CYP2C9 Alleles Research Articles

CYP2C19 and CES1 polymorphisms and efficacy of clopidogrel and aspirin dual antiplatelet therapy in patients with symptomatic intracranial atherosclerotic disease.

OBJECT Symptomatic intracranial atherosclerotic disease (ICAD) has a high risk of recurrent stroke. Genetic polymorphisms in CYP2C19 and CES1 are associated with adverse outcomes in cardiovascular patients, but have not been studied in ICAD. The authors studied CYP2C19 and CES1 single-nucleotide polymorphisms (SNPs) in symptomatic ICAD patients. METHODS Genotype testing for CYP2C19*2, (*)3, (*)8, (*)17 and CES1 G143E was performed on 188 adult symptomatic ICAD patients from 3 medical centers who were medically managed with clopidogrel and aspirin. Testing was performed prospectively at 1 center, and retrospectively from a DNA sample biorepository at 2 centers. Multiple logistic regression and Cox regression analysis were performed to assess the association of these SNPs with the primary endpoint, which was a composite of transient ischemic attack (TIA), stroke, myocardial infarction, or death within 12 months. RESULTS The primary endpoint occurred in 14.9% of the 188 cases. In multiple logistic regression analysis, the presence of the CYP2C19 loss of function (LOF) alleles *2, *3, and *8 in the medically managed patients was associated with lower odds of primary endpoint compared with wild-type homozygotes (odds ratio [OR] 0.13, 95% CI 0.03-0.62, p = 0.0101). Cox regression analysis demonstrated the CYP2C19 LOF carriers had a lower risk for the primary endpoint, with hazard ratio (HR) of 0.27 (95% CI 0.08-0.95), p = 0.041. A sensitivity analysis of a secondary composite endpoint of TIA, stroke, or death demonstrated a significant trend in multiple logistic regression analysis of CYP2C19 variants, with lower odds of secondary endpoint in patients carrying at least 1 LOF allele (*2, *3, *8) than in wild-type homozygotes (OR 0.27, 95% CI 0.06-1.16, p = 0.078). Cox regression analysis demonstrated that the carriers of CYP2C19 LOF alleles had a lower risk forthe secondary composite endpoint (HR 0.22, 95% CI 0.05-1.04, p = 0.056). CONCLUSIONS This is the first study examining genetic variants and their effects in symptomatic ICAD. Variant alleles of CYP2C19 (*2, *3, *8) were associated with lower odds of the primary and secondary composite endpoints. However, the direction of the association was opposite of what is expected based on this SNP. This may reflect an incomplete understanding of this genetic variation and its effect in symptomatic ICAD and warrants further investigations.

Analysis of CYP2C19 gene polymorphism among different sex, age, and BMI in the southeast of Henan province

Objective To study the frequency of CYP2C19 genotype and allele mutation of cytochrome P450 in the southeast part of Henan province, and to understand the effect of sex, age, body mass index (BMI) on the genetic polymorphism of CYP2C19. Methods Genetic polymorphism analysis of CYP2C19 gene in 161 healthy people in Henan province, using gene chip method, 87 male, 74 female, aged 26-82 years old, and BMI 17-31. Results The experiment, a total of CYP2C19 six different gene mutation type, CYP2C19 1 of (40.4%), CYP2C19*1/*2 (39.1%), CYP2C19*2/*2 (14.9%), CYP2C19*1/*3 (3.1%), CYP2C19*2/*3 (2.5%), CYP2C19*3/*3 (0%); allelomorph CYP2C19 * 2 (35.7%), follow (2.8%).87 male wild type homozygous for CYP2C19 1 of (39.1%), allelomorph CYP2C19 * 2 (39.1%), follow (3.1%), 74 female wild type homozygous for CYP2C19 1 of (41.9%), and other allelomorph CYP2C19 * 2 (32.3%), follow (2.5%).103 cases were more than or equal to 58 years old wild type homozygous for CYP2C19 1 of (47.6%), allelomorph CYP2C19 * 2 (39.8%), follow (3.7%), 58 25 groups of wild-type homozygous for CYP2C19 1 of (37.7%), allelomorph CYP2C19 * 2 (32.9%), follow (1.2%), BMI<25 groups of wild-type homozygous for CYP2C19 1 of (42.4%), and other allelomorph CYP2C19 * 2 (38.5%), follow (4.3%). Conclusion There was no significant difference in the genotype of CYP2C19*2 between the BMI and *3 in the southeast part of Henan province. Key words: CYP2C19 genotype; Allelomorph; Gene frequency; Nobu Juriko; Slow inactivator

