The discovery of pharmacogenomic markers in colorectal cancer (CRC) could be setting-specific. FOLFOX4 is employed in the adjuvant and metastatic setting in CRC. This prospective study is aimed to validate in the adjuvant setting the pharmacogenomic markers of toxicity reported in the metastatic setting (that is, GSTP1-rs947894, and -rs1138272; GSTM1-null genotype; AGXT-rs4426527, -rs34116584 and del-74 bp), and to discover additional markers. CRC patients (n = 144) treated with adjuvant FOLFOX4 were genotyped for 57 polymorphisms in 29 genes. Grade ≥2 neurotoxicity was associated false discovery rate-adjusted q-value <0.1) with single-nucleotide polymorphisms in ABCC1 (rs2074087: odds ratio = 0.43(0.22–0.86)), and ABCC2 (rs3740066: 2.99(1.16–7.70); rs1885301: 3.06(1.35–6.92); rs4148396: 4.69(1.60–13.74); rs717620: 14.39(1.63–127.02)). hMSH6-rs3136228 was associated with grade 3–4 neutropenia (3.23(1.38–7.57), q-value = 0.0937). XRCC3-rs1799794 was associated with grade 3–4 non-hematological toxicity (8.90(2.48–31.97), q-value = 0.0150). The markers previously identified in metastatic CRC were not validated. We have identified new markers of toxicity in genes of transport and DNA repair. If validated in other studies, they could help to identify patients at risk of toxicity.
pharmacogenomics; FOLFOX4; colorectal cancer; neurotoxicity
A possible side effect of serotonin-enhancing drugs is the serotonin syndrome, which can be lethal. Here we examined possible hypersensitivity to two such drugs, the serotonin precursor 5-hydroxy-L-tryptophan (5-HTP) and the atypical opioid tramadol, in mice lacking the genes for both monoamine oxidase A (MAOA) and MAOB. MAOA/B-knockout (KO) mice displayed baseline serotonin syndrome behaviors, and these behavioral responses were highly exaggerated following 5-HTP or tramadol versus baseline and wild-type (WT) littermates. Compared with MAOA/B-WT mice, baseline tissue serotonin levels were increased ~2.6–3.9-fold in MAOA/B-KO mice. Following 5-HTP, serotonin levels were further increased ~4.5–6.2-fold in MAOA/B-KO mice. These exaggerated responses are in line with the exaggerated responses following serotonin-enhancing drugs that we previously observed in mice lacking the serotonin transporter (SERT). These findings provide a second genetic mouse model suggestive of possible human vulnerability to the serotonin syndrome in individuals with lesser-expressing MAO or SERT polymorphisms that confer serotonergic system changes.
5-hydroxy-L-tryptophan (5-HTP); monoamine oxidase (MAO) A/B-knockout mice; serotonin syndrome; tramadol
A recent genome-wide analysis discovered an association between a haplotype (from rs317689/rs315135/rs7297610) on Chromosome 12q15 and blood pressure response to hydrochlorothiazide in African-Americans. Our aim was to replicate this association and investigate possible functional mechanisms. We observed similar associations between this haplotype and hydrochlorothiazide response in an independent sample of 746 Caucasians and African-Americans randomized to hydrochlorothiazide or atenolol treatment. The haplotype association was driven by variation at rs7297610, where C/C genotypes were associated with greater mean (systolic: 3.4mmHg, P=0.0275; diastolic: 2.5mmHg, P=0.0196) responses to hydrochlorothiazide vs. T-allele carriers. Such an association was absent in atenolol-treated participants, supporting this as hydrochlorothiazide-specific. Expression analyses in hydrochlorothiazide-treated African-Americans showed differential leukocyte YEATS4 expression between rs7297610 genotype groups at baseline (P=0.024), and reduced expression in C/C genotypes (P=0.009), but not in T-carriers. Our data confirm previous genome-wide findings at 12q15 and suggest differential YEATS4 expression could underpin rs7297610-associated HCTZ response variability, which may have future implications for guiding thiazide treatment.
hydrochlorothiazide; hypertension; pharmacogenomics; blood pressure; YEATS4; diuretics
Alterations in expression of a cannabinoid receptor (CNR1, CB1), and of fatty acid amide hydrolase (FAAH) that degrades endogenous ligands of CB1, may contribute to the development of addiction. The 385C>A in the FAAH gene and six polymorphisms of CNR1 were genotyped in former heroin addicts and control subjects (247 Caucasians, 161 Hispanics, 179 African Americans and 19 Asians). In Caucasians, long repeats (≥14) of 18087–18131 (TAA)8–17 were associated with heroin addiction (P = 0.0102). Across three ethnicities combined, a highly significant association of long repeats with heroin addiction was found (z = 3.322, P = 0.0009). Point-wise significant associations of allele 1359A (P= 0.006) and genotype 1359AA (P= 0.034) with protection from heroin addiction were found in Caucasians. Also in Caucasians, the genotype pattern, 1359G>A and −6274A>T, was significantly associated with heroin addiction experiment wise (P= 0.0244). No association of FAAH 385C>A with heroin addiction was found in any group studied.
drug addiction; SNPs; CB1; CNR1; FAAH; haplotypes
Recent studies suggest CD133, a surface protein widely used for isolation of colon cancer stem cells, to be associated with tumor angiogenesis and recurrence. We hypothesized that gene expression levels and germline variations in CD133 will predict clinical outcome in patients with mCRC, treated in first-line setting with 5-FU, oxaliplatin and bevacizumab and we investigated whether there is a correlation with gene expression levels of CD133, vascular endothelial growth factor (VEGF) and its receptors.
