The relationship between genetic polymorphism of CYP2C19 and the efficacy of Helicobacter pylori eradication therapy in children / 中华儿科杂志

Objective: To investigate the relationship between genetic polymorphisms of cytochrome P450 2C19 (CYP2C19) and the efficacy of Helicobacter pylori (Hp) eradication therapy in children. Methods: The retrospective cohort study was conducted on 125 children with gastroscopy and positive rapid urease test (RUT) from September 2016 to December 2018 who presented to the Children's Hospital of Zhejiang University School of Medicine due to gastrointestinal symptoms including nausea, vomiting, abdominal pain, bloating, acid reflux, heartburn, chest pain, vomiting blood and melena. Hp culture and drug susceptibility test were carried out with gastric antrum mucosa before treatment. All the patients completed 2 weeks of standardized Hp eradication therapy and had 13C urea breath test 1 month after that, which was used to evaluate the curative effect. The DNA of gastric mucosa after RUT was analyzed and CYP2C19 gene polymorphism was detected. Children were grouped according to metabolic type. Combined with the results of Hp culture and drug susceptibility, the relationship between CYP2C19 gene polymorphism and the efficacy of Hp eradicative treatment was analyzed in children. Chi square test was used for row and column variables, and Fisher exact test was used for comparison between groups. Results: One hundred and twenty five children were enrolled in the study, of whom 76 were males and 49 females. The genetic polymorphism of CYP2C19 in these children found poor metabolizer (PM) of 30.4% (38/125), intermediate metabolizer (IM) of 20.8% (26/125), normal metabolizer (NM) of 47.2% (59/125), rapid metabolizer (RM) of 1.6% (2/125), and ultrarapid metabolizer (UM) of 0. There were statistically significant in positive rate of Hp culture among these groups (χ2=124.00, P<0.001). In addition, the successful rates of Hp eradication in PM, IM, NM and RM genotypes were 84.2% (32/38), 53.8% (14/26), 67.8% (40/59), and 0, respectively, with significant differences (χ2=11.35, P=0.010); those in IM genotype was significantly lower than that in PM genotype (P=0.011). With the same standard triple Hp eradicative regimen, the successful rate of Hp eradication for IM type was 8/19, which was lower than that of PM (80.0%, 24/30) and NM type (77.3%, 34/44) (P=0.007 and 0.007, respectively). There was a significant difference in the efficacy of Hp eradication treatment among different genotypes (χ2=9.72, P=0.008). According to the clarithromycin susceptibility result, the successful rate of Hp eradication treatment for IM genotype was 4/15 in the sensitive group and 4/4 in the drug-resistant group (χ2=6.97, P=0.018). Conclusions: The genetic polymorphism of CYP2C19 in children is closely related to the efficacy of Hp eradication treatment. PM has a higher successful rate of eradication treatment than the other genotypes.

Analysis of the association of CYP450 gene polymorphisms with ischemic stroke / 中华医学遗传学杂志