Interethnic variation of CYP2C19 alleles, 'predicted' phenotypes and 'measured' metabolic phenotypes across world populations.

The present study evaluates the worldwide frequency distribution of CYP2C19 alleles and CYP2C19 metabolic phenotypes ('predicted' from genotypes and 'measured' with a probe drug) among healthy volunteers from different ethnic groups and geographic regions, as well as the relationship between the 'predicted' and 'measured' CYP2C19 metabolic phenotypes. A total of 52 181 healthy volunteers were studied within 138 selected original research papers. CYP2C19*17 was 42- and 24-fold more frequent in Mediterranean-South Europeans and Middle Easterns than in East Asians (P<0.001, in both cases). Contrarily, CYP2C19*2 and CYP2C19*3 alleles were more frequent in East Asians (30.26% and 6.89%, respectively), and even a twofold higher frequency of these alleles was found in Native populations from Oceania (61.30% and 14.42%, respectively; P<0.001, in all cases), which may be a consequence of genetic drift process in the Pacific Islands. Regarding CYP2C19 metabolic phenotype, poor metabolizers (PMs) were more frequent among Asians than in Europeans, contrarily to the phenomenon reported for CYP2D6. A correlation has been found between the frequencies of CYP2C19 poor metabolism 'predicted' from CYP2C19 genotypes (gPMs) and the poor metabolic phenotype 'measured' with a probe drug (mPMs) when subjects are either classified by ethnicity (r=0.94, P<0.001) or geographic region (r=0.99, P=0.002). Nevertheless, further research is needed in African and Asian populations, which are under-represented, and additional CYP2C19 variants and the 'measured' phenotype should be studied.

GW26-e2238 The Contribution of Platelet MicroRNA Expression and its Interaction with CYP2C19 Allele Variants to Clopidogrel Antiplatelet Responsiveness in Acute Coronary Syndrome Patients

GW26-e2238 The Contribution of Platelet MicroRNA Expression and its Interaction with CYP2C19 Allele Variants to Clopidogrel Antiplatelet Responsiveness in Acute Coronary Syndrome Patients

Development of a genotyping tool for a functionally relevant CYP2C19 allele (Phe100Asn, Ala103Val and Ile112Leu) in cynomolgus macaques.

In cynomolgus macaques, which are widely used in drug metabolism studies, CYP2C19 (formerly known as CYP2C75) is abundantly expressed in liver, metabolizes human CYP2C substrates and is thus an important drug-metabolizing enzyme. One of the cynomolgus CYP2C19 alleles (p.Phe100Asn, p.Ala103Val and p.Ile112Leu) results in substantially reduced metabolic activity and thus is an important allele in drug metabolism studies. For this allele, a genotyping tool was developed using allele-specific TaqMan probe. Genotyping 40 Cambodian cynomolgus macaques using this tool found 1 homozygote, 17 heterozygotes and 22 wild type animals, and the result was confirmed by direct-sequencing. Interestingly, this allele frequency was similar to that of Chinese cynomolgus macaques. The genotyping tool established is useful for drug metabolism studies using cynomolgus macaques.

Genetic and platelet function testing of antiplatelet therapy for percutaneous coronary intervention: the ARCTIC-GENE study.

