Relationships between CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 metabolic phenotypes and genotypes in a Nicaraguan Mestizo population.

Interethnic variability in the drug-metabolizing capacity of CYP450 enzymes may lead to discrepancies in the relationship between genotypes and phenotypes worldwide. The present study was aimed to analyze for the first time whether there is a relationship between clinically relevant CYP450 genetic polymorphisms and their drug oxidation capacity (metabolic phenotype) in a population of healthy Nicaraguan volunteers. Two hundred and twelve participants were genotyped for CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, and their actual metabolic phenotype (evaluated by the Metabolic Ratio, MR) was analyzed by using the CEIBA cocktail approach. The results showed the wide interindividual variability in all the studied enzymes and a significant difference (p < 0.004) in the activity of CYP1A2 between male and female subjects. The number of CYP2C19 (p < 0.0001) and CYP2D6 (p < 0.0001) active alleles were shown inversely correlated with their corresponding MR, although there were marked genotype-phenotype discrepancies. There was an actual enzyme capacity overlapping (MR) between genotypically Poor (gPMs) and Extensive Metabolizers (gEMs) of 3.14% subjects for CYP2D6 and 0.94% for CYP2C9. Similarly, there was an overlapping for metabolic phenotypes of 11.48% of genotypically ultrarapid metabolizers (gUMs) for CYP2C19 and 2.09% for CYP2D6 and gEMs. Therefore, the current approach for metabolic phenotype prediction based just on genotype does not predict properly for all individuals within this Nicaraguan Mestizo population, thus representing a potential barrier for the clinical implementation of personalized medicine in this region. However, it is necessary to improve the prediction of phenotype from genotype in order to improve the pharmacogenetic implementation in populations with specific ethnic backgrounds.

Influence of genetic variants and antiepileptic drug co-treatment on lamotrigine plasma concentration in Mexican Mestizo patients with epilepsy.

Genetic and nongenetic factors may contribute to lamotrigine (LTG) plasma concentration variability among patients. We simultaneously investigated the association of UGT1A1, UGT1A4, UGT2B7, ABCB1, ABCG2, and SLC22A1 variants, as well as antiepileptic drug co-treatment, on LTG plasma concentration in 97 Mexican Mestizo (MM) patients with epilepsy. UGT1A4*1b was associated with lower LTG dose-corrected concentrations. Patients with the UGT2B7-161T allele were treated with 21.22% higher LTG daily dose than those with CC genotype. Two novel UGT1A4 variants (c.526A>T; p.Thr185= and c.496T>C; p.Ser166Leu) were identified in one patient. Patients treated with LTG + valproic acid (VPA) showed higher LTG plasma concentration than patients did on LTG monotherapy or LTG + inducer. Despite the numerous drug-metabolizing enzymes and transporter genetic variants analyzed, our results revealed that co-treatment with VPA was the most significant factor influencing LTG plasma concentration, followed by UGT1A4*1b, and that patients carrying UGT2B7 c.-161T required higher LTG daily doses. These data provide valuable information for the clinical use of LTG in MM patients with epilepsy.

Risk for self-reported anorexia or bulimia nervosa based on drive for thinness and negative affect clusters/dimensions during adolescence: A three-year prospective study of the TChAD cohort.

OBJECTIVE: This study explored the cross-sectional and predictive effect of drive for thinness and/or negative affect scores on the development of self-reported anorexia nervosa (AN) and bulimia nervosa (BN). METHOD: K-means were used to cluster the Eating Disorder Inventory-Drive for Thinness (DT) and Child Behavior Checklist Anxious/Depressed (A/D) scores from 615 unrelated female twins at age 16-17. Logistic regressions were used to assess the effect of these clusters on self-reported eating disorder diagnosis at ages 16-17 (n = 565) and 19-20 (n = 451). RESULTS: DT and A/D scores were grouped into four clusters: Mild (scores lower than 90th percentile on both scales), DT (higher scores only on DT), A/D (higher scores only on A/D), and DT-A/D (higher scores on both the DT and A/D scales). DT and DT-A/D clusters at age 16-17 were associated cross-sectionally with AN and both cross-sectionally and longitudinally with BN. The DT-A/D cluster had the highest prevalence of AN at follow-up compared with all other clusters. Similarly, an interaction was observed between DT and A/D that predicted risk for AN. DISCUSSION: Having elevated DT and A/D scores may increase risk for eating disorder symptomatology above and beyond a high score on either alone. Findings suggest that cluster modeling based on DT and A/D may be useful to inform novel and useful intervention strategies for AN and BN in adolescents.