We evaluated intra-tumoral gene expression levels by quantitative RT-PCR from 54 patients and 3 germline variants of the CD133 gene by PCR-RFLP from 91 patients with genomic DNA. High gene expression levels of CD133 (>7.76) conferred a significantly greater tumor response (RR=86%) than patients with low expression levels (≤7.76, RR=38%, adjusted p=0.003), independent of VEGF or its receptor gene expression levels. Gene expression levels of CD133 were significantly associated with VEGF and its receptors mRNA levels (VEGFR-1 (p<.01), -2, and -3, p<0.05). Combined analyses of two polymorphisms showed a significant association with PFS (18.5 months vs 9.8 months, p=0.004), in multivariate analysis as an independent prognostic factor for PFS (adjusted p=0.002). These results suggest CD133 is a predictive marker for standard first-line bevacizumab-based treatment in mCRC.
CD133; Prominin-1; bevacizumab; predictive markers; molecular markers; colorectal cancer
A pro-asthmatic culture milieu and β2-agonist (isoproterenol) were previously shown to regulate the expression of select transcription factors (TFs) within human airway epithelial and smooth muscle cells. This study tests 1116 single nucleotide polymorphisms (SNPs) across 98 of these TF genes for association with bronchodilator response (BDR) in asthma patients. Genotyping was conducted using the Illumina HumanHap550v3 Beadchip in 403 non-Hispanic White asthmatic children and their parents. SNPs were evaluated for association with BDR using family and population-based analyses. Forty-two SNPs providing p values < 0.1 in both analyses were then genotyped in three adult asthma trials. One SNP 5’ of the thyroid hormone receptor beta gene was associated with BDR in the childhood population and two adult populations (p value = 0.0012). This investigation identified a novel locus for inter-individual variability in BDR and represents a translation of a cellular drug-response study to potential personalization of clinical asthma management.
Bronchodilator response; transcription factor; association; thyroid hormone receptor β; asthma; pharmacogenetics
Human organic cation transporter 3 (OCT3, SLC22A3) mediates the uptake of many important endogenous amines and basic drugs in a variety of tissues. OCT3 is identified as one of the important risk loci for prostate cancer and is markedly under-expressed in aggressive prostate cancers. The goal of this study was to identify genetic and epigenetic factors in the promoter region that influence the expression level of OCT3. Haplotypes that contained the common variants, g.-81G>delGA (rs60515630) (minor allele frequency (MAF) 11.5% in African American) and g.-2G>A (rs555754) (MAF>30% in all ethnic groups) showed significant increases in luciferase reporter activities and exhibited stronger transcription factor binding affinity than the haplotypes that contained the major alleles. Consistent with the reporter assays, OCT3 mRNA expression levels were significantly higher in Asian (P<0.001) and Caucasian (P<0.05) liver samples from individuals who were homozygous for g.-2A/A in comparison with those homozygous for the g.-2G/G allele. Studies revealed that the methylation level in the basal promoter region of OCT3 was associated with OCT3 expression level and tumorigenesis capability in various prostate cancer cell lines. The methylation level of the OCT3 promoter was higher in 62% of prostate tumor samples compared with matched normal samples. Our studies demonstrate that genetic polymorphisms in the proximal promoter region of OCT3 alter the transcription rate of the gene and may be associated with altered expression levels of OCT3 in human liver. Aberrant methylation contributes to the reduced expression of OCT3 in prostate cancer.
SLC22A3; Polymorphism; Methylation and Prostate Cancer
Glucocorticoids (GCs) are steroid hormones widely used as pharmaceutical interventions, which act mainly by regulating gene expression levels. A large fraction of patients (~30%), especially those of African descent, show a weak response to treatment. To interrogate the contribution of variable transcriptional response to inter-ethnic differences, we measured in vitro lymphocyte GC sensitivity (LGS) and transcriptome-wide response to GCs in peripheral blood mononuclear cells (PBMCs) from African-American and European-American healthy donors. We found that transcriptional response after 8hrs treatment was significantly correlated with variation in LGS within and between populations. We found that NFKB1, a gene previously found to predict LGS within populations, was more strongly down-regulated in European-Americans on average. NFKB1 could not completely explain population differences, however, and we found an additional 177 genes with population differences in the average log2 fold change (FDR<0.05), most of which also showed a weaker transcriptional response in African-Americans. These results suggest that inter-ethnic differences in GC sensitivity reflect variation in transcriptional response at many genes, including regulators with large effects (e.g. NFKB1) and numerous other genes with smaller effects.