The ARCTIC study randomized 2440 patients scheduled for stent implantation to a strategy of platelet function monitoring with drug adjustment in patients who had a poor response to antiplatelet therapy or to a conventional strategy without monitoring and drug adjustment. No significant improvement in clinical outcomes with platelet function monitoring was observed. The purpose of this study is to assess the relationships between CYP2C19 genotypes, clopidogrel pharmacodynamic response, and clinical outcome. In the ARCTIC-GENE study, 1394 patients were genotyped for loss- and gain-of-function CYP2C19 alleles. Randomization of treatment strategy was well balanced. Slow metabolizers identified as carriers of at least one loss-of-function allele CYP2C19*2 (n = 459) were more likely poor responders at randomization (41.6 vs. 31.6%, p = 0.0112) and 14 days later (23.8 vs. 10.4%, p < 0.0001) and more frequently on prasugrel (11.5 vs. 8.1%, p = 0.039) as compared with rapid metabolizers (n = 935). Intensification of antiplatelet treatment did not differ between slow and rapid metabolizers according to the study algorithm based on platelet function only. The primary study outcome defined as the composite of death, myocardial infarction, stent thrombosis, stroke, or urgent revascularization 1 year after stent implantation did not differ between slow and rapid metabolizers (HR 0.988, 95% CI [0.812;1.202], p = 0.90). Likewise, the primary safety outcome did not differ between rapid and slow metabolizer phenotype. The genetic clopidogrel profile was a good marker of platelet function response on clopidogrel but was not related to clinical outcome suggesting that the genetic added little to the pharmacodynamic information used in the study to adjust antiplatelet therapy. ClinicalTrials.gov: NCT00827411.

Cytochrome P450 2C19 polymorphisms and valproic acid-induced weight gain.

Cytochrome P450 (CYP) 2C19 plays a role in the biotransformation of clinically relevant drugs as well as endogenous compounds, including sex hormones, which are known to be modulators of food intake and energy balance in humans. We attempted to investigate the influence of CYP2C19 polymorphisms on valproic acid (VPA)-induced weight gain. This retrospective longitudinal study included 85 VPA-treated and 93 carbamazepine (CBZ)-treated (as a reference) young patients with epilepsy. The body mass index (BMI) gap between the patient's BMI and the cutoff value for being overweight was calculated in each patient during the follow-up period. The longitudinal associations of the CYP2C19 genotype with the BMI gap and risk for becoming overweight during VPA or CBZ therapy were examined retrospectively using the generalized estimating equations approach and the Kaplan-Meier method. During the follow-up period, the values of the BMI gap were significantly greater (P = 0.002 or P = 0.005) and the cumulative incidence of becoming overweight tended to be higher (P = 0.032) in the VPA-treated female patients with one or two loss-of-function CYP2C19 alleles than in the females without the loss-of-function CYP2C19 alleles. No associations were observed among the VPA-treated male patients and CBZ-treated male and female patients (P > 0.05). This is the first report to show a relationship between the CYP2C19 polymorphism and VPA-induced weight gain in female patients with epilepsy. Further investigations are needed to verify these findings.

Allele Frequency Distributions of the Drug Metabolizer Genes &lt;i&gt;CYP2C9*2&lt;/i&gt;, &lt;i&gt;CYP2C9*3&lt;/i&gt;, and &lt;i&gt;CYP2C19*17&lt;/i&gt; in the Buginese Population of Indonesia

The present study is part of the genetic mapping of Indonesia focusing on drug metabolizing enzymes, which started with the Buginese population of Makassar, South Sulawesi. The two CYP450 gene subfamilies, i.e. CYP2C9 and CYP2C19 are of interest as they exhibit wide inter-individual variation in expression, which influence the drug metabolism capacity. The CYP2C9 alleles of interest in this study were CYP2C9*2 and *3, and of CYP2C19 was CYP2C19*17. The study aimed to determine the frequencies of the CYP2C9 genotype, which contains *1, *2 and *3 alleles, and the CYP2C19 genotype, which comprises the *1 and *17 alleles in the Buginese. Ninety six Buginese subjects, comprising 48 males and 48 females were studied. CYP2C9 and CYP2C19 alleles were detected by a PCR-RFLP assay method. Results showed that there was no CYP2C9*2 allele present, while the frequencies of CYP2C9*3 and CYP2C19*17 overall were 1.56 % and 4.68 %, respectively. The frequency of the CYP2C9*3 allele in females was 2.08%, and not statistically different from that in males (1.05%). The frequency of the CYP2C19*17 allele in females (8.33%), was significantly different (P<0.05) from that in males (1.05%). No subject carried the CYP2C9*2/*2, CYP2C9*3/*3, CYP2C19*17/*17, or CYP2C9*3/CYP2C19*17 genotype. The study is the first to describe the drug metabolizing enzyme polymorphisms, CYP2C9 and CYP2C19, in the Indonesian Buginese population.

