nicotine and coumarin are not metabolically equivalent. Nicotine is a better probe according to its specificity, while coumarin is still valuable to be used for a routine CYP2A6 phenotyping since the test employs a non-invasive method.     

Allele and genotype frequencies of polymorphic cytochromes P450 (CYP2C9, CYP2C19, CYP2E1) and dihydropyrimidine dehydrogenase (DPYD) in the Egyptian population

AIMS: The goal of this study was to determine the frequencies of important allelic variants of CYP2C9, CYP2C19, CYP2E1 and DPYD in the Egyptian population and compare them with the frequencies in other ethnic populations. METHODS: Genotyping of CYP2C9 (*2 and *3), CYP2C19 (*2 and *3), c2 variant of CYP2E1 and DPYD alleles (*2 A-*6 ) was carried out in a total of 247 unrelated Egyptian subjects. An allele-specific fluorogenic 5' nuclease chain reaction assay was applied for detection of CYP2C9 and CYP2C19 variants. Other variants of the CYP2E1 and DPYD genes were determined using polymerase chain reaction (PCR)-restriction fragment length polymorphism and allele-specific PCR based assays. RESULTS: CYP2C9 allele frequencies in 247 Egyptian subjects were 0.820 for CYP2C9*1, 0.120 for CYP2C9*2 and 0.060 for CYP2C9*3. For CYP2C19, the frequencies of the wild type (CYP2C19*1) and the nonfunctional (*2 and *3) alleles were 0.888, 0.110 and 0.002, respectively. CYP2C19*3, which is considered an Asian mutation, was detected in one subject (0.40%) who was heterozygous (*1/*3). Two subjects (0.80%) were homozygous for *2/*2, while no compound heterozygotes (*2/*3) or homozygotes for *3 were detected. For CYP2E1, only four subjects (1.70%) had the rare c2 variant, expressed heterozygously, giving an allele frequency of 0.009. Five variants of DPYD were analysed, with no splice sites (*2 A) or DeltaC1897 (*3) found in this population. The frequencies of other variants were 0.028, 0.115 and 0.090 for *4, *5 and *6, respectively. CONCLUSIONS: Comparing our data with that obtained in several Caucasian, African-American and Asian populations, we found that Egyptians resemble Caucasians with regard to allelic frequencies of the tested variants of CYP2C9, CYP2C19, CYP2E1 and DPYD. Our results may help in better understanding the molecular basis underlying ethnic differences in drug response, and contribute to improved individualization of drug therapy in the Egyptian population.     

Genetic polymorphism of CYP2D6 and CYP2C19 in East- and Southern African populations including psychiatric patients

OBJECTIVES: The study was carried out to investigate the distribution of cytochrome P450 2D6 (CYP2D6) and CYP2C19 genotype frequencies in three African populations and to compare these frequencies between healthy individuals and psychiatric patients. METHODS: Three hundred and eighty-four subjects from South Africa (Venda), Tanzania, and Zimbabwe who consented to the study were genotyped for CYP2D6 (CYP2D6*1, *2, *3, *4, *5, and *17) and CYP2C19 (CYP2C19*1, *2, and *3) by PCR-RFLP (polymerase chain reaction restriction fragment length polymorphism) techniques. RESULTS: The genotypes for CYP2D6 predicted a poor metabolizer frequency of 2.3% (2/88) in Tanzanian psychiatric patients, 1.9% (2/106) in Tanzanian healthy controls and 2.6% (2/76) in the South African Venda. The low-activity CYP2D6*17 allele frequency was higher in psychiatric patients (30%, 53/176) than in healthy individuals (20%, 43/212) in Tanzanians. The frequencies for CYP2C19*2 genotypes were predictive of a low prevalence of poor metabolizers (PMs). The CYP2C19*3 allele was absent in the three populations studied. There was no difference in CYP2D6 or CYP2C19 PM genotype frequencies between psychiatric patients and healthy subjects. CONCLUSION: The genotype results predict a low prevalence of people with deficient CYP2D6 and CYP2C19 activity among linguistically (Bantu) related populations of East and Southern Africa. The high frequency of the low-activity CYP2D6*17 allele predicts that the Bantu people have a reduced capacity to metabolise drugs that are CYP2D6 substrates.     