OBJECTIVE@#To assess the association of cytochrome P450 (CYP450) gene polymorphisms with the occurrence of ischemic stroke (IS).@*METHODS@#From January 2020 to August 2022, 390 IS patients treated at the Zhengzhou Seventh People's Hospital were enrolled as the study group, and 410 healthy individuals undergoing physical examination during the same period were enrolled as the control group. Clinical data of all subjects were collected, which included age, sex, body mass index (BMI), smoking history and results of laboratory tests. Chi-square test and independent sample t test were used for comparing the clinical data. Multivariate logistic regression analysis was used to analyze the non-hereditary independent risk factors for IS. Fasting blood samples of the subjects were collected, and the genotypes of rs4244285, rs4986893, rs12248560 of the CYP2C19 gene and rs776746 of the CYP3A5 gene were determined by Sanger sequencing. The frequency of each genotype was calculated by using SNPStats online software. The association between the genotype and IS under the dominant, recessive and additive models was analyzed.@*RESULTS@#The levels of total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL-C), apolipoprotein B (Apo-B) and homocysteine (Hcy) of the case group were significantly higher than those of the control group, whilst the levels of high density lipoprotein (HDL-C) and Apo-A1 (APO-A1) were significantly lower (P < 0.05). Multivariate Logistic regression analysis showed that TC (95%CI = 1.13-1.92, P = 0.02), LD-C (95%CI = 1.03-2.25, P = 0.03), Apo-A1 (95%CI = 1.05-2.08, P = 0.04), Apo-B (95%CI = 1.7-4.22, P < 0.01) and Hcy (95%CI = 1.12-1.83, P = 0.04) were non-genetic independent risk factors for the occurrence of IS. Analysis of the association between the genetic polymorphisms and the risk of IS showed that the AA genotype at rs4244285 of the CYP2C19 gene, the AG genotype and A allele at rs4986893 of the CYP2C19 gene, and the GG genotype and G allele at rs776746 of the CYP3A5 gene were significantly associated with IS. Under the recessive/additive model, dominant model and dominant/additive model, polymorphisms of the rs4244285, rs4986893 and rs776746 loci were also significantly associated with the IS.@*CONCLUSION@#TC, LDL-C, Apo-A1, Apo-B and Hcy can all affect the occurrence of IS, and CYP2C19 and CYP3A5 gene polymorphisms are closely associated with the IS. Above finding has confirmed that the CYP450 gene polymorphisms can increase the risk of IS, which may provide a reference for the clinical diagnosis.

Association of SCN2A, ABCB1 and CYP2C19*3 with genetic susceptibility to major depressive disorder / 中华预防医学杂志

Objective: Due to genetic factors might increase the risk of depression, this study investigated the genetic risk factors of depression in Chinese Han population by analyzing the association between 13 candidate genes and depression. Methods: 439 depression patients and 464 healthy controls were included in this case-control study. Case group consisted of 158 males and 281 females, aged (29.84±14.91) years old, who were hospitalized in three departments of the affiliated Brain Hospital of Guangzhou Medical University including Affective Disorders Department, Adult Psychiatry Department and Geriatrics Department, from February 2020 to September 2021. The control group consisted of 196 males and 268 females, aged (30.65±12.63) years old. 20 loci of 13 candidate genes in all subjects were detected by MALDI-TOF mass spectrometry. Age difference was compared using the student's t-test, the distributions of gender and genotype were analyzed with Pearson's Chi-square test. The analyses of Hardy-Weinberg equilibrium, allele frequency and the genetic association of depression were conducted using the corresponding programs in PLINK software. Results: PLINK analysis showed that SCN2A rs17183814, ABCB1 rs1045642, CYP2C19*3 rs4986893 and NAT2*5A rs1799929 were associated with depression before Bonferroni correction (χ2=10.340, P=0.001; χ2=11.010, P=0.001; χ2=9.781, P=0.002; χ2=4.481, P=0.034). The frequencies of minor alleles of above loci in the control group were 12.07%, 43.64%, 2.59% and 3.88%, respectively. The frequencies of minor alleles of loci mentioned above in the case group were 17.43%, 35.99%, 5.47% and 6.04%, respectively. OR values were 1.538, 0.726, 2.178 and 1.592, respectively. After 1 000 000 permutation tests using Max(T) permutation procedure, the four loci were still statistically significant, the empirical P-value were 0.002, 0.001, 0.003 and 0.042, respectively. However, only three loci including SCN2A rs17183814, ABCB1 rs1045642 and CYP2C19 rs4986893 had statistical significance after Bonferroni correction, the adjusted P-value were 0.026, 0.018 and 0.035, respectively. Conclusion: SCN2A rs17183814, ABCB1 rs1045642 and CYP2C19*3 rs4986893 were associated with depression's susceptibility in Chinese Han population. The A allele of SCN2A rs17183814 and CYP2C19*3 rs4986893 were risk factors for depression, while the T allele of ABCB1 rs1045642 was a protective factor for depression.

