Pharmacogenetic Biomarkers Research Articles

Interethnic differences in the prevalence of main cardiovascular pharmacogenetic biomarkers.

Background: The aim of this study was to determine the prevalence of CYP2C9, VKORC1, CYP2C19, ABCB1, CYP2D6 and SLCO1B1 genes polymorphisms among residents of the Volga region (Chuvash and Mari) and northernCaucasus (Kabardins and Ossetians). Materials & methods: The study involved 845 apparently healthy volunteers of both sexes of the four different ethnic groups living in the Russian Federation: 238 from the Chuvash ethnic group, 206 Mari, 157 Kabardins and 244 Ossetians. Results: Significant differences were identified in allele frequency of CYP2C9, VKORC1, CYP2C19, ABCB1, CYP2D6 and SLCO1B1 genes polymorphisms between the Chuvash and Kabardins, Chuvash and Ossetians, Mari and Kabardians, Mari and Ossetians.

Predictive pharmacogenetic biomarkers for breast cancer recurrence prevention by simvastatin

Background: Statins treat hyperlipidemia and prevent cardiovascular morbidity and mortality. Evidence suggests that they also have anti-neoplastic activity. Several studies show a reduced rate of breast cancer recurrence among lipophilic statin users (e.g., simvastatin), motivating calls for clinical trials of statins in breast cancer patients. We measured the impact of genetic variation in statin-metabolizing enzymes and drug transporters on the recurrence rate in simvastatin-treated breast cancer patients.Methods: We conducted a nested case-control study among Danish women diagnosed with non-metastatic, invasive breast cancer between 2004–2010 who had filled ≥1 prescription for simvastatin after diagnosis. Cases were all breast cancer recurrences from the source population; one control was matched to each case on cancer stage, estrogen receptor and hormone therapy status, calendar period of diagnosis, and duration of simvastatin exposure. We genotyped variants in simvastatin-metabolizing enzymes (CYP3A4/rs35599367 and CYP3A5/rs776746) and drug transporters (ABCB1/rs2032582 and SLCO1B1/rs4149056), and estimated their association with recurrence with logistic regression models.Results: We observed protective (though imprecisely-measured) associations between variants in genes encoding drug transporters (ABCB1 and SLCO1B1) and simvastatin-metabolizing enzymes (CYP3A4 and CYP3A5) and breast cancer recurrence in simvastatin-treated women. For example, carrying two variant alleles in ABCB1 was associated with a 31% lower rate of recurrence (multivariable OR = 0.69, 95% CI: 0.31, 1.5).Conclusion: Our study provides weak evidence to support the use of genetic variation in ABCB1, SLCO1B1, CYP3A4, and CYP3A5 as biomarkers of breast tumor response to simvastatin. Validation of these findings within adjuvant clinical trials is encouraged.

Identification of pharmacogenetic biomarkers for efficacy of cytoreductive surgery plus hyperthermic intraperitoneal mitomycin C in patients with colorectal peritoneal metastases

IntroductionMitomycin C (MMC) is commonly used in patients with colorectal peritoneal metastases (CPM) treated with cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CRS + HIPEC). MMC requires metabolic activation prior to exert its cytotoxic effect of which the main activating enzymes are NQO1 and POR. However, not all patients are able to activate MMC for example due to polymorphisms in the genes encoding these enzymes. The aim of this study was to investigate the association of NQO1∗2, NQO1∗3, and POR∗28 with the efficacy of CRS + HIPEC with MMC in patients with CPM. MethodA retrospective follow-up design was used to study genetic association in patients with histologically proven CPM treated with CRS + HIPEC with MMC with respect to peritoneal recurrence rate after 3 months (primary endpoint), after 6 months, disease-free survival and overall survival. Genetic polymorphisms NQO1∗2, NQO1∗3, and POR∗28 were tested for association. ResultsA total of 253 patients were included. In NQO1∗3 carriers the peritoneal recurrence rate 3 and 6 months after HIPEC was significantly higher than in wild type patients, respectively 30.0% vs 3.8% (p = 0.009) and 40.0% vs 12.1% (p = 0.031). In line with these results, NQO1∗3 was associated with a shorter disease-free survival (HR 2.04, 95% CI [1.03–4.03]). There was no significant association with overall survival (HR 1.42, 95% CI [0.66–3.07]). ConclusionCarriership of the NQO1∗3 allele is associated with worse peritoneal recurrence rate and disease-free survival. These results suggest that individualization of patients treated with CRS + HIPEC based upon pharmacogenetics may be beneficial.