Allele and genotype frequencies of polymorphic cytochromes P4502D6, 2C19 and 2E1 in aborigines from western Australia

The polymorphisms of the important xenobiotic metabolizing enzymes CYP2D6, CYP2C19 and CYP2E1 have been studied extensively in a large number of populations and show significant heterogeneity in the frequency of different alleles/genotypes and in the prevalence of the extensive and poor metabolizer phenotypes. Understanding of inter-ethnic differences in genotypes is important in prediction of either beneficial or adverse effects from therapeutic agents and other xenobiotics. Since no data were available for Australian Aborigines, we investigated the frequencies of alleles and genotypes for CYP2D6, CYP2C19 and CYP2E1 in a population living in the far north of Western Australia. Because of its geographical isolation, this population can serve as a model to study the impact of evolutionary forces on the distribution of different alleles for xenobiotic metabolizing enzymes. Twelve CYP2D6 alleles were analysed. The wild-type allele *1 was the most frequent (85.81%) and the non-functional alleles (*4, * 5, * 16) had an overall frequency of less than 10%. Only one subject (0.4%) was a poor metabolizer for CYP2D6 because of the genotype *5/*5. For CYP2C19, the frequencies of the *1 (wild-type) and the non-functional (*2 and *3) alleles were 50.2%, 35.5% and 14.3%, respectively. The combined CYP2C19 genotypes (*2/*2, *2/*3 or *3/*3) correspond to a predicted frequency of 25.6% for the CYP2C19 poor metabolizer phenotype. For CYP2EI, only one subject had the rare c2 allele giving an overall allele frequency of 0.2%. For CYP2D6 and CYP2C19, allele frequencies and predicted phenotypes differed significantly from those for Caucasians but were similar to those for Orientals indicating a close relationship to East Asian populations. Differences between Aborigines and Orientals in allele frequencies for CYP2D6* 10 and CYP2E1 c2 may have arisen through natural selection, or genetic drift, respectively.     

Genetic polymorphisms of CYP2D6, CYP1A1, GSTM1 and p53 genes in a unique Siberian population of Tundra Nentsi

The purpose of this study was to establish the frequencies of CYP2D6, CYP1A1, GSTM1 and p53 polymorphic genotypes in Tundra Nentsi, which comprises the small group of indigenous people belonging to Northern Mongoloids and Caucasians of Western Siberia. A total number of 102 Tundra Nentsi individuals and 96 Caucasians of Western Siberia were genotyped by means of polymerase chain reaction-based assays. Mutated alleles comprising CYP2D6*4, CYP1A1Val, GSTM1*0 and p53Pro were analysed along with the wild-type alleles. The results showed the intermedial position of CYP2D6*4 allele frequency in Tundra Nentsi, compared to Caucasians and Orientals (0.07 versus 0.2, P = 0.0003; 0.07 versus 0.003, P = 1 x 10(-6), respectively). Thus, our data indicate that the intermedial position of Tundra Nentsi between Orientals and Caucasians most likely shows the Caucasian ancestral origin of CYP2D6*4 allele. Comparative analysis of p53Pro allele frequency showed the pronounced ethnic differences with geographic gradient. Though the frequency of p53Pro allele ranged from 0.17 in Tundra Nentsi up to 0.3 in Caucasians of Western Siberia (P = 0.002), which is in agreement with the previously reported radial distribution of the known genetic markers. No differences were found in the CYP1A1Val allele distribution among Caucasians of Western Siberia and Caucasoid populations presented in other studies, whereas the frequency of Val allele in Nentsi was 1.5-fold higher (P = 0.076) compared to the Japanese group. It was found that the frequency of GSTM1 null genotype in Tundra Nentsi was only 39.8%. The frequency of GSTM1 null genotype in females was higher than in males (0.27 and 0.50, respectively) but that difference was not statistically significant. Comparative analyses of the distribution of putative markers towards cancer susceptibility, CYP1A1Val, GSTM1*0 and p53Pro alleles, have shown that the healthy Tundra Nentsi population (Northern Mongoloids) have a low number of p53Pro alleles and GSTM1*0/*0 genotypes and a high level of CYP1A1Val alleles. Further investigations of gene polymorphisms in isolated Northern native populations would be valuable in clarifying the origin of Northern natives. All this is important for comparative analyses of pharmacogenetic data in Mongoloid populations.     

Frequency of cytochrome P450 2C9 mutant alleles in a Korean population

AIMS: To determine the frequencies of CYP2C9 variants in the Korean population and compare them with the frequencies in other ethnic populations. METHODS: Genotyping of CYP2C9*2 and CYP2C9*3 allelic variants was carried out in 574 Korean subjects by PCR and restriction fragment length pattern analysis. RESULTS: Thirteen of 574 subjects (2.3%) were heterozygous for CYP2C9*3 (Ile359Leu), but no subjects with a CYP2C9*2 allele or homozygous for CYP2C9*3 were identified. The allele frequency of CYP2C9*3 in Korean subjects (0.0113, 95% CI 0.0066-0.0193) was similar to that of other East Asian populations, but was considerably lower than that of Caucasian populations. CONCLUSIONS: CYP2C9*3 seems to be an allelic variant related to the functional polymorphism of CYP2C9, but this variant is rarely seen among Koreans compared with Caucasians. Routine genotyping of the CYP2C9*2 allele is considered to be unnecessary in Korean and East Asians, because this allele appears to be extremely rare or absent in these populations.     