Antiplatelet and myocardial protective effect of Shexiang Tongxin Dropping Pill in patients undergoing percutaneous coronary intervention: A randomized controlled trial / 中西医结合学报

BACKGROUND@#High on-clopidogrel platelet reactivity could be partially explained by loss-of-function alleles of CYP2C19, the enzyme that converts clopidogrel into its active form. Shexiang Tongxin Dropping Pill (STDP) is a traditional Chinese medicine to treat angina pectoris. STDP has been shown to improve blood flow in patients with slow coronary flow and attenuate atherosclerosis in apolipoprotein E-deficient mice. However, whether STDP can affect platelet function remains unknown.@*OBJECTIVE@#The purpose of this study is to examine the potential effects of STDP on platelet function in patients undergoing percutaneous coronary intervention (PCI) for unstable angina. The interaction between the effects of STDP with polymorphisms of CYP2C19 was also investigated.@*DESIGN, PARTICIPANTS AND INTERVENTION@#This was a single-center, randomized controlled trial in patients undergoing elective PCI for unstable angina. Eligible subjects were randomized to receive STDP (210 mg per day) plus dual antiplatelet therapy (DAPT) with clopidogrel and aspirin or DAPT alone.@*MAIN OUTCOME MEASURES@#The primary outcome was platelet function, reflected by adenosine diphosphate (ADP)-induced platelet aggregation and platelet microparticles (PMPs). The secondary outcomes were major adverse cardiovascular events (MACEs) including recurrent ischemia or myocardial infarction, repeat PCI and cardiac death; blood biomarkers for myocardial injury including creatine kinase-MB isoenzyme (CK-MB) and high-sensitive troponin I (hsTnI); and biomarkers for inflammation including intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1) and galectin-3.@*RESULTS@#A total of 118 subjects (mean age: [66.8 ± 8.9] years; male: 59.8%) were included into analysis: 58 in the control group and 60 in the STDP group. CYP2C19 genotype distribution was comparable between the 2 groups. In comparison to the control group, the STDP group had significantly lower CK-MB (P < 0.05) but similar hsTnI (P > 0.05) at 24 h after PCI, lower ICAM-1, VCAM-1, MCP-1 and galectin-3 at 3 months (all P < 0.05) but not at 7 days after PCI (P > 0.05). At 3 months, the STDP group had lower PMP number ([42.9 ± 37.3] vs. [67.8 ± 53.1] counts/μL in the control group, P = 0.05). Subgroup analysis showed that STDP increased percentage inhibition of ADP-induced platelet aggregation only in slow metabolizers (66.0% ± 20.8% in STDP group vs. 36.0% ± 28.1% in the control group, P < 0.05), but not in intermediate or fast metabolizers. The rate of MACEs during the 3-month follow-up did not differ between the two groups.@*CONCLUSION@#STDP produced antiplatelet, anti-inflammatory and cardioprotective effects. Subgroup analysis indicated that STDP inhibited residual platelet reactivity in slow metabolizers only.@*TRIAL REGISTRATION@#This study was registered on www.chictr.org.cn: ChiCTR-IPR-16009785.

Association of CYP2C19 and CYP3A5 gene polymorphisms with myocardial infarction / 中华医学遗传学杂志

OBJECTIVE@#To assess the association of CYP2C19 and CYP3A5 gene polymorphisms with the risk of myocardial infarction.@*METHODS@#Five hundred patients with myocardial infarction and 500 healthy controls were randomly selected. Fluorescent PCR and Sanger sequencing were used to detect the CYP2C19 and CYP3A5 gene polymorphisms. Logistic regression was used to analyze the correlation between the polymorphisms and myocardial infarction. Quanto software was used to evaluate the statistical power.@*RESULTS@#The two groups had significant difference in the frequency of AG, GG genotypes and A allele of the CYP2C19 gene rs4986893 locus and the AA, AG, GG genotypes and G allele of the CYP3A5 gene rs776746 locus ( P<0.05), but not in the frequency of genotypes and alleles of CYP2C19 gene rs4244285 and rs12248560 loci, and the AA genotype of the rs4986893 locus. After correction for age, gender, and body mass index, Logistic regression indicated that the AG genotype and A allele of the CYP2C19 gene rs4986893 locus, and the GG genotype and G allele of CYP3A5 gene rs776746 locus are associated with susceptibility of myocardial infarction, while rs4986893 GG genotype and AA and AG genotypes of rs776746 may confer a protective effect. Based on the sample size and allele frequency, analysis with Quanto software suggested that the result of this study has a statistical power of 99%.@*CONCLUSION@#CYP2C19 and CYP3A5 gene polymorphisms may increase the risk for myocardial infarction.

