Showing papers in "Pharmacogenomics Journal in 2015"
TL;DR: The data indicate that endoxifen formation in premenopausal women depends on CYP2D6 irrespective of ethnicity, and low endoxIFen concentration/formation and decreased CYP 2D6 activity predict shorter DRFS.
Abstract: Tamoxifen is the standard-of-care treatment for estrogen receptor-positive premenopausal breast cancer. We examined tamoxifen metabolism via blood metabolite concentrations and germline variations of CYP3A5, CYP2C9, CYP2C19 and CYP2D6 in 587 premenopausal patients (Asians, Middle Eastern Arabs, Caucasian-UK; median age 39 years) and clinical outcome in 306 patients. N-desmethyltamoxifen (DM-Tam)/(Z)-endoxifen and CYP2D6 phenotype significantly correlated across ethnicities (R2: 53%, P 35 nM) endoxifen concentrations were associated with shorter DRFS (univariate P=0.03; multivariate HR=1.94; 95% CI, 1.04–4.14; P=0.064). Our data indicate that endoxifen formation in premenopausal women depends on CYP2D6 irrespective of ethnicity. Low endoxifen concentration/formation and decreased CYP2D6 activity predict shorter DRFS.
152 citations
TL;DR: A meta-analysis of studies evaluating the effect of CYP3A5 polymorphism on kidney transplant recipients with tacrolimus plasma concentration divided by daily dose per body weight and clinical outcomes concluded that the expresser genotype might have higher risk of acute rejection and chronic nephrotoxicity.
Abstract: The highly variable pharmacokinetics of tacrolimus can hamper the optimal management of kidney transplant patients. This variability has been attributed to the genetic polymorphism of CYP3A5 6986A>G, but the evidence is not clear. We conducted a meta-analysis of studies evaluating the effect of CYP3A5 polymorphism on kidney transplant recipients with tacrolimus plasma concentration divided by daily dose per body weight (C/D) and clinical outcomes. We searched in MEDLINE and EMBASE. We found evidence suggesting a significantly lower C/D among CYP3A5*1 allele carriers compared with carriers of the CYP3A5*3/*3 genotype at weeks 1 and 2, and months 1, 3, 6 and 12. We demonstrated that the expresser genotype might have higher risk of acute rejection and chronic nephrotoxicity. In conclusion, CYP3A5 6986A>G polymorphism can affect tacrolimus pharmacokinetics and the incidence of acute rejection and chronic nephrotoxicity on kidney transplant recipients. Patients at high risk of developing tacrolimus-related complications could be detected even before their kidney transplant.
112 citations
TL;DR: It is found that the number of drugs with pharmacogenomic labels in EU increases now steadily and that it will be an important task for the future to refine the legislation on how this information should be utilised for improvement of drug therapy.
Abstract: Pharmacogenomics (PGx) has a growing impact on healthcare and constitutes one of the major pillars of personalised medicine. For the purpose of improved individualised drug treatment, there is an increasing effort to develop drugs suitable for specific subpopulations and to incorporate pharmacogenomic drug labels in existing and novel medicines. Here, we review the pharmacogenomic drug labels of all 517 medicinal products centrally approved in the European Union (EU) since the establishment of the European Medicines Agency in 1995. We identified all pharmacogenomic-related information mentioned in the product labels and classified it according to its main effect and function on drug treatment, that is, metabolism, transport and pharmacodynamics, and according to the place of the respective section of the Summary of Product Characteristics (SmPC). The labels are preferentially present in drugs having antineoplastic properties. We find that the number of drugs with pharmacogenomic labels in EU increases now steadily and that it will be an important task for the future to refine the legislation on how this information should be utilised for improvement of drug therapy.
112 citations
TL;DR: Multigenic combinatorial testing discriminates and predicts the poorer antidepressant outcomes and greater health-care utilizations by depressed subjects better than do phenotypes derived from single genes.
Abstract: Clinical validity: Combinatorial pharmacogenomics predicts antidepressant responses and healthcare utilizations better than single gene phenotypes
89 citations
TL;DR: Children with GG and GA genotypes of ABCB1 polymorphism rs9282564 had higher risks of RD resulting in prolonged hospital stays; adding one copy of the minor allele (G) increased the odds of prolonged hospital stay due to postoperative RD by 4.7-fold.
Abstract: Opioid-related respiratory depression (RD) is a serious clinical problem as it causes multiple deaths and anoxic brain injuries. Morphine is subject to efflux via P-glycoprotein transporter encoded by ABCB1, also known as MDR1. ABCB1 polymorphisms may affect blood-brain barrier transport of morphine and therefore individual response to its central analgesic and adverse effects. This study aimed to determine specific associations between common ABCB1 genetic variants and clinically important outcomes including RD and RD resulting in prolonged stay in hospital with intravenous morphine in a homogenous pediatric surgical pain population of 263 children undergoing tonsillectomy. Children with GG and GA genotypes of ABCB1 polymorphism rs9282564 had higher risks of RD resulting in prolonged hospital stays; adding one copy of the minor allele (G) increased the odds of prolonged hospital stay due to postoperative RD by 4.7-fold (95% confidence interval: 2.1-10.8, P=0.0002).