Phenoconversion of CYP2C9 in epilepsy limits the predictive value of CYP2C9 genotype in optimizing valproate therapy.

Since prominent role in valproate metabolism is assigned to CYP2C9 in pediatric patients, the association between children's CYP2C9-status and serum valproate concentrations or dose-requirements was evaluated. The contribution of CYP2C9 genotype and CYP2C9 expression in children (n = 50, Caucasian) with epilepsy to valproate pharmacokinetics was analyzed. Valproate concentrations were significantly lower in normal expressers with CYP2C9*1/*1 than in low expressers or in patients carrying polymorphic CYP2C9 alleles. Consistently, the dose-requirement was substantially higher in normal expressers carrying CYP2C9*1/*1 (33.3 mg/kg vs 13.8-17.8 mg/kg, p < 0.0001). Low CYP2C9 expression significantly increased the ratio of poor metabolizers predictable from CYP2C9 genotype (by 46%). Due to the substantial downregulation of CYP2C9 expression in epilepsy, inferring patients' valproate metabolizing phenotype merely from CYP2C9 genotype results in false prediction.

The impact of genetic polymorphisms of drug metabolizing enzymes on the pharmacodynamics of clopidogrel under steady state conditions

Clopidogrel is an antiplatelet drug that requires biotransformation steps to its active metabolite via cytochromes P450 (CYP), particularly CYP2C19 and CYP3A5 as well as paraoxonase-1 (PON1). The impact of CYP3A5 and PON1 genetic polymorphisms on the response of this drug is unclear. This study aimed to elucidate the degree of genetic polymorphisms of key drug metabolizing enzymes on the antiplatelet effect of clopidogrel. Thirty-five healthy subjects were treated with 75 mg/day clopidogrel for 7 days and serial blood samples were collected for measurement of antiplatelet effect using whole blood impedance aggregometry and VerifyNow® P2Y12 methods. The areas under the antiplatelet effect–time curves, maximal and minimal antiplatelet effects of clopidogrel obtained from both methods were significantly different among subjects with different CYP2C19 genotypes. In contrast, these pharmacodymamic parameters measured by both methods of subjects with different PON1 or CYP3A5 genotypes were not significantly different. Among the heterozygous CYP2C19*2 subjects, all pharmacodynamic parameters measured by whole blood impedance aggregometry were significantly different between subjects with different CYP3A5*3 genotypes. Our data suggests that CYP2C19 genetic polymorphism play a major role in the clopidogrel response, however, the impact of CYP3A5 genetic polymorphism, may be pronounced in the subjects who carried the loss-functional allele of CYP2C19.

HM4 - How Much Evidence Do We Need Before Implementing Pharmacogenomic Testing In The Clinic?