Effects of clopidogrel resistence and CYP2C19 genotype on the clinical prognosis of patients with acute coronary syndrome undergoing percutaneous coronary intervention / 中华心血管病杂志

Objective: To investigate the effects of clopidogrel resistence and CYP2C19 genotype on the clinical prognosis of acute coronary syndrome(ACS) patients undergoing percutaneous coronary intervention(PCI). Methods: This study was a retrospective cohort study. ACS patients who underwent PCI in Beijing Anzhen Hospital from October 2015 to January 2017 were recruited. The inhibition rate of adenosine diphosphate(ADP) was monitored by thromboelastography. All of these patients were divided into clopidogrel resistance and non-resistance group according to the monitoring results. CYP2C19 genotype was detected by TaqMan probe-based real-time quantitative PCR. Patients were divided into slow, medium and fast metabolic group, according to the CYP2C19 genotype. After 12 months of follow-up, the end points included all-cause death, cardiac death, angina, myocardial infarction, stent thrombosis, ischemic stroke and hemorrhage were collected. Combined thrombotic events were defined as a composite of angina, myocardial infarction, stent thrombosis and ischemic stroke. The differences of the incidence of clinical events between groups were compared. Cox regression was used to analyze the effects of clopidogrel resistance and CYP2C19 genotype on the combined thrombotic events, cardiac death and hemorrhage. Results: A total of 1 696 patients were included, and the age was (59.4±9.6) years, with 1 280(75.5%) males. There were 471 cases(27.8%) in clopidogrel resistance group, and 1 225 cases(72.2%) in clopidogrel non-resistance group. There were 218 patients(12.9%) were in slow metabolic group, 668(39.4%) in medium metabolic group, and 810 (47.8%) in fast metabolic group. The median follow-up time was 13.3 months, and 131 cases were lost to follow-up, with a loss follow-up rate of 7.7%. Compared with the clopidogrel non-resistance group, the clopidogrel resistance group had a higher incidence of myocardial infarction(7.6%(36/471) vs. 5.1%(62/1 225), P=0.041), a lower incidence of hemorrhage (13.2%(62/471) vs. 17.9%(219/1 225), P=0.020) and minor hemorrhage(11.5%(54/471) vs. 15.8% (194/1 225), P=0.022). There were no statistically significant difference in all-cause death, cardiac death, angina, stent thrombosis, ischemic stroke and severe bleeding between clopidogrel resistance and non-resistance group(all P>0.05). There was no statistically significant difference in the incidence of endpoint events among different CYP2C19 genotypes (all P>0.05). Cox regression analysis showed that clopidogrel resistance was an independent factor of combined thrombotic events (OR=2.334, 95%CI 1.215-4.443, P=0.016) and bleeding events (OR=0.481, 95%CI 0.174-0.901, P=0.023). While CYP2C19 genotype was not independent factor for combined thrombotic events, cardiac death and hemorrhage (all P>0.05). Conclusion: For ACS patients after PCI, clopidogrel resistance can increase the risk of combined thrombotic events, but also reduce the risk of bleeding; while CYP2C19 genotype is not an independent factor for clinical prognosis.

Association of CYP2C19*2 polymorphism with clopidogrel resistance among patients with high cardiovascular risk in Northeastern Mexico / Asociación del polimorfismo CYP2C19*2 con resistencia a clopidogrel en pacientes con alto riesgo cardiovascular en el noreste de México