Effect of CYP3A4*22 and CYP3A4*1B but not CYP3A5*3 polymorphisms on tacrolimus pharmacokinetic model in Tunisian kidney transplant

The pharmacokinetics of Tacrolimus is characterized by a high interindividual variability that is mainly explained by pharmacogenetics biomarkers. The aims were to develop a population pharmacokinetic model (Pk pop) taking into account post-transplant phases (PTP), CYP3A4*1B, CYP3A4*22 and CYP3A5*3 polymorphisms on Tac pharmacokinetics in adult kidney transplant patients.The Pk pop study was performed using a nonparametric approach (Pmetrics*). The influence of covariates (age, weight, sex, hematocrit and CYP3A4*1B, CYP3A4*22 and CYP3A5*3 polymorphisms) was tested on the model's Pk parameters. The performance of the final model was assessed using an external dataset.A one-compartment model (Vd: volume of distribution, CL: Tac Clearance) was found to correctly describe the evolution of the C0/D regardless of the PTP. The influence of the covariates has shown that only the CYP3A4*1B and CYP3A4*22 polymorphisms were significantly associated only with CL, regardless of PTP (p = .04 and 0.02, respectively). Only the CYP3A4*22 polymorphism influenced CL during early PTP (P1: the first three months, p = .02). During the late PTP (P2: >3 months), only CYP3A4 polymorphisms were found to affect CL (p = .03 for both). The external validation of the final model, including both CYP3A4 polymorphisms, showed an acceptable predictive performance during P1 and P2.We developed and validated a tac Pk pop model including both CYP3A4*22 and CYP3A4*1B polymorphisms, taking into account PTP. This model was very useful in the Tac dose proposal in this population on any PT day but could not be used in other organ transplants due to pharmacokinetic differences.

Pharmacogenetic-Whole blood and intracellular pharmacokinetic-Pharmacodynamic (PG-PK2-PD) relationship of tacrolimus in liver transplant recipients.

Tacrolimus (TAC) is the cornerstone of immunosuppressive therapy in liver transplantation. This study aimed at elucidating the interplay between pharmacogenetic determinants of TAC whole blood and intracellular exposures as well as the pharmacokinetic-pharmacodynamic relationship of TAC in both compartments. Complete pharmacokinetic profiles (Predose, and 20 min, 40 min, 1h, 2h, 3h, 4h, 6h, 8h, 12h post drug intake) of twice daily TAC in whole blood and peripheral blood mononuclear cells (PBMC) were collected in 32 liver transplanted patients in the first ten days post transplantation. A non-parametric population pharmacokinetic model was applied to explore TAC pharmacokinetics in blood and PBMC. Concurrently, calcineurin activity was measured in PBMC. Influence of donor and recipient genetic polymorphisms of ABCB1, CYP3A4 and CYP3A5 on TAC exposure was assessed. Recipient ABCB1 polymorphisms 1199G>A could influence TAC whole blood and intracellular exposure (p<0.05). No association was found between CYP3A4 or CYP3A5 genotypes and TAC whole blood or intracellular concentrations. Finally, intra-PBMC calcineurin activity appeared incompletely inhibited by TAC and less than 50% of patients were expected to achieve intracellular IC50 concentration (100 pg/millions of cells) at therapeutic whole blood concentration (i.e.: 4–10 ng/mL). Together, these data suggest that personalized medicine regarding TAC therapy might be optimized by ABCB1 pharmacogenetic biomarkers and by monitoring intracellular concentration whereas the relationship between intracellular TAC exposure and pharmacodynamics biomarkers more specific than calcineurin activity should be further investigated.