CYP2D6 variation, behaviour and psychopathology: implications for pharmacogenomics-guided clinical trials.

Individual and population differences in polymorphic cytochrome P450 enzyme function have been known for decades. The biological significance of these differences has now been deciphered with regard to drug metabolism, action and toxicity as well as disposition of endogenous substrates, including neuroactive compounds. While the cytochrome P450 enzymes occur abundantly in the liver, they are expressed in most tissues of the body, albeit in varying amounts, including the brain. The latter location of cytochrome P450s is highly pertinent for susceptibility to neuropsychiatric diseases, not to mention local drug metabolism at the site of psychotropic drug action in the brain. In the current era of personality medicine with companion theranostics (i.e. the fusion of therapeutics with diagnostics), this article underscores that such versatile biological roles of cytochrome P450s offer multiple points of entry for personalized medicine and rational therapeutics. We focus our discussion on CYP2D6, one of the most intensively researched drug and endogenous compound metabolism pathways, with a view to relevance for, and optimization of, pharmacogenomic-guided clinical trials. Working on the premise that CYP2D6 is related to human behaviour and certain personality traits such as serotonin and dopamine system function, we further suggest that the motivation of healthy volunteers to participate in clinical trials may in part be influenced by an under- or over-representation of certain CYP2D6 metabolic groups.

Pharmacogenetic and pharmacogenomic treatment of rheumatoid arthritis: a review of Pharmacogenomics Knowledge Base scientific evidence.

Tweetable abstract Update on the genetic variants with the highest level of Pharmacogenomics Knowledge Base evidence for their association with toxicity and efficacy in response to the most commonly used disease-modifying antirheumatic drugs for the treatment of rheumatoid arthritis.

Interethnic differences in UGT1A4 genetic polymorphisms between Mexican Mestizo and Spanish populations.

UDP-glucuronosyltransferase 1A4 (UGT1A4) is a phase II drug-metabolizing enzyme that catalyzes the glucuronidation of many clinically-important drugs. Interethnic differences in the genetic polymorphism of UGT1A4 have been reported; however, there is no information in Mexican Mestizos (MMs) and Spaniards (SPs). Furthermore, MM is an admixed population with 26 % of Caucasian genes mainly from Spain. Therefore, this study aimed to investigate the potential differences between 318 SPs and 248 MMs healthy individuals regarding UGT1A4*1b, UGT1A4*2 and UGT1A4*3 alleles and to compare the observed frequencies with those previously reported in different populations. The allelic frequencies of the three UGT1A4 polymorphisms showed interethnic differences between MMs and SPs (p < 0.05). The analyzed SNPs variants in this genetic region were not in linkage disequilibrium (LD) for the MM population, suggesting that these mutations have arisen independently in the same genetic background. In contrast, UGT1A4*2 and UGT1A4*3 were in LD in the SP population. Comparison of present data with other in different ethnic groups revealed that the frequencies of UGT1A4*2 and UGT1A4*3 in SP were similar to other Caucasians and higher than in Asians, whereas in MMs were lower than in Caucasians and higher than in Asians only for UGT1A4*2. Present results could be helpful to improve the use of UGT1A4 drug substrates in order to adjust them to the ethnic background of a given population, specifically for Hispanics.

Cognitive behaviour therapy response and dropout rate across purging and nonpurging bulimia nervosa and binge eating disorder: DSM-5 implications.