abstract Objective: Oral antiplatelet drugs are a key to modern pharmacotherapy in cardiovascular atherothrombotic diseases. Clopidogrel (CLO) constitutes the main preventive treatment of atherothrombosis. However, a considerable inter-individual variation in CLO response has been documented, resulting in suboptimal therapy and an increased risk of recurrent adverse effects in some patients. The enzyme CYP2C19 has been reported to be the CYP isoform that activates CLO to its active metabolite. Several single nucleotide polymorphisms in the CYP2C19 gene have been identified as strong predictors of CLO-impaired pharmacological response. At least 16 variants have been associated with changes in CYP2C19 activity. Materials and Methods: The following research was composed of a total of 102 subjects with high cardiovascular risk in the northeast of Mexico, with a maintenance dose of 75 mg of CLO per day. The platelet reactivity was measured with VerifyNow P2Y12 assay, while the presence of CYP2C19*2 was identified by real-time polymerase chain reaction. Results: Patients were categorized by CYP2C19 metabolizer status based on *2 genotypes using the common consensus star allele nomenclature as normal metabolizer (G/G), intermediate metabolizer (G/A), and poor metabolizer (A/A), respectively. The phenotype frequency for CYP2C19*2 was 74.5% (G/G), 21.6% (G/A), and 3.9% (A/A). The subjects with the A allele presented ≥235 P2Y12 reaction unit levels, classifying them how poor metabolizer. The prevalence of reduced CLO effectiveness was associated with the presence of CYP2C19*2 polymorphism among Mexican patients. Conclusion: The presence of the CYP2C19*2 allele is related to resistance to the antiplatelet effect of CLO (p = 0.003).

Resumen Objetivo: Los antiplaquetarios orales son clave en la farmacoterapia moderna de las enfermedades aterotrombóticas cardiovasculares. Clopidogrel (CLO) constituye el principal tratamiento preventivo de aterotrombosis (AT). Sin embargo, se ha documentado una considerable variación interindividual en la respuesta a CLO, lo que da como resultado una terapia subóptima y mayor riesgo de efectos adversos en algunos pacientes. La enzima CYP2C19 es la isoforma CYP que activa CLO a su metabolito activo. Se han identificado varios polimorfismos de un solo nucleótido en el gen CYP2C19 como fuertes predictores de respuesta farmacológica alterada a CLO. Al menos 16 variantes se han asociado con cambios en la actividad de CYP2C19. Método: Se reclutaron un total de 102 sujetos con alto riesgo cardiovascular del noreste de México, con dosis de mantenimiento de 75 mg de CLO/día. La reactividad plaquetaria se midió con el ensayo Verify Now P2Y12, la presencia de CYP2C19*2 se identificó mediante polymerase chain reaction en tiempo real. Resultado: Los pacientes fueron clasificados por el estado metabolizador CYP2C19*2 utilizando nomenclatura consenso, como metabolizador normal (G/G), metabolizador intermedio (G/A) y metabolizador pobre (A/A), respectivamente. La frecuencia del fenotipo para CYP2C19*2 fue 74.5% (G/G), 21.6% (G/A) y 3.9% (A/A). Los sujetos con alelo A presentaron ≥235 niveles P2Y12 reaction unit, clasificándolos como metabolizadores deficientes. La prevalencia de eficacia reducida a CLO se asoció con la presencia del polimorfismo CYP2C19*2 en pacientes mexicanos. Conclusiones: La presencia del alelo CYP2C19*2 se relaciona con resistencia al efecto antiagregante plaquetario del CLO (p = 0.003).

Decreased platelet responsiveness to clopidogrel correlates with CYP2C19 and PON1 polymorphisms in atherosclerotic patients

Clopidogrel and aspirin are the most commonly used medications worldwide for dual antiplatelet therapy after percutaneous coronary intervention. However, clopidogrel hyporesponsiveness related to gene polymorphisms is a concern. Populations with higher degrees of genetic admixture may have increased prevalence of clopidogrel hyporesponsiveness. To assess this, we genotyped CYP2C19, ABCB1, and PON1 in 187 patients who underwent percutaneous coronary intervention. Race was self-defined by patients. We also performed light transmission aggregometry with adenosine diphosphate (ADP) and arachidonic acid during dual antiplatelet therapy. We found a significant difference for presence of the CYP2C19*2 polymorphism between white and non-white patients. Although 7% of patients had platelet resistance to clopidogrel, this did not correlate with any of the tested genetic polymorphisms. We did not find platelet resistance to aspirin in this cohort. Multivariate analysis showed that patients with PON1 and CYP2C19 polymorphisms had higher light transmission after ADP aggregometry than patients with native alleles. There was no preponderance of any race in patients with higher light transmission aggregometry. In brief, PON1 and CYP2C19 polymorphisms were associated with lower clopidogrel responsiveness in this sample. Despite differences in CYP2C19 polymorphisms across white and non-white patients, genetic admixture by itself was not able to identify clopidogrel hyporesponsiveness.