78 citations
TL;DR: There is a statistically significant association between ABCB 1 polymorphisms, efficacy and toxicity in the treatment of ALL, and ABCB1 1199G>A may be a new possible predictive marker for outcome in childhood ALL.
Abstract: The membrane transporter P-glycoprotein, encoded by the ABCB1 gene, influences the pharmacokinetics of anti-cancer drugs. We hypothesized that variants of ABCB1 affect outcome and toxicity in childhood acute lymphoblastic leukemia (ALL). We studied 522 Danish children with ALL, 93% of all those eligible. Risk of relapse was increased 2.9-fold for patients with the 1199GA variant versus 1199GG (P=0.001), and reduced 61% and 40%, respectively, for patients with the 3435CT or 3435TT variants versus 3435CC (overall P=0.02). The degree of bone marrow toxicity during doxorubicin, vincristine and prednisolone induction therapy was more prominent in patients with 3435TT variant versus 3435CT/3435CC (P=0.01/P A may be a new possible predictive marker for outcome in childhood ALL.
78 citations
TL;DR: Methotrexate (MTX) is an effective and toxic chemotherapeutic drug in the treatment of pediatric acute lymphoblastic leukemia and only patients with the wild-type variant of rs7317112 SNP in the ABCC4 gene had more mucositis, and there was no evidence that erythrocyte folate levels mediate in the association between the rs73 17112 and mucositIS.
Abstract: Methotrexate (MTX) is an effective and toxic chemotherapeutic drug in the treatment of pediatric acute lymphoblastic leukemia(ALL). In this prospective study, we aimed to identify metabolic and genetic determinants of MTX toxicity. One hundred and thirty-four Dutch pediatric ALL patients were treated with four high infusions MTX (HD-MTX: 5 g m(-2)) every other week according to the DCOG-ALL-10 protocol. Mucositis (National Cancer Institute grade ⩾ 3) was the most frequent occurring toxicity during the HD-MTX phase (20%) and occurred especially after the first MTX course. Mucositis was not associated with plasma MTX, plasma folate or plasma homocysteine levels. Patients with mucositis had higher erythrocyte folate levels at the start of protocol M than patients without mucositis (median 1.4 vs 1.2 μmol l(-1), P<0.008), this could reflect an increased MTX uptake in mucosal cells of patients with mucositis. From 17 single-nucleotide polymorphisms in the MTX pathway, only patients with the wild-type variant of rs7317112 SNP in the ABCC4 gene had more mucositis (AA (39%) vs AG/GG (15%), P=0.016). We found no evidence that erythrocyte folate levels mediate in the association between the rs7317112 and mucositis.
53 citations
TL;DR: Using survival prediction analysis, three independent gene signatures which are associated with sensitivity of colorectal cancer cells to 5-FU, oxaliplatin or irinotecan are identified and three score systems were developed to stratify patients from sensitive to resistance.
Abstract: Different combinations of 5-fluorouracil (5-FU), oxaliplatin, irinotecan and other newly developed agents have been used to treat colorectal cancer. Despite the advent of new treatment regimens, the 5-year survival rate for metastatic colorectal cancer remains low (~10%). Knowing the drug sensitivity of a given tumor for a particular agent could significantly impact decision making and treatment planning. Biomarkers are proven to be successful in characterizing patients into different response groups. Using survival prediction analysis, we have identified three independent gene signatures, which are associated with sensitivity of colorectal cancer cells to 5-FU, oxaliplatin or irinotecan. On the basis of the three gene signatures, three score systems were developed to stratify patients from sensitive to resistance. These score systems exhibited robustness in stratify patients in two independent clinical studies. Patients with high scores in all three drugs exhibited the lowest survival.
50 citations
TL;DR: Two concurrent observations in stable renal allograft recipients are consistent with a reduced in vivo CYP3A4 activity for the CYP2A4*22T-allele, which is associated with lower dose requirements for tacrolimus.
Abstract: Tacrolimus, a dual substrate of CYP3A4 and CYP3A5 has a narrow therapeutic index and is characterized by high between-subject variability in oral bioavailability. This study investigated the effects of the recently described CYP3A4*22 intron 6 C>T single nucleotide polymorphism on in vivo CYP3A4 activity as measured by midazolam (MDZ) clearance and tacrolimus pharmacokinetics in two cohorts of renal allograft recipients, taking into account the CYP3A5*1/*3 genotype and other determinants of drug disposition. In CYP3A5 non-expressers, the presence of one CYP3A4*22T-allele was associated with a 31.7-33.6% reduction in MDZ apparent oral clearance, reflecting reduced in vivo CYP3A4 activity. In addition, at ⩾12 months after transplantation, steady-state clearance of tacrolimus was 36.8% decreased compared with homozygous CYP3A4*22CC-wild type patients, leading to 50% lower dose requirements. Both concurrent observations in stable renal allograft recipients are consistent with a reduced in vivo CYP3A4 activity for the CYP3A4*22T-allele.The Pharmacogenomics Journal advance online publication, 7 October 2014; doi:10.1038/tpj.2014.49.