Estrogen receptor alpha gene variant, PvuII (rs2234693), as a potential pharmacogenetic biomarker for aneurysmal subarachnoid hemorrhage in postmenopausal women

Aneurysmal subarachnoid hemorrhage (aSAH) occurs more often in postmenopausal women than in men. Estrogen plays an important role in vascular homeostasis. Our aim was to elucidate whether a drop in circulating estradiol in conjunction with variants of estrogen receptor genes have a role in female gender susceptibility to aSAH. A total of 709 subjects were enrolled (349 aSAH patients, 360 controls) and genotyped for rs2234693 or PvuII (intron 1, T>C) in the ESR1 gene and rs4986938 or AluI (exon 8, 1730G>A) of ESR2 gene by PCR-RFLP. Serum estradiol was estimated by ELISA. Estrogen receptor gene expression was studied by qRT-PCR. Logistic regression analysis indicated a significant recessive effect of the T allele of PvuII on aSAH in females, and this association remained statistically significant even after adjusting for confounders(OR 1.702, CI 95% 1.062, 2.726, Pvalue = 0.027). ESR1 gene expression was significantly reduced (P value = 0.0089) in subjects carrying PvuII T allele. In postmenopausal women with TT genotype and low serum estradiol, the odds for developing aSAH were found to be 3.5-fold increase compared with premenopausal women (CI 95% 1.424-8.828, P value = 0.0074). However, this variant showed no significant association with aSAH in men. No significant difference was found in genotype and allelic distribution of AluI polymorphism in ESR2 gene, between patients and controls. We propose that the PvuII T allele could be a potential pharmacogenetic marker for strategizing personal medicine for preventing aSAH in postmenopausal women with low circulating estradiol. Further larger studies in other population are warranted.

A preliminary study of pharmacogenetic biomarkers for individuals with autism and gastrointestinal dysfunction

BackgroundAutism Spectrum Disorder (ASD) symptoms are commonly treated with a variety of pharmaceuticals which can have adverse side effects. A study of pharmacogenetic biomarkers for ASD medications and association with gastrointestinal (GI) dysfunction symptoms was conducted in individuals diagnosed with autism and/or GI dysfunction to provide further information on the genetic risk in relation to treatment effectiveness. MethodsA total of sixty participants were recruited, 10 with autism and GI dysfunction, 21 with GI dysfunction (without autism) and 29 without autism or GI dysfunction (typical controls). Buccal cell samples were collected and sequenced. A GI dysfunction questionnaire which included questions regarding prescription of medications associated with treating ASD symptoms was provided to the participants. To calculate Odds Ratios and compare the average of risk allele expression frequency of the SNPS being investigated, the sequencing and questionnaire data were analyzed using the epiR package and Welch Two Sample T-tests, respectively, using the R statistics program. The Bonferroni correction was utilized to correct for multiple comparisions. ResultsPeople in the autism group were more likely to express the risk alleles for the Cytochrome P450 family 2 subfamily C member 9 rs1057910 and Solute Carrier family 6, member 2 rs3785143 SNPs; however, after the Bonferroni correction these findings were not statistically significant (CYP2C9 rs1057910, P = 0.074; SLC6A2, rs3785143, P = 0.4218). ConclusionsFurther research is warranted to reveal the potential use of CYP2C9 and SLC6A2 SNP expression as pharmacogenetic biomarkers to determine the most appropriate medication for individuals with autism and/or GI dysfunction.

Mycophenolic acid pharmacogenomics in kidney transplantation

Mycophenolic acid (MPA) is a potent antiproliferative drug prescribed to prevent acute rejection in kidney transplantation. MPA reversibly inhibits the enzymes involved in the synthesis of guanosine nucleotides, thus preventing DNA replication of immune cells. Consequently, the repression of both cell and humoral immunity induces renal allograft tolerance. MPA is an effective and safe immunosuppressive drug, but some patients show variability in drug concentration, acute rejection, graft dysfunction, or MPA-related adverse events. Although the pharmacogenomics of immunosuppressive drugs has been widely investigated, MPA has been explored to a lesser extent. This review of MPA pharmacogenomic studies, included pharmacokinetics, adverse events, and main clinical outcomes of MPA treatment in kidney transplantation. Associations of variants in genes encoding MPA metabolizing enzymes, transporters, and targets with drug efficacy and safety are described. Most pharmacogenetic studies have focused on small sample sizes and few simultaneously analyzed genetic variants. Some studies reported significant associations of pharmacokinetics- and pharmacodynamics-related genes with MPA exposure, acute rejection, graft dysfunction, hematological events, and gastrointestinal complications. However, even large cohorts did not replicate the findings, possibly due to divergent study design, immunosuppressive scheme, follow-up time, and other factors. Finally, the heterogeneity of aspects between studies limit conclusions on pharmacogenetic biomarkers of MPA in kidney transplantation.