Clinical Pharmacogenetic Testing and Application: Laboratory Medicine Clinical Practice Guidelines

Pharmacogenetic testing for clinical applications is steadily increasing. Correct and adequate use of pharmacogenetic tests is important to reduce unnecessary medical costs and adverse patient outcomes. This document contains recommended pharmacogenetic testing guidelines for clinical application, interpretation, and result reporting through a literature review and evidence-based expert opinions for the clinical pharmacogenetic testing covered by public medical insurance in Korea. This document aims to improve the utility of pharmacogenetic testing in routine clinical settings.

Evaluation of clopidogrel response variability and identification of the CYP2C19 polymorphism in Mexican patients / Evaluación de la variabilidad en la respuesta a clopidogrel e identificación del polimorfismo CYP2C19 en pacientes mexicanos

Abstract Objective Drug inhibition of platelet P2Y12 adenosine diphosphate receptor has reduced the incidence of adverse cardiovascular events after percutaneous coronary interventions. The analysis of the phosphorylation status of vasodilator-stimulated phosphoprotein by flow cytometry has shown a predictive value for adverse events and stent thrombosis. Polymorphisms of CYP2C19 in high risk patients may also relate to adverse cardiovascular events. Methods Ninety patients were enrolled. Patients received a 600 mg clopidogrel loading dose. Blood samples were obtained at the time of the procedure and 24 h later, platelet reactivity was assessed by vasodilator-stimulated phosphoprotein phosphorylation measurement using flow cytometry. Low response to clopidogrel was defined as a platelet reactivity index ≥ 50%. The presence of CYP2C19*2 was identified with the restriction enzyme Smal. Results Mean platelet reactivity index: 53.45 ± 22.48% in the baseline sample and 57.14 ± 23.08% at 24 h (p = 0.183); 40% of patients behaved as good responders, the rest behaved as non-responders with 38% of patients showing platelet reactivity indexes between 50-70% and 22% showing indexes above 70%. The CYP2C19*2 polymorphism was found in 17% of patients, with a 3.9% AA homozygous genotype carriers. Conclusion Response to the clopidogrel loading dose showed a wide variability among patients with 40% responding to the drug according to previously established cut-off values. Our results showed that 3.9% of patients show the AA genotype. To our knowledge, this is the first study involving clopidogrel response by flow citometry and genotype typification in Mexican Mestizo population.

Resumen Objetivo La inhibición del receptor plaquetario P2Y12 se ha asociado con reducción en incidencia de eventos cardiovasculares mayores en pacientes sometidos a intervenciones coronarias percutáneas. El estudio de la fosfoproteína estimulada por vasodilatadores mediante citometría de flujo tiene valor predictivo para desarrollo de eventos adversos y trombosis del stent. Los polimorfismos del CYP2C19 en pacientes de alto riesgo pueden también asociarse con eventos adversos. Método 90 pacientes, dosis de carga de clopidogrel: 600 mg. Se obtuvieron muestras de sangre basales y post-24 horas. La reactividad plaquetaria se estudió mediante medición de fosfoproteína estimulada por vasodiatadores por citometría de flujo. Se consideró baja respuesta al clopidogrel un índice de reactividad plaquetaria ≥50%. La presencia del CYP2C19*2 se identificó con enzima de restricción Smal. Resultados La media del índice de reactividad plaquetaria fue: 53.45 ± 22.48% en muestras basales y 57.14 ± 23.08% a 24 h (p = 0.183); 40% de los pacientes repondieron a clopidogrel, el resto de comportó como no-respondedores, un 38%, mostró índices de reactividad plaquetaria entre 50 -70% y 22%, índices > 70%. El polimorfismo CYP2C19*2 se encontró en 17% pacientes, con un 3.9% portadores de genotipo homozigótico AA. Conclusiones La respuesta a clopidogrel mostró amplia variabilidad entre pacientes, el 40% presentó respuesta de acuerdo con puntos de corte pre establecidos. Un 3.9% de los pacientes presentó genotipo AA. Consideramos que este es el primer estudio realizado en población mestizo-mexicana utilizado citometría de flujo para evaluar la respuesta a clopidogrel así como la tipificación genética de los pacientes.