49 citations
TL;DR: The world distribution and origin of CYP3A4*20 mutation is characterized and it is shown that this allele is compatible with a Spanish founder effect and classifies CYP 3A4 as a polymorphic enzyme.
Abstract: Cytochrome P450 3A4 (CYP3A4) is a key drug-metabolizing enzyme. Loss-of-function variants have been reported as rare events, and the first demonstration of a CYP3A4 protein lacking functional activity is caused by CYP3A4*20 allele. Here we characterized the world distribution and origin of CYP3A4*20 mutation. CYP3A4*20 was determined in more than 4000 individuals representing different populations, and haplotype analysis was performed using CYP3A polymorphisms and microsatellite markers. CYP3A4*20 allele was present in 1.2% of the Spanish population (up to 3.8% in specific regions), and all CYP3A4*20 carriers had a common haplotype. This is compatible with a Spanish founder effect and classifies CYP3A4 as a polymorphic enzyme. This constitutes the first description of a CYP3A4 loss-of-function variant with high frequency in a population. CYP3A4*20 results together with the key role of CYP3A4 in drug metabolism support screening for rare CYP3A4 functional alleles among subjects with adverse drug events in certain populations.
48 citations
TL;DR: Two data sets, each comprising data from healthy Japanese individuals of difference sample sizes, were used to build custom classifiers and these classifiers can be used to supplement the current lack of HLA genotyping data in widely available genome-wide association study data sets.
Abstract: Statistical imputation of classical human leukocyte antigen (HLA) alleles is becoming an indispensable tool for fine-mappings of disease association signals from case–control genome-wide association studies. However, most currently available HLA imputation tools are based on European reference populations and are not suitable for direct application to non-European populations. Among the HLA imputation tools, The HIBAG R package is a flexible HLA imputation tool that is equipped with a wide range of population-based classifiers; moreover, HIBAG R enables individual researchers to build custom classifiers. Here, two data sets, each comprising data from healthy Japanese individuals of difference sample sizes, were used to build custom classifiers. HLA imputation accuracy in five HLA classes (HLA-A, HLA-B, HLA-DRB1, HLA-DQB1 and HLA-DPB1) increased from the 82.5–98.8% obtained with the original HIBAG references to 95.2–99.5% with our custom classifiers. A call threshold (CT) of 0.4 is recommended for our Japanese classifiers; in contrast, HIBAG references recommend a CT of 0.5. Finally, our classifiers could be used to identify the risk haplotypes for Japanese narcolepsy with cataplexy, HLA-DRB1*15:01 and HLA-DQB1*06:02, with 100% and 99.7% accuracy, respectively; therefore, these classifiers can be used to supplement the current lack of HLA genotyping data in widely available genome-wide association study data sets.
TL;DR: The mRNA expression patterns of predictive and prognostic biomarkers, as well as associations with KRAS and BRAF mutation status depend on primary tumor location.
Abstract: Colorectal cancer (CRC) is a heterogeneous disease with genetic profiles and clinical outcomes dependent on the anatomic location of the primary tumor. How location has an impact on the molecular makeup of a tumor and how prognostic and predictive biomarkers differ between proximal versus distal colon cancers is not well established. We investigated the associations between tumor location, KRAS and BRAF mutation status, and the messenger RNA (mRNA) expression of proteins involved in major signaling pathways, including tumor growth (epidermal growth factor receptor (EGFR)), angiogenesis (vascular endothelial growth factor receptor 2 (VEGFR2)), DNA repair (excision repair cross complement group 1 (ERCC1)) and fluoropyrimidine metabolism (thymidylate synthase (TS)). Formalin-fixed paraffin-embedded tumor specimens from 431 advanced CRC patients were analyzed. The presence of seven different KRAS base substitutions and the BRAF V600E mutation was determined. ERCC1, TS, EGFR and VEGFR2 mRNA expression levels were detected by reverse transcriptase-PCR. BRAF mutations were significantly more common in the proximal colon (P<0.001), whereas KRAS mutations occurred at similar frequencies throughout the colorectum. Rectal cancers had significantly higher ERCC1 and VEGFR2 mRNA levels compared with distal and proximal colon tumors (P=0.001), and increased TS levels compared with distal colon cancers (P=0.02). Mutant KRAS status was associated with lower ERCC1, TS, EGFR and VEGFR2 gene expression in multivariate analysis. In a subgroup analysis, this association remained significant for all genes in the proximal colon and for VEGFR2 expression in rectal cancers. The mRNA expression patterns of predictive and prognostic biomarkers, as well as associations with KRAS and BRAF mutation status depend on primary tumor location. Prospective studies are warranted to confirm these findings and determine the underlying mechanisms.