Consensus on the evidence required to recommend clinical pharmacogenomic testing is unclear. A formal assessment of pharmacogenomic evidence levels in relation to other clinical interventions, such as avoiding drug-drug interactions (DDI), may be helpful for policymakers. The objective of this study was to quantitatively compare the evidence levels of two contested drug-attenuating interactions with clopidogrel antiplatelet therapy, and assess the value of obtaining additional evidence to inform clinical practice guidelines. We developed analogous value of information (VOI) decision models for: (1) avoidance of proton pump inhibitors (PPIs) in clopidogrel patients, and (2) pharmacogenomic-guided antiplatelet selection, both versus no intervention. Interaction-specific parameters and model structures were the only dissimilarities. We calculated the expected value of obtaining perfect information (EVPI) per patient, and the expected population value of obtaining additional information through future studies (EVSI). Current evidence for interaction-1 was slightly less uncertain (a 20% probability of making a non-optimal recommendation) than for interaction-2 (23%). The relative risk for cardiovascular death (conferred by concomitant PPI use in interaction-1, and reduced-function CYP2C19 alleles in interaction-2) was the greatest source of uncertainty in both models. The expected value of perfect information for interaction-1 was $139 per patient, compared to $242 per patient for interaction-2. In simulated 10,000-patient clinical trials, the expected population value of future research for interaction-1 was $2 million, versus $110 million for interaction-2. The evidence levels for clopidogrel DDI and pharmacogenomic effects appear to be fairly similar. However, the value of conducting future research on clopidogrel pharmacogenomics is higher because of greater uncertainty about the impact of pharmacogenomic testing on cardiovascular mortality. Our findings imply that evidence-based clinical guidelines for DDI and pharmacogenomic effects should be generally similar with regard to direction and strength of recommendation. This contrasts to some degree with current guidelines and drug labeling.

Effect of CYP2C9 Genetic Polymorphism in a Chinese Population on the Metabolism of Mestranol in vitro

Background: Mestranol is a widely used estrogen, which is converted into its active metabolite ethinyl estradiol by cytochrome P450 (CYP) 2C9. To comprehensively examine the enzymatic activity of reported CYP2C9 variants in Chinese individuals in response to mestranol, wild-type CYP2C9*1 and 35 allelic variants were highly expressed in Sf21 insect cell microsomes and used for the detection of their enzymatic values in vitro. These results showed that the majority of tested variants exhibited decreased clearance values compared to wild type, except for CYP2C9*40 and *36. Method: Insect microsomes expressing the 36 CYP2C9 variants were incubated with 0.25-8 μmol/l mestranol for 30 min at 37°C. Then, the production of the metabolite of mestranol, ethinyl estradiol, was analyzed using high-performance liquid chromatography. Results: Most CYP-catalyzed reactions were sufficiently described by classical Michaelis-Menten kinetic parameters (e.g., K_m and V_max), while 9 variants exhibited atypical or non-Michaelis-Menten kinetic values, which were largely due to the self-inhibitory effect in response to mestranol. Conclusion: This is the first report of these rare alleles for mestranol metabolism, which provides fundamental data for further clinical studies on CYP2C9 alleles for mestranol metabolism.

In vitro assessment of 39 CYP2C9 variants found in the Chinese population on the metabolism of the model substrate fluoxetine and a summary of their effects on other substrates.

Cytochrome P450 2C9 (CYP2C9) is a polymorphic enzyme that is responsible for clearing approximately 15% of clinically important drugs. The objective of this study was to assess the catalytic characteristics of 39 CYP2C9 isoforms found in the Chinese population and their effects on the metabolism of the model substrate fluoxetine invitro. Baculovirus-mediated expressing system was used to highly express wild-type and the 38 CYP2C9 allelic variants in insect cell microsomes. Then, the enzymatic characteristics of each variant were evaluated using fluoxetine as the substrate. Reactions were performed at 37°C with the insect microsomes and 10-200μm fluoxetine for 60min. After termination, the products were precipitated and used for signal collection by UPLC-MS/MS. Of the 39 tested CYP2C9 isoforms, only four variants (CYP2C9*3, CYP2C9*27, CYP2C9*34 and CYP2C9*37) exhibited similar relative clearance values to that of the wild-type CYP2C9*1. Moreover, five variants (CYP2C9*14, CYP2C9*36, CYP2C9*45, CYP2C9*48 and CYP2C9*55) showed a higher intrinsic clearance value than the wild-type protein, whereas the remaining 29 CYP2C9 isoforms exhibited significantly decreased clearance values (from 6·23% to 87·74%) compared to CYP2C9*1. In addition, 28 CYP2C9 isoforms including CYP2C9*3 exhibited a trend towards substrate inhibition for fluoxetine. This study provides the most comprehensive data on the enzymatic activities associated with all reported CYP2C9 variants in the Chinese population with regard to the widely used antidepressant drug, fluoxetine. Our data indicate that more attention should be paid to subjects carrying the corresponding infrequent CYP2C9 alleles when administering fluoxetine in the clinic.