Pharmacogenetics biomarkers of antipsychotics’ safety in adolescents with acute psychotic episode

Currently, there is a lack of pharmacogenetic research of antipsychotics’ safety in children and adolescents with acute psychotic episodes. Genetic polymorphisms of CYP2D6 and ABCB1 are the most likely candidates for such studies. AIM.To establish possible associations of CYP3A, CYP2D6, ABCB1 polymorphisms with safety of antipsychotics of an acute psychotic episode in adolescents during the first 14 days of treatment. MATERIALS AND METHODS. We observed 53 adolescents, hospitalized with acute psychotic episode, during 14 days of treatment. Mean age was 15,08±1,7 years. All patients took antipsychotic as the main drug. The tolerance to antipsychotics was assessed using UKU SERS, SAS, BARS. We collected a buccal epitelium from each patient and genotyped CYP3A4*22 (rs2740574), CYP3A5*3 (6986A&gt;G, rs7767746), CYP2D6*4, *10 (rs3892097, rs1065852), ABCB1 1236C&gt;T (rs1128503), 2677G&gt;T/A (rs2032582), 3435C&gt;T (rs1045642) by real-time PCR. RESULTS. Scores of UKU SERS, SAS, BARS, AIMS scales did not correlated with average doses of antipsychotics. Distribution of genetic polymorphisms were in the Hardy-Weinberg equilibrium. The carriage of CYP2D6*4 was associated with the presence of «Asthenia / Lassitude / lncreased Fatigability» (70% vs. 3.6%, p=0.039), the carriage of CYP2D6*10 was associated with «Increased dream activity» (53.8% vs. 22.5%, p=0.043). The «Increased Duration of Sleep» was more often observed in homozygotes according to the polymorphisms ABCB1 2677G&gt;T/A (50% vs. 15.8%, p=0.006) and 3435C&gt;T (41.7% vs. 8.2%, p=0.007). Carriers of TT polymorphism homozygote ABCB1 2677G&gt;T/A also more frequently noted «Polyuria/polydypsia» (37.5% vs. 5.18%, p=0.045). CONCLUSION.Genetic polymorphisms CYP2D6*4, *10, ABCB1 2677G&gt;T/A and 3435C&gt;T increased a risk of adverse drug effects of antipsychotics in adolescents with acute psychotic episode.

Association between serotonin 2A receptor (HTR2A), serotonin transporter (SLC6A4) and brain-derived neurotrophic factor (BDNF) gene polymorphisms and citalopram/sertraline induced sexual dysfunction in MDD patients.

Sexual dysfunction (SD) is a troublesome adverse effect of selective serotonin reuptake inhibitors (SSRIs). A variety of mechanisms might be involved in the occurrence of SD but the exact mechanism is still not clear. Genetic variations among patients treated with SSRIs are strong determinants of intolerance and poor compliance. The present study aimed to determine the relationship between serotonin-2A receptor (HTR2A) gene -1438A/G and 102T/C polymorphisms, serotonin transporter gene (SLC6A4) 5-HTT-linked polymorphic region (5-HTTLPR) insertion/deletion variant and brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphisms and the occurrence of SD adverse effect in major depressive disorder patients treated with citalopram (CIT) or sertraline (SERT). The result from this investigation revealed that the -1438A/G and 102T/C polymorphisms appear to be associated with the SD induced by CIT. It was also demonstrated that patients receiving SERT, carrying T allele of HTR2A or L allele of 5-HTTLPR more likely to experience SD. Most important overall finding of the study is the combined effects of -1438A/G, 102T/C, and 5-HTTLPR polymorphisms. In a logistic regression model, the occurrence of SD increased with the number of risky alleles. As compared with subjects receiving SERT with few risky (≤2) alleles, those with had 5-6 alleles had an increased SD risk. After all, according to these findings, -1438A/G, 102T/C, and 5-HTTLPR polymorphisms could be considered as promising pharmacogenetic biomarkers in CIT/SERT treatment in major depressive disorder (MDD) patients to avoid the occurrence of SD.