TL;DR: Genotyping of MRP4 genotyping may be useful for personalizing the therapeutic dose of 6-MP during the ALL maintenance therapy in Japanese.
Abstract: Multidrug resistance protein 4 ( MRP4 ) polymorphisms impact the 6-mercaptopurine dose tolerance during maintenance therapy in Japanese childhood acute lymphoblastic leukemia
TL;DR: In this paper, the authors performed a meta-analysis by combining data from a total of 12 reports including 1826 patients and found that the 2677G allele or 3435T allele predicted a worse response to imatinib in CML patients, whereas the 1236CC genotype was associated with better response in patients from Asian region.
Abstract: Imatinib mesylate, a competitive tyrosine kinase inhibitor, is considered the first-line therapy drug for Ph+ chronic myeloid leukemia (CML). Three single-nucleotide polymorphisms (SNPs) in the ATP-binding cassette, subfamily B (MDR/TAP), member 1 gene (ABCB1/MDR1), c.1236C>T, c.2677G>T/A and c.3435C>T, have been shown to affect cellular transport/metabolism of imatinib. The associations between these SNPs and imatinib response in CML patients have been widely evaluated, but the results were inconsistent. To derive a conclusive assessment of the associations, we performed a meta-analysis by combining data from a total of 12 reports including 1826 patients. The results showed that the 2677G allele or 3435T allele predicted a worse response to imatinib in CML patients, whereas 1236CC genotype was associated with better response in CML patients from Asian region. In conclusion, this meta-analysis suggests that c.1236C>T, c.2677G>T/A and c.3435C>T can be served as predictive markers for the therapeutical use of imatinib in CML patients.
TL;DR: Previous observations that minor alleles of two ABCB1 SNPs predict remission to treatment with substrates are confirmed and extended and it is demonstrated that common homozygotes on these SNPs experience greater side effects.
Abstract: The hypothesis that allelic variation in the multidrug resistance-1 (MDR1 or ABCB1) gene encoding the P-glycoprotein (P-gp) blood–brain barrier efflux pump is associated with remission and side effects was tested in chronic major depression patients treated with P-gp substrates. In 83 patients from the REVAMP trial, frequency of and time to remission as well as side effects was tested among genotype groups at 6 ABCB1 single nucleotide polymorphisms (SNPs). These six SNPs are significantly associated with remission and time to remission, with minor allele carriers on rs2235040 and rs9282564 attaining statistical significance after controlling for the other ABCB1 SNPs. The six ABCB1 SNPs are also significantly associated with the average side effects. However, here common homozygotes on rs2235040 and rs9282564 demonstrated significantly higher side effects after controlling for the effects of the other ABCB1 SNPs. These findings confirm and extend previous observations that minor alleles of two ABCB1 SNPs predict remission to treatment with substrates and demonstrate that common homozygotes on these SNPs experience greater side effects. Results point to the potential importance of ABCB1 variation for personalized medicine approaches to treating depression.
TL;DR: This study reveals a general picture of pharmacogenomic control for asthma intervention and implements a mechanistic model to analyze the GWAS data, enhancing the scope of inference about the genetic architecture of asthma intervention.
Abstract: Asthma is a chronic lung disease that has a high prevalence. The therapeutic intervention of this disease can be made more effective if genetic variability in patients' response to medications is implemented. However, a clear picture of the genetic architecture of asthma intervention response remains elusive. We conducted a genome-wide association study (GWAS) to identify drug response-associated genes for asthma, in which 909 622 SNPs were genotyped for 120 randomized participants who inhaled multiple doses of glucocorticoids. By integrating pharmacodynamic properties of drug reactions, we implemented a mechanistic model to analyze the GWAS data, enhancing the scope of inference about the genetic architecture of asthma intervention. Our pharmacodynamic model observed associations of genome-wide significance between dose-dependent response to inhaled glucocorticoids (measured as %FEV1) and five loci (P=5.315 × 10(-7) to 3.924 × 10(-9)), many of which map to metabolic genes related to lung function and asthma risk. All significant SNPs detected indicate a recessive effect, at which the homozygotes for the mutant alleles drive variability in %FEV1. Significant associations were well replicated in three additional independent GWAS studies. Pooled together over these three trials, two SNPs, chr6 rs6924808 and chr11 rs1353649, display an increased significance level (P=6.661 × 10(-16) and 5.670 × 10(-11)). Our study reveals a general picture of pharmacogenomic control for asthma intervention. The results obtained help to tailor an optimal dose for individual patients to treat asthma based on their genetic makeup.
TL;DR: The results indicate that the risks associated with PPI use among clopidogrel-treated Caucasian post-MI patients are impacted by CYP2C19 genotype, and suggest knowledge of genotype may be useful for personalizing P PI use among patients following AMI to reduce rehospitalization.