CYP2C19 polymorphism and clinical outcomes among patients of different races treated with clopidogrel: A systematic review and meta-analysis

Several studies have investigated the association between CYP2C19 polymorphism and clinical outcomes of patients treated with clopidogrel, but few have noticed the difference in association between Westerners and Asians. We searched MEDLINE, EMBASE and Cochrane Library database and conducted a systematic review and meta-analysis. Thirty-six studies involving 44 655 patients with coronary artery disease (CAD) treated with clopidogrel were included, of which more than 68% had undergone percutaneous coronary intervention (PCI). The primary outcome of our interest was the recurrence of major adverse cardiovascular events (MACE) in those CAD patients. Firstly, we found that the distribution of reduced-function CYP2C19 allele varied between Westerners and Asians. Among Asians, 1 and 2 reduced-function CYP2C19 mutant allele carriers accounted for 42.5% and 10%, respectively. While among Westerners, 1 and 2 reduced-function CYP2C19 mutant allele carriers accounted for 25.5% and 2.4%, respectively. Secondly, the impact of CYP2C19 polymorphism on clinical outcomes of patients treated with clopidogrel varied with races. Among Asians, only 2 reduced-function CYP2C19 mutant allele carriers had the reduced effect of clopidogrel. And the reduced effect was significant only after the 30th day of treatment. While among Westerners, both 1 and 2 reduced-function CYP2C19 allele carriers had the reduced effect, and it mainly occurred within the first 30 days. Thirdly, the safety of clopidogrel was almost the same among races. Reduced-function allele non-carriers had higher risk for total bleeding but did not have higher risk for major bleeding. It is suggested that CYP2C19 polymorphism affects the efficacy of clopidogrel differently among Westerners and Asians.

(258) CYP2C8 and CYP2C9 metabolic profiles and frequency of emergency department visits for sickle cell disease pain management

The CYP2C8 and CYP2C9 variant alleles play a significant role in NSAIDs analgesic effect and toxicity. NSAIDs are used to treat vasoocclusive pain at the prodromal stage in sickle cell disease (SCD) patients. We describe CYP2C8 and CYP2C9 genotypes and phenotypes and frequency of emergency department (ED) visits in an African American SCD patient cohort. DNA from 165 unrelated SCD patients (82 males/83 females, aged from 16 to 61 years) was genotyped for seven CYP2C8 (*1, *2, *3, *4, *5, *7 & *8) alleles and 15 CYP2C9 alleles (*1, *2,*3, *4, *5, *6, *8, *9, *10, *11, *12, *13, *15, *25 & *27) using the iPLEX® ADME PGx multiplexed panel.

CYP2C9 genotype vs. metabolic phenotype for individual drug dosing--a correlation analysis using flurbiprofen as probe drug.

Currently, genotyping of patients for polymorphic enzymes responsible for metabolic elimination is considered a possibility to adjust drug dose levels. For a patient to profit from this procedure, the interindividual differences in drug metabolism within one genotype should be smaller than those between different genotypes. We studied a large cohort of healthy young adults (283 subjects), correlating their CYP2C9 genotype to a simple phenotyping metric, using flurbiprofen as probe drug. Genotyping was conducted for CYP2C9*1, *2, *3. The urinary metabolic ratio MR (concentration of CYP2C9-dependent metabolite divided by concentration of flurbiprofen) determined two hours after flurbiprofen (8.75 mg) administration served as phenotyping metric. Linear statistical models correlating genotype and phenotype provided highly significant allele-specific MR estimates of 0.596 for the wild type allele CYP2C9*1, 0.405 for CYP2C9*2 (68 % of wild type), and 0.113 for CYP2C9*3 (19 % of wild type). If these estimates were used for flurbiprofen dose adjustment, taking 100 % for genotype *1/*1, an average reduction to 84 %, 60 %, 68 %, 43 %, and 19 % would result for genotype *1/*2, *1/*3, *2/*2, *2/*3, and *3/*3, respectively. Due to the large individual variation within genotypes with coefficients of variation ≥ 20 % and supposing the normal distribution, one in three individuals would be out of the average optimum dose by more than 20 %, one in 20 would be 40 % off. Whether this problem also applies to other CYPs and other drugs has to be investigated case by case. Our data for the given example, however, puts the benefit of individual drug dosing to question, if it is exclusively based on genotype.