CYP2C19 and PON1 polymorphisms regulating clopidogrel bioactivation in Chinese, Malay and Indian subjects

AIM, MATERIALS & METHODS: We investigated the functional significance of CYP2C19*2, *3, *17 and PON1 Q192R SNPs in 89 consecutive Asian patients on clopidogrel treatment and the prevalence of functionally significant polymorphisms among 300 Chinese, Malays and Asian Indians. RESULTS: Both CYP2C19 loss-of-function alleles (*2 or *3) were associated with higher platelet reactivity while the CYP2C19 gain-of-function allele (*17) had lower platelet reactivity. For PON1, the median PRI was not significantly different between the QQ, QR and RR groups. The allele frequencies of CYP2C19*2, CYP2C19*3 and CYP2C19*17 were 0.280, 0.065 and 0.010 (rare) for Chinese, 0.310, 0.050 and 0.025 for Malays, and 0.375, 0.010 (rare) and 0.165 for Indians, respectively. CONCLUSION: Our data suggest that genotyping studies to investigate clopidogrel response should include CYP2C19*2 and *3 but not *17 polymorphisms in Chinese, and CYP2C19*2 and *17 polymorphisms but not *3 in Indians. All three polymorphisms should preferably be genotyped in Malays.     

中国汉族和回族药物代谢酶细胞色素P450(CYP)3A4、CYP2C9、CYP2C19及CYP2D6基因多态性分析

目的对中国汉族、回族健康人群细胞色素P450(CYP)3A4、CYP2C9、CYP2C19及CYP2D6进行基因多态性分析,比较汉族和回族健康人群基因表型和基因频率分布。方法多聚酶链反应-限制性片段长度多态性(PCR-RFLP)法,对300名志愿者的几种基因进行分型。结果汉族、回族CYP3A4*5等位基因频率均为0,CYP3A4*18等位基因频率分别为0.18,0.19;汉族、回族CYP2C9*2等位基因频率分别为0.01,0.05;CYP2C9*13等位基因频率均为0;汉族、回族CYP2C19*2等位基因频率分别为0.39,0.50;CYP2C19*3等位基因频率分别为0.05,0.05;汉族、回族CYP2D6*10等位基因频率分别为0.57,0.39。结论汉族、回族健康人群的CYP3A4*18、CYP2C9*2、CYP2C19*2、CYP2C19*3均没有显著性差异;在汉族、回族健康人群中未发现CYP3A4*5和CYP2C9*13突变;汉族、回族CYP2D6*10等位基因频率有显著性差异(P<0.01);回族人群CYP2D6中速代谢型(*10/*10)频率为13.4%,明显低于汉族的33.1%(P<0.01)。     

High prevalence of cytochrome P 450 2A6*1A alleles in a black African population of Ghana

Objective We investigated the frequencies of the functionally important variants of the CYP2A6 gene in black African populations.Methods Using genomic DNA sequencing, polymerase chain reaction (PCR)–restriction fragment length polymorphism and allele-specific PCR, the allele frequencies of CYP2A6 *1A, *1B, *2, *4A, *5, *6, *7, *8, *9, *10 and * 11 among 120 black Africans— including 105 Ghanaians, 12 Nigerians, 2 Ivorians and 1 Ugandan—were determined.Results The allele frequencies were 80.5% for CYP2A6*1A, 11.9% for CYP2A6*1B, 1.9% for CYP2A6*4A and 5.7% for CYP2A6*9 in the Ghanaian subjects. No subject homozygous for the CYP2A6*4A allele, a whole gene deletion type of polymorphism prevalent among Orientals, was found. Furthermore, CYP2A6 variants such as *2, *5, *6, *7, *8, *10 and *11 were absent in these black African populations.Conclusions This study provides, for the first time, the results of the analysis of CYP2A6 allele frequency in black African populations and confirms large ethnic differences in the polymorphic CYP2A6 gene.     

Analysis of CYP2C9*5 in Caucasian,Oriental and black-African populations

OBJECTIVE: CYP2C9 is a polymorphic gene with at least six known allelic variants (CYP2C9*1 to *6). CYP2C9*5 has been recently described in African-Americans. The lower activity of CYP2C9*5 encoded enzyme than *1 has been reported for the S-warfarin 7-hydroxylation in vitro. The aim of the present study was to develop an assay for the analysis of this variant and to determine the frequency of this polymorphism in different ethnic populations. MATERIALS AND METHODS: A PCR-based endonuclease digestion method, using a mismatched forward primer that introduced a recognition site for AvaII in all the CYP2C9 genotypes except CYP2C9*5, is described. DNA samples from 150 Ethiopians, 183 Tanzanians, 200 Caucasians from Sweden and 150 Orientals from Korea were screened for this variant allele. RESULTS AND CONCLUSION: The CYP2C9*5 allele was analysed using a polymerase chain reaction-based endonuclease method, and it was found in three Tanzanians (allele frequency, 0.0082) but not in Ethiopians, Caucasians or Orientals.