Abstract: We examined clinical outcomes with proton pump inhibitors (PPI) use within CYP2C19 genotype groups during clopidogrel treatment following acute myocardial infarction (AMI). 2062 patients were genotyped for CYP2C19*2 and *17 variants in TRIUMPH. 12 month clinical outcomes were analyzed among patients discharged on clopidogrel within CYP2C19*2 carrier, CYP2C19*17 carrier, and CYP2C19*1 homozygote genotype groups. PPI use was not associated with a difference in mortality. Among clopidogrel-treated Caucasians following AMI, PPI use was associated with a significantly higher rate of cardiac rehospitalization (HR 1.62, 95% CI 1.19-2.19; P=0.002) compared with no PPI use. PPI users who were carriers of the CYP2C19*17 variant experienced significantly higher rates of cardiac rehospitalization (HR 2.05, 95% CI 1.26-3.33; P=0.003), carriers of the CYP2C19*2 variant had a trend toward increased 1-year cardiac rehospitalization (HR 1.69, 95% CI 0.95-2.99; P=0.07), while no significant differences were observed among CYP2C19*1 homozygotes. These results indicate that the risks associated with PPI use among clopidogrel-treated Caucasian post-MI patients are impacted by CYP2C19 genotype, and suggest knowledge of genotype may be useful for personalizing PPI use among patients following AMI to reduce rehospitalization.
TL;DR: SN gene co-expression analysis revealed a highly connected network, demonstrating coordinated patterns of gene expression and highlighting alcohol-responsive biological pathways, such as long-term potentiation, long- term depression, glutamate signaling, RNA processing and upregulation of alcohol- responsive genes within neuroimmune modules.
Abstract: Chronic alcohol consumption changes gene expression, likely causing persistent remodeling of synaptic structures via altered translation of mRNAs within synaptic compartments of the cell. We profiled the transcriptome from synaptoneurosomes (SNs) and paired total homogenates (THs) from mouse amygdala following chronic voluntary alcohol consumption. In SN, both the number of alcohol-responsive mRNAs and the magnitude of fold-change were greater than in THs, including many GABA-related mRNAs upregulated in SNs. Furthermore, SN gene co-expression analysis revealed a highly connected network, demonstrating coordinated patterns of gene expression and highlighting alcohol-responsive biological pathways, such as long-term potentiation, long-term depression, glutamate signaling, RNA processing and upregulation of alcohol-responsive genes within neuroimmune modules. Alterations in these pathways have also been observed in the amygdala of human alcoholics. SNs offer an ideal model for detecting intricate networks of coordinated synaptic gene expression and may provide a unique system for investigating therapeutic targets for the treatment of alcoholism.
TL;DR: A prospective genotype-blinded study conducted in 88 healthy adolescents who underwent spine fusion for scoliosis showed that the risk of MIRD in patients with AA genotype was significantly higher, and presence of G allele was associated with higher pain scores.
Abstract: The μ1 opioid receptor (OPRM1) genetic variant A118G results in decreased μ-receptor binding potential in the brain and increases morphine requirement. We hypothesized that OPRM1 A118G polymorphism will affect morphine-induced respiratory depression (MIRD) risk in children receiving morphine. A prospective genotype-blinded study was conducted in 88 healthy adolescents (11-18 years; 67% female, 85% Caucasian) who underwent spine fusion for scoliosis. They were followed for 48 h postoperatively for MIRD, pain scores, morphine consumption and use of analgesic adjuvants. Patients were genotyped for OPRM1 A118G variant-76% were wild type (AA) and 24% heterozygous/homozygous for variant (AG/GG). Multivariable logistic regression showed that the risk of MIRD in patients with AA genotype was significantly higher (odds ratio 5.6, 95% CI: 1.4-37.2, P=0.030). Presence of G allele was associated with higher pain scores (effect size 0.73, P=0.045). This novel association is an important step toward predicting MIRD susceptibility and personalizing morphine use.
TL;DR: Specific FAAH polymorphisms are associated with refractory PONV, opioid-related RD, and prolonged PACU stay due to opioid adverse effects in white children undergoing tonsillectomy.