Damaging coding variants within kainate receptor channel genes are enriched in individuals with schizophrenia, autism and intellectual disabilities

Schizophrenia (Scz), autism spectrum disorder (ASD) and intellectual disability are common complex neurodevelopmental disorders. Kainate receptors (KARs) are ionotropic glutamate ion channels involved in synaptic plasticity which are modulated by auxiliary NETO proteins. Using UK10K exome sequencing data, we interrogated the coding regions of KAR and NETO genes in individuals with Scz, ASD or intellectual disability and population controls; performed follow-up genetic replication studies; and, conducted in silico and in vitro functional studies. We found an excess of Loss-of-Function and missense variants in individuals with Scz compared with control individuals (p = 1.8 × 10−10), and identified a significant burden of functional variants for Scz (p < 1.6 × 10−11) and ASD (p = 6.9 × 10−18). Single allele associations for 6 damaging missense variants were significantly replicated (p < 5.0 × 10−15) and confirmed GRIK3 S310A as a protective genetic factor. Functional studies demonstrated that three missense variants located within GluK2 and GluK4, GluK2 (K525E) and GluK4 (Y555N, L825W), affect agonist sensitivity and current decay rates. These findings establish that genetic variation in KAR receptor ion channels confers risk for schizophrenia, autism and intellectual disability and provide new genetic and pharmacogenetic biomarkers for neurodevelopmental disease.

Predictive genetic biomarkers for the efficacy of methotrexate in rheumatoid arthritis: a systematic review.

Multiple pharmacogenetic studies investigated the effectiveness of methotrexate. However, due to the use of nonvalidated outcomes, lack of validation or conflicting results it remains unclear if genetic markers can help to predict response to MTX treatment. Therefore, a systematic review was performed. PubMed was searched for articles reporting potential pharmacogenetic biomarkers associated (p < 0.05) with MTX efficacy using the validated endpoints DAS(28), EULAR, or ACR response criteria. The PICO method was used for study selection, and PRISMA guidelines to prepare the report. Thirty-five studies met the inclusion criteria, providing 39 potential genetic biomarkers in 19 genes. After Bonferroni correction, six genetic biomarkers were associated with the efficacy of MTX: ATIC rs7563206; SLC19A1 rs1051266; DHFR rs836788; TYMS rs2244500, rs2847153, and rs3786362 in at least one study. Only SLC19A1 rs1051266 was replicated in an independent cohort and promising for predicting methotrexate efficacy.

Vinca alkaloids, thalidomide and eribulin-induced peripheral neurotoxicity: From pathogenesis to treatment.

Vinca alkaloids, thalidomide, and eribulin are widely used to treat patients with childhood acute lymphoblastic leukemia (ALL), adults affected by multiple myeloma and locally invasive or metastatic breast cancer, respectively. However, soon after their introduction into clinical practice, chemotherapy-induced peripheral neurotoxicity (CIPN) emerged as their main non-hematological and among dose-limiting adverse events. It is generally perceived that vinca alkaloids and the antiangiogenic agent thalidomide are more neurotoxic, compared to eribulin. The exposure to these chemotherapeutic agents is associated with an axonal, length-dependent, sensory polyneuropathy of mild to moderate severity, whereas it is considered that the peripheral nerve damage, unless severe, usually resolves soon after treatment discontinuation. Advanced age, high initial and prolonged dosing, coadministration of other neurotoxic chemotherapeutic agents and pre-existing neuropathy are the common risk factors. Pharmacogenetic biomarkers might be used to define patients at increased susceptibility of CIPN. Currently, there is no established therapy for CIPN prevention or treatment; symptomatic treatment for neuropathic pain and dose reduction or withdrawal in severe cases is considered, at the cost of reduced cancer therapeutic efficacy. This review critically examines the pathogenesis, epidemiology, risk factors (both clinical and pharmacogenetic), clinical phenotype and management of CIPN as a result of exposure to vinca alkaloids, thalidomide and its analogue lenalidomide as also eribulin.