Relevance of the ancestry for the variability of the Drug-Metabolizing Enzymes CYP2C9, CYP2C19 and CYP2D6 polymorphisms in a multiethnic Costa Rican population / Relevancia de la ancestría para la variabilidad de polimorfismos de las enzimas metabolizadoras de fármacos CYP2C9, CYP2C19 y CYP2D6 en una población multiétnica de Costa Rica

Abstract:CYP2C9, CYP2C19 and CYP2D6 metabolize around 40 % of drugs and their genes vary across populations. The Costa Rican population has a trihybrid ancestry and its key geographic location turns it into a suitable scenario to evaluate interethnic differences across populations. This study aims to describe the diversity of CYP2C9, CYP2C19 and CYP2D6 polymorphisms in Costa Rican populations in the context of their ancestry. A total of 448 healthy individuals were included in the study: Bribri (n= 47), Cabécar (n= 27), Maleku (n= 16), Guaymí (n= 30), Huetar (n= 48), Chorotega (n= 41), Admixed/Mestizos from the Central Valley/Guanacaste (n= 189), and Afro-Caribbeans (n= 50) from Limón. CYP2C9 (alleles *2, *3, *6) and CYP2C19 (*2, *3, *4, *5, *17) genotypes were determined by Real-Time PCR. African, European and Native American ancestry were inferred using 87 ancestry informative markers. The frequency of the decreased activity allele CYP2C9*2 is lower in the self-reported Amerindian groups compared to the admixed population, and the highest frequencies of CYP2C19*2 (null activity) and the CYP2C19*17 (increased activity) were found in the self-reported AfroCaribbean population. Moreover, a frequency of 0.7 % CYP2C9 gPMs in the Admixed population and a variable frequency of CYP2C19 gUMs (0.0-32.6 %, more prevalent in Afro-Caribbeans) in Costa Rican populations, was found. Finally, the following alleles were positively correlated with genomic African ancestry and negatively correlated with genomic Native American ancestry: CYP2D6*5 (null activity), CYP2D6*17 (decreased activity), CYP2D6*29 (decreased activity) and CYP2C19*17 (increased activity). No correlation for CYP2C9 polymorphisms and genomic ancestry was found. Further studies assessing the CYP2C9 and CYP2C19 sequence in these populations, preferentially by sequencing these genes, are warranted. Rev. Biol. Trop. 64 (3): 1067-1076. Epub 2016 September 01.

ResumenCYP2C9, CYP2C19 y CYP2D6 metabolizan aproximadamente el 40 % de los fármacos y los genes que las codifican varían en las distintas poblaciones humanas. La población costarricense posee ancestría trihíbrida y su posición geográfica estratégica la convierten en un escenario idóneo para evaluar la variabilidad interétnica en sus poblaciones multiétnicas. El presente estudio tiene como objetivo describir la diversidad de los polimorfismos CYP2C9, CYP2C19 y CYP2D6 en las poblaciones costarricenses en el contexto de su ancestría. Un total de 448 individuos sanos fueron incluidos: Bribri (n= 47), Cabécar (n= 27), Maleku (n= 16), Guaymí (n= 30), Huetar (n= 48), Chorotega (n= 41), mestizos del Valle Central y Guanacaste (n= 189) y afrocaribeños de Limón (n= 50). Los genotipos CYP2C9 (alelos *2, *3, *6) y CYP2C19 (*2, *3, *4, *5 y *17) fueron determinados mediante PCR tiempo real. Las ancestrías africana, europea y nativa americana fueron inferidas usando 87 marcadores informativos de ancestría. La frecuencia del alelo de actividad disminuida CYP2C9*2 fue menor en los grupos autodefinidos de amerindios que en la población mestiza y las frecuencias más altas de CYP2C19*2 (actividad nula) y CYP2C19*17 (actividad incrementada) se encontraron en la población autodefinida afrocaribeña. Asimismo, se encontró una frecuencia de gPMs CYP2C9 de 0.7 % en la población mestiza y una frecuencia variable de gUMs CYP2C19 (0.0 a 32.6 %, más prevalente en afrocaribeños) en las poblaciones costarricenses. Por último, los siguientes alelos fueron positivamente correlacionados con la ancestría africana y negativamente con la ancestría nativa americana: CYP2D6*5 (actividad nula), CYP2D6*17, CYP2D6*29 (ambos de actividad disminuida) y CYP2C19*17 (actividad incrementada). No se encontró correlación entre los polimorfismos CYP2C9 y la ancestría. Se requieren estudios posteriores que evalúen la secuencia de CYP2C9 y CYP2C19 en estas poblaciones, preferiblemente mediante la secuenciación de estos genes.