Abstract: Opioid effects are potentiated by cannabinoid agonists including anandamide, an endocannabinoid. Inter-individual variability in responses to opioids is a major clinical problem. Multiple deaths and anoxic brain injuries occur every year because of opioid-induced respiratory depression (RD) in surgical patients and drug abusers of opioids and cannabinoids. This study aimed to determine specific associations between genetic variants of fatty acid amide hydrolase (FAAH) and postoperative central opioid adverse effects in children undergoing tonsillectomy. This is a prospective genotype-blinded observational study in which 259 healthy children between 6 and 15 years of age who received standard perioperative care with a standard anesthetic and an intraoperative dose of morphine were enrolled. Associations between frequent polymorphisms of FAAH and central postoperative opioid adverse effects including, RD, postoperative nausea and vomiting (PONV) and prolonged stay in Post Anesthesia Recovery Room (postoperative anesthesia care unit, PACU) due to RD and PONV were analyzed. Five specific FAAH single nucleotide polymorphisms (SNPs) had significant associations with more than twofold increased risk for refractory PONV (adjusted P<0.0018), and nominal associations (P<0.05) with RD and prolonged PACU stay in white children undergoing tonsillectomy. The FAAH SNP, rs324420, is a missense mutation with altered FAAH function and it is linked with other FAAH SNPs associated with PONV and RD in our cohort; association between PONV and rs324420 was confirmed in our extended cohort with additional 66 white children. Specific FAAH polymorphisms are associated with refractory PONV, opioid-related RD, and prolonged PACU stay due to opioid adverse effects in white children undergoing tonsillectomy.
TL;DR: This review focuses exclusively on those drugs for which some pharmacogenetic data are available, and aims at highlighting the need for further clinical research in this area.
Abstract: The SCL22A1 gene encodes the broad selectivity transporter hOCT1. hOCT1 is expressed in most epithelial barriers thereby contributing to drug pharmacokinetics. It is also expressed in different drug target cells, including immune system cells and others. Thus, this membrane protein might also contribute to drug pharmacodynamics. Up to 1000 hOCT1 polymorphisms have been identified so far, although only a small fraction of those have been mechanistically studied. A paradigm in the field of drug transporter pharmacogenetics is the impact of hOCT1 gene variability on metformin clinical parameters, affecting area under the concentration-time curve, Cmax and responsiveness. However, hOCT1 also mediates the translocation of a variety of drugs used as anticancer, antiviral, anti-inflammatory, antiemetic agents as well as drugs used in the treatment of neurological diseases among. This review focuses exclusively on those drugs for which some pharmacogenetic data are available, and aims at highlighting the need for further clinical research in this area.
TL;DR: Seven cohort studies were found showing a significantly higher overall survival among carriers of the variant allele of 1236C>T at year 4, and Caucasians carrying variant allele showed consistent results in OS, while ABCB1 influence upon complete remission could not be demonstrated.
Abstract: The ABCB1 gene encodes for P-glycoprotein (P-gp), an efflux pump for a variety of xenobiotics. The role of ABCB1 polymorphisms in acute myeloid leukemia (AML) outcomes of standard chemotherapy (cytarabine plus anthracyclines) remains controversial. A systematic search was made of studies evaluating the association between ABCB1 polymorphisms 1236C>T, 2677G>T/A and 3435C>T and effectiveness variables. We found seven cohort studies (1241 patients) showing a significantly higher overall survival (OS) among carriers of the variant allele of 1236C>T at year 4 (odds ratio (OR): 1.47, 95% confidence interval (CI): 1.07-2.01), 2677G>T/A at years 4-5 (OR: 1.37, 95% CI: 1.01-1.86) and 3435C>T at years 3 (OR: 1.41, 95% CI: 1.03-1.94) and 4-5 (OR: 1.42, 95% CI: 1.05-1.91). In the subgroup analysis according to ethnicity, Caucasians carrying variant allele showed consistent results in OS. ABCB1 influence upon complete remission could not be demonstrated. Future studies based on larger populations and multiethnic groups should help clarify the effect of P-gp polymorphisms upon other outcomes.
University of Bologna1, University of Messina2, Tel Aviv University3, Federal Institute for Drugs and Medical Devices4, University of Bonn5, Mario Negri Institute for Pharmacological Research6, Medical University of Vienna7, Sheba Medical Center8, Université libre de Bruxelles9, Imperial College London10
TL;DR: GAP43 molecular pathway was associated with both response and remission in the STAR*D, with ELAVL4 representing the gene with the highest percentage of single nucleotide polymorphisms (SNPs) associated with outcomes.
Abstract: Drug-effect phenotypes in human lymphoblastoid cell lines recently allowed to identify CHL1 (cell adhesion molecule with homology to L1CAM), GAP43 (growth-associated protein 43) and ITGB3 (integrin beta 3) as new candidates for involvement in the antidepressant effect. CHL1 and ITGB3 code for adhesion molecules, while GAP43 codes for a neuron-specific cytosolic protein expressed in neuronal growth cones; all the three gene products are involved in synaptic plasticity. Sixteen polymorphisms in these genes were genotyped in two samples (n=369 and 90) with diagnosis of major depressive episode who were treated with antidepressants in a naturalistic setting. Phenotypes were response, remission and treatment-resistant depression. Logistic regression including appropriate covariates was performed. Genes associated with outcomes were investigated in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) genome-wide study (n=1861) as both individual genes and through a pathway analysis (Reactome and String databases). Gene-based analysis suggested CHL1 rs4003413, GAP43 rs283393 and rs9860828, ITGB3 rs3809865 as the top candidates due to their replication across the largest original sample and the STAR*D cohort. GAP43 molecular pathway was associated with both response and remission in the STAR*D, with ELAVL4 representing the gene with the highest percentage of single nucleotide polymorphisms (SNPs) associated with outcomes. Other promising genes emerging from the pathway analysis were ITGB1 and NRP1. The present study was the first to analyze cell adhesion genes and their molecular pathways in antidepressant response. Genes and biomarkers involved in neuronal adhesion should be considered by further studies aimed to identify predictors of antidepressant response.