BACKGROUND: With the imminent publication of the new edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), there has been a growing interest in the study of the boundaries across the three bulimic spectrum syndromes [bulimia nervosa-purging type (BN-P), bulimia nervosa-non purging type (BN-NP) and binge eating disorder (BED)]. Therefore, the aims of this study were to determine differences in treatment response and dropout rates following Cognitive Behavioural Therapy (CBT) across the three bulimic-spectrum syndromes. METHOD: The sample comprised of 454 females (87 BED, 327 BN-P and 40 BN-NP) diagnosed according to DSM-IV-TR criteria who were treated with 22 weekly outpatient sessions of group CBT therapy. Patients were assessed before and after treatment using a food and binging/purging diary and some clinical questionnaires in the field of ED. "Full remission" was defined as total absence of binging and purging (laxatives and/or vomiting) behaviors and psychological improvement for at least 4 (consecutive). RESULTS: Full remission rate was found to be significantly higher in BED (69.5%) than in both BN-P (p < 0.005) and BN-NP (p < 0.001), which presented no significant differences between them (30.9% and 35.5%). The rate of dropout from group CBT was also higher in BED (33.7%) than in BN-P (p < 0.001) and BN-NP (p < 0.05), which were similar (15.4% and 12.8%, respectively). CONCLUSIONS: Results suggest that purging and non-purging BN have similar treatment response and dropping out rates, whereas BED appears as a separate diagnosis with better outcome for those who complete treatment. The results support the proposed new DSM-5 classification.

The genetics of eating disorders.

Over the past decade, considerable advances have been made in understanding genetic influences on eating pathology. Eating disorders aggregate in families, and twin studies reveal that additive genetic factors account for approximately 40% to 60% of liability to anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED). Molecular genetics studies have been undertaken to identify alterations in deoxyribonucleic acid sequence and/or gene expression that may be involved in the pathogenesis of disordered eating behaviors, symptoms, and related disorders and to uncover potential genetic variants that may contribute to variability of treatment response. This article provides an in-depth review of the scientific literature on the genetics of AN, BN, and BED including extant studies, emerging hypotheses, future directions, and clinical implications.

Pharmacogenetics: ethnicity, treatment and health in Latin American populations.

The Ibero-American Network of Pharmacogenetics and Pharmacogenomics (RIBEF) studies Latin American populations to benefit from the implementation of personalized medicine. Since 2006, it has studied ethnicity to apply pharmacogenetics knowledge in autochthonous populations of Latin America, considering ancestral medicine. The meeting 'Pharmacogenetics: ethnicity, Treatment and Health in Latin American Populations' was held in Mexico City, Mexico, and presented the relevance of RIBEF collaboration with Latin American researchers and the governments of Mexico, Spain and the Autonomous Community of Extremadura. The results of 17 years of uninterrupted work by RIBEF, the Declaration of Mérida/T'Hó and the call for the Dr José María Cantú Award for studies focused on the pharmacogenetics of native populations in Latin America were presented.

Development of a HPLC method for the determination of losartan urinary metabolic ratio to be used for the determination of CYP2C9 hydroxylation phenotypes.

BACKGROUND: Losartan is metabolized to losartan carboxylic acid (E-3174) by the polymorphic cytochrome CYP2C9. The aim of the study was to develop a high-performance liquid chromatographic (HPLC) method with fluorescence detection for simultaneously measuring losartan and its metabolite E-3174 in urine to evaluate the losartan urinary metabolic ratio (MR: losartan/E-3174) for CYP2C9 phenotyping in humans. METHODS: The compounds were separated in a reversed-phase chromatographic column and detected by fluorescence at a wavelength of 250 nm for excitation and of 370 nm for emission. RESULTS: No analytical interferences with endogenous compounds were found, and the extraction recoveries were over 88%. Limits of quantification of 2 ng mL-1 for losartan and 5 ng mL-1 for E-3174 were achieved, as well as good reproducibility with coefficients of variation of <9% in all cases. Analyses with the present HPLC method show significant differences (p<0.05) in losartan MRs between the four CYP2C9 genotype groups in 13 Spanish healthy volunteers. CONCLUSIONS: The method developed is simple and affordable, as well as sensitive and reliable to calculate the MR. Therefore, it appears to be useful for CYP2C9 phenotyping using losartan as a drug test in populations, such as Hispanics with different allele combinations.