Correlation Between the CYP2C19 Phenotype Status and the Results of Three Different Platelet Function Tests in Cardiovascular Disease Patients Receiving Antiplatelet Therapy: An Emphasis on Newly Introduced Platelet Function Analyzer-200 P2Y Test

BACKGROUND: An association has been reported between CYP2C19 polymorphism and the altered antiplatelet activity of clopidogrel. We investigated this association using the newly introduced platelet function analyzer (PFA)-200 (INNOVANCE PFA-200 System; Siemens Healthcare, Germany) P2Y test. METHODS: Polymorphisms of CYP2C19*2, *3, *17 and the degree of inhibition of platelet function were determined in 83 patients. Three different platelet function tests were used to evaluate the degree of platelet inhibition and to check the association with genotype. RESULTS: The post-procedure PFA-200 values of extensive metabolizers (EM) patients (285.3+/-38.8) were higher than those of intermediate metabolizers (IM) and poor metabolizers (PM) patients (227.7+/-98.3 and 133.7+/-99.2, respectively; P=0.024). Light transmittance aggregometry (LTA) and the VerifyNow system showed that the post-procedure values for EM patients were lower than those of IM and PM patients (LTA: 24.4+/-15.7, 34.1+/-17.6, and 42.2+/-16.9, respectively, P<0.001; VerifyNow: 133.2+/-60.5, 171.5+/-42.6, and 218.7+/-59.3, respectively, P<0.001). The high residual platelet reactivity (HPR) rates were significantly different among the EM, IM, and PM groups using PFA-200 (PM:IM:EM=82.4:40.6:11.8, P<0.001). CONCLUSIONS: Approximately, 59.0% of Korean patients with cardiovascular disease receiving clopidogrel had CYP2C19 loss-of-function genotypes classified as IM or PM, and the frequency was similar to the data from Asian people. The PFA-200, LTA, and VerifyNow platelet function tests revealed evidence of a significant association between the efficacy of clopidogrel and CYP2C19 genotypes.

Underlying Mechanisms and Management of Refractory Gastroesophageal Reflux Disease / 대한소화기학회지

The prevalence of gastroesophageal reflux disease (GERD) in South Korea has increased over the past 10 years. Patients with erosive reflux disease (ERD) shows better response to proton pump inhibitors (PPIs) than those with non-erosive reflux disease (NERD). NERD is a heterogeneous condition, showing pathological gastroesophageal reflux or esophageal hypersensitivity to reflux contents. NERD patients with pathological gastroesophageal reflux or hypersensitivity to acid may respond to PPIs. However, many patients with esophageal hypersensitivity to nonacid or functional heartburn do not respond to PPIs. Therefore, careful history and investigations are required when managing patients with refractory GERD who show poor response to conventional dose PPIs. Combined pH-impedance studies and a PPI diagnostic trial are recommended to reveal underlying mechanisms of refractory symptoms. For those with ongoing reflux-related symptoms, split dose administration, change to long-acting PPIs or PPIs less influenced by CYP2C19 genotypes, increasing dose of PPIs, and the addition of alginate preparations, prokinetics, selective serotonin reuptake inhibitors, or tricyclic antidepressants can be considered. Pain modulators, selective serotonin reuptake inhibitors, or tricyclic antidepressants are more likely to be effective for those with reflux-unrelated symptoms. Surgery or endoscopic per oral fundoplication may be effective in selected patients.