TL;DR: The direct PCR represents a good alternative to the traditional methods of HLA-B*57:01 pharmacogenetic test, especially for those laboratories or countries where currently available approaches are often not available or not affordable.
Abstract: One of the most successful applications of pharmacogenetics research is the genetic screening for HLA-B*57:01, strongly associated with an increased risk to develop hypersensitivity reaction in HIV-positive patients following abacavir administration. Taking into consideration the limits of current genotyping methodologies, we have developed and validated (150 buccal swabs) an inexpensive pharmacogenetic approach for HLA-B*57:01 typing. In our assay DNA extraction and amplification are combined in one single step (direct PCR protocol), which is performed directly on the biological sample without the need of extraction and sequencing passages. The amplicons obtained by direct PCR can be easily separated on the agarose gel under ultraviolet. As per our results, the direct PCR represents a good alternative to the traditional methods of HLA-B*57:01 pharmacogenetic test, especially for those laboratories or countries where currently available approaches are often not available or not affordable. Furthermore it is an innovative approach, promoting a personalized, safer and cost-effective therapy.
TL;DR: This first study to identify pericyte germline polymorphisms associated with clinical outcome in mCRC patients treated first line with FOLFIRI+bevacizumab finds that the biomarker value of the SNPs was dependent on primary tumor location.
Abstract: Pericytes are crucial for angiogenesis. The impact of pericyte function to bevacizumab efficacy in mCRC treatment has not been comprehensively examined. This retrospective study investigated germline polymorphisms in genes related to early pericyte maturation to predict bevacizumab efficacy in 424 patients of two clinical trials treated first line with FOLFIRI+bevacizumab. Eight single-nucleotide polymorphisms (SNPs) were tested for potential biomarker value: RGS5 (regulator of G-protein signaling 5; rs1056515, rs2661280), PDGFR-β (platelet-derived growth factor receptor-β; rs2229562, rs2302273), CSPG4 (chondroitin sulfate proteoglycan NG2; rs8023621, rs1127648) and RALBP1 (RalA binding protein 1; rs10989, rs329007). For progression-free survival (PFS), PDGFR-β (rs2302273) was able to define significantly different patient cohorts in uni- and multivariate testing. RALPB1 (rs329007) showed predictive value for tumor response. The C allele in RGS5 (rs2661280) predicted longer overall survival and CSPG4 rs1127648 was associated with differences in PFS, but for both value was lost when multivariate analysis was applied. A comprehensive statistical analysis revealed that the biomarker value of the SNPs was dependent on primary tumor location. This is the first study to identify pericyte germline polymorphisms associated with clinical outcome in mCRC patients treated first line with FOLFIRI+bevacizumab. The differences seen with regard to primary tumor location may lead to further research to understand the clinical outcome differences seen in right- and left-sided colon cancer.
TL;DR: The study suggests that germ-line variants in the MTX metabolic pathway are associated with survival and side effects in patients treated with MTX.
Abstract: Osteosarcoma patients are commonly treated with high doses of methotrexate (MTX). MTX is an analog of folate, which is essential for DNA synthesis. Genetic polymorphism at single nucleotide can be indicative to the prognostic outcome in patients. Germ-line variants in candidate genes, coding for enzymes active in the metabolism of MTX, were studied in 62 osteosarcoma patients. Patients harboring the GG genotype in reduced folate carrier 1 (RFC1) rs1051266 had significantly better survival in comparison with patients having the AA genotype (P=0.046). These patients also had a lower frequency of metastasis (15%, P=0.029). Also patients homozygous for the G allele of rs1053129 in the dihydrofolate reductase (DHFR) gene were more likely to have a metastasis (45%, P= 0.005), and the methylenetetetrahydrofolate reductase (MTHFR) 677C allele was associated with higher degree of liver toxicity (88%, P=0.007). The study suggests that germ-line variants in the MTX metabolic pathway are associated with survival and side effects in patients treated with MTX.
TL;DR: A highly significant association is found between PDE3A-SLCO1C1 and the clinical response to TNF blockers and the allele that was previously associated with the lack of response to rheumatoid arthritis was associated with a higher anti-TNF efficacy in psoriasis.