Evidence to Support Inclusion of Pharmacogenetic Biomarkers in Randomised Controlled Trials.

Pharmacogenetics and biomarkers are becoming normalised as important technologies to improve drug efficacy rates, reduce the incidence of adverse drug reactions, and make informed choices for targeted therapies. However, their wider clinical implementation has been limited by a lack of robust evidence. Suitable evidence is required before a biomarker’s clinical use, and also before its use in a clinical trial. We have undertaken a review of five pharmacogenetic biomarker-guided randomised controlled trials (RCTs) and evaluated the evidence used by these trials to justify biomarker inclusion. We assessed and quantified the evidence cited in published rationale papers, or where these were not available, obtained protocols from trial authors. Very different levels of evidence were provided by the trials. We used these observations to write recommendations for future justifications of biomarker use in RCTs and encourage regulatory authorities to write clear guidelines.

Concerns regarding use of patient-reported outcomes in biomarker studies of chemotherapy-induced peripheral neuropathy

Clinician-rated toxicity data has been systematically collected within oncology clinical research using the National Cancer Institute’s CTCAE scale, providing estimates of the occurrence and severity of toxicity from cancer treatment. CTCAE is being supplemented by collection of patient-reported outcome (PRO) toxicity within clinical research and clinical practice, where PRO has demonstrable benefits. There is general agreement that PRO data is more sensitive and reliable than CTCAE data, particularly for subjective adverse effects. Based on this premise, researchers have begun to use PRO toxicity data collected within prospective clinical trials as the primary endpoint to discover pharmacogenetic and other predictive biomarkers of treatment-related toxicity. This perspective raises caution about the superiority of PRO data to CTCAE data for biomarker research, particularly in regards to chemotherapy-induced peripheral neuropathy (PN). The reader is provided an introduction to PRO and their integration into clinical research and practice, comparisons of PN data collected by PRO and CTCAE, examples of attempts to use PRO PN data for biomarker discovery, and evidence suggesting that PRO may not be superior to CTCAE for PN biomarker studies. The perspective concludes with a proposed approach for empirically testing whether PRO or CTCAE data is the better option for use in PN biomarker research, which can serve as a model for similar comparisons within other treatment-related toxicities.

Prediction models for voriconazole pharmacokinetics based on pharmacogenetics: AN exploratory study in a Spanish population

Individualisation of the therapeutic strategy for the oral antifungal agent voriconazole (VCZ) is extremely important for treatment optimisation. To date, regulatory agencies include CYP2C19 as the only major pharmacogenetic (PGx) biomarker in their dosing guidelines; however, the effect of other genes might be important for VCZ dosing prediction. We developed an exploratory PGx study to identify new biomarkers related to VCZ pharmacokinetics. We first designed a 'clinical practice VCZ-AUC prediction model' based on CYP2C19 to be used as a reference model in this study. We then designed a multifactorial polygenic prediction model and found that genetic variability in FMO3, NR1I2, POR, CYP2C9 and CYP3A4 partially contributes to VCZ total area under the concentration-time curve (AUC0-∞) interindividual variability, and its inclusion in VCZ AUC0-∞ prediction algorithms improves model precision. To our knowledge, there are no PGx studies specifically relating POR, FMO3 and NR1I2 polymorphisms to VCZ pharmacokinetic variability. Further research is needed in order to test the model proposed here.

Pharmacogenetics of alcohol addiction: current perspectives.

Genetics of alcohol addiction is currently a contradictive and complex field, where data in the most studies reflect methods’ limitations rather than meaningful and complementary results. In our review, we focus on the genetics of alcohol addiction, leaving genetics of acute alcohol intoxication out of the scope. A review of the literature on pharmacogenetic biomarkers development for the pharmacotherapy personalization reveals that today the evidence base concerning these biomarkers is still insufficient. In particular, now the researches with the design of randomized controlled trials and meta-analysis investigating the effect of the SNPs as biomarkers on the therapy efficacy are available for naltrexone only. For other medications, there are only a few studies in small samples. It decreases the possibilities to implement the pharmacogenetic algorithms for the pharmacotherapy personalization in patients with alcohol use disorders (AUD). In view of the importance of the precision approaches development not in addiction medicine only, but in other fields of medicine also to increase the efficacy and safety of the therapy, studies on pharmacogenetic biomarkers development for the medications used in patients with AUD (eg, naltrexone, disulfiram, nalmefene, acamprosate, etc.) remain relevant to this day.