Genetic variability of CYP2C19 in a Mexican population: contribution to the knowledge of the inheritance pattern of CYP2C19*17 to develop the ultrarapid metabolizer phenotype.

CYP2C19 is a polymorphic enzyme that metabolizes a wide variety of therapeutic drugs that has been associated with altered enzymatic activity and adverse drug reactions. Differences in allele frequencies of the CYP2C19 gene have been detected in populations worldwide. Thus, we analysed the alleles CYP2C19*2, CYP2C19*3, CYP2C19*4 and CYP2C19*5 related to the poor metabolizer (PM) phenotype in a Mexican population sample (n = 238), as well as CYP2C19*17, unique allele related to ultrarapid metabolizer phenotype (UMs). Genotypes were determined using SNaPshot and TaqManqPCR assays. In addition to the wild-type CYP2C19*1 allele (77.1%), we only found CYP2C19*17 (14.3%) and CYP2C19*2 (8.6%). Comparison with previous population reports demonstrated that these two SNPs are homogeneously distributed in Latin America (P > 0.05). Based on comparison with a previous pharmacokinetic study that determined the frequency of CYP2C19 phenotypes in the same population (western Mexican), we obtained the following findings: (i) based on the difference between the frequency of genotypes CYP2C19*2/*2 (presumably PM) versus the observed prevalence of PM phenotypes (0.4 versus 6.3%; Χ(2) = 9.58, P = 0.00196), we inferred the plausible presence of novel CYP2C19 alleles related to the PM phenotype; (ii) the prevalence of UMs was in disagreement with the dominant inheritance pattern suggested for CYP2C19*17 (23.1 versus 4%; P < 0.00001); (iii) the apparent recessive inheritance pattern of CYP2C19*17, based on the agreement between homozygous CYP2C19*17/*17 (presumably UMs) and the observed prevalence of UMs (2.1 versus 4%; (Χ(2) = 1.048; P = 0.306).

Preemptive Genotyping of CYP2C8 and CYP2C9 Allelic Variants Involved in NSAIDs Metabolism for Sickle Cell Disease Pain Management.

Interindividual variability in analgesic effects of nonsteroidal anti-inflammatory drugs prescribed for sickle cell disease (SCD) pain is attributed to polymorphisms in the CYP2C8 and CYP2C9 enzymes. We described CYP2C8 and CYP2C9 genotype/phenotype profiles and frequency of emergency department (ED) visits for pain management in an African American SCD patient cohort. DNA from 165 unrelated patients was genotyped for seven CYP2C8 and 15 CYP2C9 alleles using the iPLEX ADME PGx multiplexed panel. CYP2C8*1 (0.806),*2 (0.164), *3 (0.018), and *4 (0.012) alleles were identified. Genotype frequencies were distributed as homozygous wild type (66.7%), heterozygous (27.8%), and homozygous variant/compound heterozygous (5.4%), respectively. CYP2C9*1 (0.824), *2 (0.027), *3 (0.012), *5 (0.009), *6 (0.009), *8 (0.042), *9 (0.061), and *11(0.015) were observed with extensive (68.5%), intermediate (18.1%) and poor predicted metabolizers (0.6%), respectively. Fifty-two and 55 subjects, respectively had at least one variant CYP2C8 or CYP2C9 allele. Although the distribution of the CYP2C9 (p = 0.0515) phenotypes was marginally significantly in high and low ED users; some CYP2C8 and CYP2C9 allelic combinations observed in 15.2% (25) of the cohort are associated with higher risks for analgesic failure. CYP2C8 and CYP2C9 preemptive genotyping could potentially enable clinicians to identify patients with impaired metabolic phenotypes.