High-performance liquid chromatography method using ultraviolet detection for the quantification of aripiprazole and dehydroaripiprazole in psychiatric patients.

BACKGROUND: Aripiprazole (ARI) is an antipsychotic drug that is metabolized to dehydroaripiprazole (DARI) by CYP2D6. Because of the large interindividual variability in ARI and DARI plasma concentrations, therapeutic drug monitoring may be of use in psychiatric patients during treatment with ARI. The aim of the present study was to develop a simple and reliable method for the quantitative determination of ARI and DARI in plasma using liquid-liquid extraction and reverse-phase high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection. The method was tested in psychiatric patients during regular treatment with ARI. METHODS: Separation was by the liquid-liquid method, and UV detection at 254 nm. Linear responses for ARI and DARI were obtained between 2 and 1000 ng/mL, and precision assays were lower than 10.4 for both analytes. RESULTS: Lower limit of quantification and detection were 1 and 0.38 ng/mL for ARI and 0.78 and 0.44 ng/mL for DARI, respectively. The method was successfully applied to plasma samples drawn from 22 patients with concentrations ranging between 2 and 189 ng/mL for ARI and between 11 and 359 ng/mL for DARI. CONCLUSIONS: The chromatographic method developed has been demonstrated to be sensitive and reliable for the measurement of ARI and DARI simultaneously in human plasma, and the present method represents an alternative procedure to evaluate plasma concentration in patients during treatment with ARI.

Personality changes in bulimia nervosa after a cognitive behaviour therapy.

OBJECTIVES: The goals of this study were to evaluate changes in personality traits in outpatients with bulimia nervosa and specific clinical predictors of such personality changes, after cognitive behaviour therapy (CBT). METHOD: The sample comprised 100 purging bulimia nervosa outpatients (DSM-IV-TR). Assessment measures included the Eating Disorders Inventory-2, Symptom Check List Revised and Temperament and Character Inventory-Revised, as well as other clinical and psychopathological indices. All measures were administered before and after 22 weeks of group CBT. RESULTS: The temperament traits of Harm Avoidance and Reward Dependence and the character traits of Self-Directedness and Self-Transcendence changed after CBT. Pre-post CBT reduction in Eating Disorders Inventory-2 total score predicted the decrease and increase in Harm Avoidance and Self-Directedness, respectively. CONCLUSIONS: Results suggest that group CBT in outpatient women settings influence changes in some personality traits, which appear mainly related to an overall improvement in eating pathology.

Lifetime obesity in patients with eating disorders: increasing prevalence, clinical and personality correlates.

OBJECTIVES: The aims of our study were to examine the lifetime prevalence of obesity rate in eating disorders (ED) subtypes and to examine whether there have been temporal changes among the last 10 years and to explore clinical differences between ED with and without lifetime obesity. METHODS: Participants were 1383 ED female patients (DSM-IV criteria) consecutively admitted, between 2001 and 2010, to Bellvitge University Hospital. They were assessed by means of the Eating Disorders Inventory-2, the Symptom Checklist-90-Revised, the Bulimic Investigatory Test Edinburgh and the Temperament and Character Inventory-Revised. RESULTS: The prevalence of lifetime obesity in ED cases was 28.8% (ranging from 5% in anorexia nervosa to 87% in binge-eating disorders). Over the last 10 years, there has been a threefold increase in lifetime obesity in ED patients (p < .001). People with an ED and obesity had higher levels of childhood and family obesity (p < .001), a later age of onset and longer ED duration; and had higher levels of eating, general and personality symptomatology. CONCLUSIONS: Over the last 10 years, the prevalence of obesity associated with disorders characterized by the presence of binge episodes, namely bulimic disorders, is increasing, and this is linked with greater clinical severity and a poorer prognosis.