Pharmacogenetic biomarkers predictive of the pharmacokinetics and pharmacodynamics of immunosuppressive drugs

Pharmacogenetic biomarkers predictive of the pharmacokinetics and pharmacodynamics of immunosuppressive drugs

SA82 - HLA-DQB1 6672G>C INFLUENCES THE RISK OF CLOZAPINE-INDUCED AGRANULOCYTOSIS IN INDIVIDUALS OF EUROPEAN ANCESTRY

Background The atypical antipsychotic drug clozapine is the only effective drug for treatment-resistant schizophrenia, but also bears the risk of inducing severe adverse drug responses including neutropenia and agranulocytosis. Agranulocytosis and neutropenia occurs in about 1% and 3% of treated individuals. The aetiology is largely unknown, but there is evidence for contributing genetic factors. Identifying biomarkers could decrease blood monitoring effort and enable a more widespread use of clozapine. Several studies identified HLA variants (e.g. Athanasiou et al. 2011) and especially a polymorphism located in HLA-DBQ1 (6672 G>C, rs113332494) as associated with clozapine-induced agranulocytosis or neutropenia. Our study was conducted to replicate previous findings on HLA-DBQ1 6672 G>C. Methods The sample was comprised of individuals from sites of Finland, Germany, the Netherlands and the UK and was collected in the course of the CRESTAR project, which aimed at the development of pharmacogenetic biomarkers for schizophrenia. We analysed the risk allele distribution of rs113332494 in individuals of different ethnic background including 180 clozapine-induced neutropenia cases of which 61 developed agranulocytosis and 1396 controls treated with clozapine but not affected by this severe adverse drug response. We also performed association analyses in subsamples using logistic regression with an additive model seeking replication of previous findings on rs113332494. This CRESTAR project was funded by the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement #279227. Results rs113332494 was associated with neutropenia (OR=6.34, P=2.13E-06) and agranulocytosis (OR=9.59, P=1.11E-05) in individuals of European ancestry. The association signal was mainly driven by agranulocytosis cases. Discussion Our study gives further evidence of an implication of HLA-DQB1 in agranulocytosis. We were able to replicate previous findings. This implicates immune function as contributing process to this severe adverse drug response.

Pharmacogenetics Biomarkers Predictive of Drug Pharmacodynamics as an Additional Tool to Therapeutic Drug Monitoring.

Conventional therapeutic drug monitoring refers to the individualization of drug dosage by maintaining plasma or blood drug concentrations within a targeted therapeutic range. Accordingly, an individualized dose is proposed to the clinician according to the drug plasma or blood concentration using an a posteriori approach. Pharmacogenetics (PGx) has recently emerged as an additional tool to refine dose selection or, more interestingly to select, a priori, the first dose to administer. To date, the vast majority of genes explored in the context of PGx are those coding for metabolizing enzymes or membrane drug transporters, which mainly influence drug pharmacokinetics parameters. Indeed, among the 94 PGx-based drug dosing guidelines currently published by the Clinical Pharmacogenetics Implementation Consortium and the Dutch Pharmacogenetics Working Group on PharmGKB web site, 81 (86%) are associated with the genotype determination of either a metabolizing enzyme or a membrane drug transporter, whereas only 13 (14%) are associated with the genotype determination of a pharmacodynamics (PD)-associated gene. In this article, we describe selected PGx biomarkers that predict or could predict PD (both in terms of efficacy and toxicity). First, the most relevant clinical applications already subject to validated international guidelines (Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group), and ready to be implemented in routine clinical settings, are discussed to illustrate the clinical potential of PD-associated PGx biomarkers (G6PD, HLA-B*57:01, HLA-B*15:02, and VKORC1). Then, to illustrate not only the research potential of such biomarkers but also the complexity of PGx-PD relationships, the case of immunosuppressive drugs (for which conventional therapeutic drug monitoring is widely accepted) is extensively described with the potential to include some of these PGx biomarkers in future PGx dosing guidelines.