Poor warfarin dose prediction with pharmacogenetic algorithms that exclude genotypes important for African Americans.

Recent clinical trial data cast doubt on the utility of genotype-guided warfarin dosing, specifically showing worse dosing with a pharmacogenetic versus clinical dosing algorithm in African Americans. However, many genotypes important in African Americans were not accounted for. We aimed to determine whether omission of the CYP2C9*5, CYP2C9*6, CYP2C9*8, CYP2C9*11 alleles and rs12777823 G > A genotype affects performance of dosing algorithms in African Americans. In a cohort of 274 warfarin-treated African Americans, we examined the association between the CYP2C9*5, CYP2C9*6, CYP2C9*8, CYP2C9*11 alleles and rs12777823 G > A genotype and warfarin dose prediction error with pharmacogenetic algorithms used in clinical trials. The http://www.warfarindosing.org algorithm overestimated doses by a median (interquartile range) of 1.2 (0.02-2.6) mg/day in rs12777823 heterozygotes (P<0.001 for predicted vs. observed dose), 2.0 (0.6-2.8) mg/day in rs12777823 variant homozygotes (P = 0.004), and 2.2 (0.5-2.9) mg/day in carriers of a CYP2C9 variant (P < 0.001). The International Warfarin Pharmacogenetics Consortium (IWPC) algorithm underdosed warfarin by 0.8 (-2.3 to 0.4) mg/day for patients with the rs12777823 GG genotype (P < 0.001) and overdosed warfarin by 0.7 (-0.4 to 1.9) mg/day in carriers of a variant CYP2C9 allele (P = 0.04). Modifying the http://www.warfarindosing.org algorithm to adjust for variants important in African Americans led to better dose prediction than either the original http://www.warfarindosing.org (P < 0.01) or IWPC (P < 0.01) algorithm. These data suggest that, when providing genotype-guided warfarin dosing, failure to account for variants important in African Americans leads to significant dosing error in this population.

Optimal cutoff value of P2Y12 reaction units to prevent major adverse cardiovascular events in the acute periprocedural period: Post-hoc analysis of the randomized PRASFIT-ACS study

BackgroundFew studies have examined the effects of on-treatment platelet reactivity on the risk of major adverse cardiovascular events (MACE). We aimed to determine the optimal cutoff value of P2Y12 reaction units (PRUs) to prevent MACE occurring within 3days after percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS). MethodsWe performed post-hoc analyses of 1363 patients enrolled in PRASFIT-ACS, which compared the effects of a prasugrel regimen adjusted for Japanese patients (loading dose/maintenance dose: 20mg/3.75mg) with those of clopidogrel (300mg/75mg) on MACE and bleeding events for 24–48weeks after PCI in ACS patients. PRU was serially measured using the VerifyNow® P2Y12 assay and we assessed the relationship between PRU and MACE. ResultsReceiver operating characteristic curve analysis showed that PRU ≤262 at 5–12h after ADP receptor antagonist loading was the optimal cutoff value for preventing MACE at up to 3days after PCI. The incidences of MACE were 5.2% and 10.8% in patients with PRU ≤262 or >262, respectively (odds ratio 0.50, 95% confidence interval 0.25–0.99, p<0.01). Significantly more prasugrel-treated patients had lower on-treatment platelet reactivity (defined as PRU ≤262) compared with clopidogrel-treated patients (79.9% vs. 30.4%, p<0.0001). Similar differences were observed between the prasugrel and clopidogrel groups for patients with normal or reduced-function CYP2C19 alleles. ConclusionsThe optimal PRU cutoff value for preventing MACE was 262 in Japanese ACS patients. Prasugrel rapidly reduced PRU with a large proportion of patients having low on-treatment platelet reactivity.