A one-year follow-up study of treatment-compliant suicide attempt survivors: relationship of CYP2D6-CYP2C19 and polypharmacy with suicide reattempts.

This study of a cohort of 1-year treatment-compliant survivors of a suicide attempt examined for the first time whether a high CYP2D6-CYP2C19 metabolic capacity (pharmacogenes related to psychopathology, suicide, and attempt severity) and/or polypharmacy treatments predicted repeat suicide attempts, adjusting for sociodemographic and clinical factors as confounders. Of the 461 (63% women) consecutively hospitalized patients who attempted suicide and were evaluated and treated after an index attempt, 191 (67.5% women) attended their 6- and 12-month follow-up sessions. Clinicians were blinded to the activity scores (AS) of their genotypes, which were calculated as the sum of the values assigned to each allele (CYP2C19 *2, *17; CYP2D6 *3, *4, *4xN, *5, *6, *10, wtxN). No differences were found in polypharmacy prescription patterns and the variability of CYP2D6 and CYP2C19 genotypes between adherents and dropouts, but the formers were older, with a higher frequency of anxiety and bipolar disorders and fewer alcohol and substance use disorders. The risk of reattempts was higher for CYP2D6 ultrarapid (AS > 2) metabolizers (ß = 0.561, p = 0.005) and violent suicide survivors (ß = -0.219, p = 0.042) if the attempt occurred during the first 6-month period, individuals with an increased number of MINI DSM-IV Axis I mental disorders (ß = 0.092, p = 0.032) during the second 6-month period and individuals with a combined high CYP2D6-CYP2C19 metabolic capacity (AS > 4) (ß = 0.345, p = 0.024) and an increased use of drugs other than antidepressants, anxiolytics-depressants and antipsychotics-lithium (ß = 0.088, p = 0.005) in multiple repeaters during both periods. CYP2D6 and CYP2C19 rapid metabolism and polypharmacy treatment for somatic comorbidities must be considered to prevent the severe side effects of short-term multiple suicide reattempts after a previous attempt.

Pharmacogenetics of the antiepileptic drugs phenytoin and lamotrigine.

Patients treated with antiepileptic drugs can exhibit large interindividual variability in clinical efficacy or adverse effects. This could be partially due to genetic variants in genes coding for proteins that function as drug metabolizing enzymes, drug transporters or drug targets. The purpose of this article is to provide an overview of the current knowledge on the pharmacogenetics of two commonly prescribed antiepileptic drugs with similar mechanisms of action; phenytoin (PHT) and lamotrigine (LTG). These two drugs have been selected in order to model the pharmacogenetics of Phase I and Phase II metabolism for PHT and LTG, respectively. In light of the present evidence, patients treated with PHT could benefit from CYP2C9 and CYP2C19 genotyping/phenotyping. For those under treatment with LTG, UGT1A4 and UGT2B7 genotyping might be of clinical use and could contribute to the interindividual variability in LTG concentration to dose ratio in epileptic patients.

Relevance of NR1I2 variants on carbamazepine therapy in Mexican Mestizos with epilepsy at a tertiary-care hospital.

Aim: We evaluated the potential influence of genetic (CYP3A5, EPHX1, NR1I2, HNF4A, ABCC2, RALBP1, SCN1A, SCN2A and GABRA1) and nongenetic factors on carbamazepine (CBZ) response, adverse drug reactions and CBZ plasma concentrations in 126 Mexican Mestizos (MM) with epilepsy. Subjects & methods: Patients were genotyped for 27 variants using TaqMan® assays. Results: CBZ response was associated with NR1I2 variants and lamotrigine cotreatment. CBZ-induced adverse drug reactions were related to antiepileptic polytherapy and SCN1A rs2298771/rs3812718 haplotype. CBZ plasma concentrations were influenced by NR1I2-rs2276707 and -rs3814058, and by phenytoin cotreatment. CBZ daily dose was also influenced by NR1I2-rs3814055 and EPHX1-rs1051740. Conclusion: Interindividual variability in CBZ treatment was partly explained by NR1I2, EPHX1 and SCN1A variants, as well as antiepileptic cotreatment in MM with epilepsy.