Abstract: Psoriasis is a prevalent autoimmune disease of the skin that causes significant psychological and physical disability. Tumor necrosis factor (TNF)-blocking agents have proven to be highly efficacious in the management of moderate-to-severe psoriasis. However, a significant percentage of patients do not respond to this treatment. Recently, variation at the PDE3A-SLCO1C1 (phosphodiesterase 3A-SoLute Carrier Organic anion transporter family member 1C1) locus has been robustly associated with anti-TNF response in rheumatoid arthritis. Using a cohort of 130 psoriasis patients treated with anti-TNF therapy, we sought to analyze the association of this locus with treatment response in psoriasis. We found a highly significant association between PDE3A-SLCO1C1 and the clinical response to TNF blockers (P=0.0031). Importantly, the allele that was previously associated with the lack of response to rheumatoid arthritis (G allele, single-nucleotide polymorphism rs3794271) was associated with a higher anti-TNF efficacy in psoriasis. The results of this study are an important step in the characterization of the pharmacogenetic profile associated with anti-TNF response in psoriasis.
TL;DR: Findings will assist in customizing therapy to effectively manage postpartum pain by examining select genetic polymorphisms in the codeine pharmacological pathway.
Abstract: The objective of this study was to examine interindividual variability in codeine requirements and pain management by examining select genetic polymorphisms in the codeine pharmacological pathway. The study included a nested cohort of 98 women who were prescribed codeine following cesarean section. Participants were genotyped for select polymorphisms of the COMT, ABCB1, CYP2D6, UGT2B7 and OPRM1 genes and instructed to describe their level of pain using the visual analog scale (mm) 1 h following each dose of codeine. Analysis revealed that reported pain increases with maternal age (P=0.041). Asians required more codeine than Caucasians (P=0.048). Significant differences in mean dose consumption were seen among the genotypic groups of the OPRM1 A118G (P=0.001) and UGT2B7 C802T (P=0.015) variants. These variants were found to predict codeine consumption in the cohort overall (P=0.000) and among Caucasians (P=0.001). These findings will assist in customizing therapy to effectively manage postpartum pain.
TL;DR: Results indicate that NEGR1 could be an important locus influencing certain personality dimensions in BN patients and associated with psychological traits commonly displayed by eating disorder patients and/or with the risk for the disorder.
Abstract: Genetics variants in the NEGR1 gene, strongly expressed in the brain, have been reported to affect the neuronal control of food intake therefore inducing obesity. With the same rationale, we hypothesized that this genetic variability may be associated with psychological traits commonly displayed by eating disorder (ED) patients and/or with the risk for the disorder. We analyzed 21 tag-single-nucleotide polymorphisms (SNPs) in the coding sequence and adjacent regions of the NEGR1 gene. A total of 169 ED patients (106 with anorexia nervosa (AN) and 63 with bulimia nervosa (BN)) and 312 healthy subjects were genotyped. Personality traits and general psychopathological symptoms were assessed by the Eating Disorders Inventory Test-2 (EDI-2) and Symptom Checklist 90 Revised inventories. None of the SNPs or haplotypes analyzed were associated with a greater risk of ED or correlated with anthropometric parameters. However, in patients with BN, four SNPs (rs12740031, rs10789322, rs6659202 and rs591540) correlated with the scores in Drive for Thinness (DT), Ineffectiveness (I) and Interoceptive Awareness (IA) (Bonferroni-P<0.05 in all instances). The first two SNPs along with rs954299 and rs2422021 formed a haplotype block, which showed a consistent association with the EDI-2 score in BN patients (Bonferroni-P=0.01). A subsequent three-SNP sliding-window approach identified a central area, encompassing both the haplotype block and the individually relevant SNPs that strongly correlated with the scores of BN patients in DT, I, IA and Bulimia. No associations were identified in the AN group. These preliminary results indicate that NEGR1 could be an important locus influencing certain personality dimensions in BN patients.
TL;DR: Patients with a high CYP2D6-CYP2C19 metabolic capacity showed an increased risk for a severe suicide attempt, and the risk was greater in those without a family history of suicide.
Abstract: This study examined, for the first time, whether a high CYP2D6-CYP2C19 metabolic capacity combination increases the likelihood of suicidal intent severity in a large study cohort. Survivors of a suicide attempt (n=587; 86.8% women) were genotyped for CYP2C19 (*2, *17) and CYP2D6 (*3, *4, *4xN, *5, *6, *10, wtxN) genetic variation and evaluated with the Beck Suicide Intent Scale (SIS). Patients with a high CYP2D6-CYP2C19 metabolic capacity showed an increased risk for a severe suicide attempt (P<0.01) as measured by the SIS-objective circumstance subscale (odds ratio (OR)=1.37; 95% confidence interval (CI)=1.05-1.78; P=0.02) after adjusting for confounders (gender, age, level of studies, marital status, mental disorders, tobacco use, family history of suicide, personal history of attempts and violence of the attempt). Importantly, the risk was greater in those without a family history of suicide (OR=1.82; CI=1.19-2.77; P=0.002). Further research is warranted to evaluate whether the observed relationship is mediated by the role of CYP2D6 and CYP2C19 involvement in the endogenous physiology or drug metabolism or both.