Challenges and Opportunities for Clinical Pharmacogenetic Research Studies in Resource-limited Settings: Conclusions From the Council for International Organizations of Medical Sciences-Ibero-American Network of Pharmacogenetics and Pharmacogenomics Meeting.

PURPOSE: The symposium Health and Medicines in Indigenous Populations of America was organized by the Council for International Organizations of Medical Sciences (CIOMS) Working Group on Clinical Research in Resource-Limited Settings (RLSs) and the Ibero-American Network of Pharmacogenetics and Pharmacogenomics (RIBEF). It was aimed to share and evaluate investigators' experiences on challenges and opportunities on clinical research and pharmacogenetics. METHODS: A total of 33 members from 22 countries participated in 2 sessions: RIBEF studies on population pharmacogenetics about the relationship between ancestry with relevant drug-related genetic polymorphisms and the relationship between genotype and phenotype in Native Americans (session 1) and case examples of clinical studies in RLSs from Asia (cancer), America (diabetes and women health), and Africa (malaria) in which the participants were asked to answer in free text their experiences on challenges and opportunities to solve the problems (session 2). Later, a discourse analysis grouping common themes by affinity was conducted. FINDINGS: The main result of session 1 was that the pharmacogenetics-related ancestry of the population should be considered when designing clinical studies in RLSs. In session 2, 21 challenges and 20 opportunities were identified. The social aspects represent the largest proportion of the challenges (43%) and opportunities (55%), and some of them seem to be common. IMPLICATIONS: The main discussion points were gathered in the Declaration of Mérida/T'Hó and announced on the Parliament of Extremadura during the CIOMS-RIBEF meeting in 4 of the major Latin American autochthonous languages (Náhualth, Mayan, Miskito, and Kichwa). The declaration highlighted the following: (1) the relevance of population pharmacogenetics, (2) the sociocultural contexts (interaction with traditional medicine), and (3) the education needs of research teams for clinical research in vulnerable and autochthonous populations.

Genomic Ancestry, CYP2D6, CYP2C9, and CYP2C19 Among Latin Americans.

We present the distribution of CYP2D6, CYP2C9, and CYP2C19 variants and predicted phenotypes in 33 native and admixed populations from Ibero-America (n > 6,000) in the context of genetic ancestry (n = 3,387). Continental ancestries are the major determinants of frequencies of the increased-activity allele CYP2C19*17 and CYP2C19 gUMs (negatively associated with Native American ancestry), decreased-activity alleles CYP2D6*41 and CYP2C9*2 (positively associated with European ancestry), and decreased-activity alleles CYP2D6*17 and CYP2D6*29 (positively associated with African ancestry). For the rare alleles, CYP2C9*2 and CYPC19*17, European admixture accounts for their presence in Native American populations, but rare alleles CYP2D6*5 (null-activity), CYP2D6-multiplication alleles (increased activity), and CYP2C9*3 (decreased-activity) were present in the pre-Columbian Americas. The study of a broad spectrum of Native American populations from different ethno-linguistic groups show how autochthonous diversity shaped the distribution of pharmaco-alleles and give insights on the prevalence of clinically relevant phenotypes associated with drugs, such as paroxetine, tamoxifen, warfarin, and clopidogrel.

Predictors of early change in bulimia nervosa after a brief psychoeducational therapy.

We aimed to examine baseline predictors of treatment response in bulimic patients. 241 seeking-treatment females with bulimia nervosa completed an exhaustive assessment and were referred to a six-session psychoeducational group. Regression analyses of treatment response were performed. Childhood obesity, lower frequency of eating symptomatology, lower body mass index, older age, and lower family's and patient's concern about the disorder were predictors of poor abstinence. Suicidal ideation, alcohol abuse, higher maximum BMI, higher novelty seeking and lower baseline purging frequency predicted dropouts. Predictors of early symptom changes and dropouts were similar to those identified in longer CBT interventions.