regulatory variation; gene expression; glucocorticoids; ethnic disparities; asthma; NFκB
The drug efflux pump P-glycoprotein possesses two common and often linked polymorphisms that result in variable drug action. G2677T results in A893S, whereas C3435T is synonymous and has been reported to alter protein folding. We tested the effect of these MDR1 variants on Human Ether-Related A Go-Go (HERG) block by ibutilide in CHO cells 48 h following transient transfection with an IRES-dsRed vector containing MDR1, G2677T MDR1, G2677T/C3435T MDR1 or an empty bicistronic site and an IRES-GFP vector containing HERG (KCNH2). Cotransfection of MDR1 variants had no effect on IKr amplitude at baseline. Cells cotransfected with MDR1-G2677T showed resistance to ibutilide vs HERG alone (IC50: 105.3±1.42 nM vs 27.4±2.5 nM; P<0.0001), consistent with the idea that A893S attenuates IKr block by enhancing drug efflux and thus reducing the drug available to interact with the channel binding site. However, G2677T/C3435T cells showed ibutilide sensitivity similar to cells expressing HERG alone (IC50: 22.2±0.9 nM). Immunostaining showed that the C3435T variant did not traffic to the cell surface. Coculture with fexofenadine(1 μM), an MDR1 substrate known to rescue misfolding in other membrane proteins, restored cell surface expression of MDR1 G2677T/C3435T and restored resistance to block HERG by ibutilide 200 nM (98.5±0.98% vs 42.3±2.2%, P<0.001). The non-synonymous MDR1 variant G2677 T (A893S) confers resistance to ibutilide block of IKr, which is mitigated by the C3435T polymorphism through reduced protein expression, an effect that can be restored by coculture with fexofenadine. These data identify ibutilide as an MDR1 substrate and further support the concept that variable drug transport function can modulate the action of HERG blockers.
pharmacology; long QT syndrome; P-glycoprotein; ATP-binding cassette transporters; antiarrhythmia agents
Platinating agents are used in the treatment of many cancers, yet they can induce toxicities and resistance that limit their utility. Using previously published and additional world population panels of diverse ancestry totaling 608 lymphoblastoid cell lines (LCLs), we performed meta-analyses of over 3 million SNPs for both carboplatin- and cisplatin-induced cytotoxicity. The most significant SNP in the carboplatin meta-analysis is located in an intron of NBAS (p = 5.1 × 10−7). The most significant SNP in the cisplatin meta-analysis is upstream of KRT16P2 (p = 5.8 × 10−7). We also show that cisplatin-susceptibility SNPs are enriched for carboplatin-susceptibility SNPs. Most of the variants that associate with platinum-induced cytotoxicity are polymorphic across multiple world populations; therefore, they could be tested in follow-up studies in diverse clinical populations. Seven genes previously implicated in platinating agent response, including BCL2, GSTM1, GSTT1, ERCC2, and ERCC6 were also implicated in our meta-analyses.
meta-analysis; pharmacogenomics; cisplatin; carboplatin; cross-population
The ω-hydroxylase CYP4A11 catalyzes the transformation of epoxyeicosatrienoic acids to omega-hydroxylated-epoxyeicosatrienoic acids, endogenous peroxisome proliferator-activated receptor α (PPARα) agonists. PPARα activation increases high-density lipoprotein-cholesterol (HDL-C). A cytosine-for-thymidine (T8590C) variant of CYP4A11 encodes for a ω-hydroxylase with reduced activity. This study examined the relationship between CYP4A11 T8590C genotype and metabolic parameters in the Framingham Offspring Study and in a clinical practice-based biobank, BioVU. In women in the Framingham Offspring Study, the CYP4A11 8590C allele was associated with reduced HDL-C concentrations (54.2±0.9 mg/dL in CYP4A11 CC or CT genotype women versus 56.7±0.5 mg/dL in TT women, p=0.02), and with an increased prevalence of low HDL-C, defined categorically as ≤50mg/dL [odds ratio 1.39 (95% CI 1.02-1.90), p=0.04]. In the BioVU cohort, the CYP4A11 8590C allele was also associated with low HDL-C in women [odds ratio 1.69 (95% CI 1.03-2.77, p=0.04)]. There was no relationship between genotype and HDL-C in men in either cohort.
We conducted gender-stratified analyses on a systems-based candidate gene study of 53 regions involved in nicotinic response and the brain-reward pathway in two randomized clinical trials of smoking cessation treatments (placebo, bupropion, transdermal and nasal spray nicotine replacement therapy). We adjusted P-values for multiple correlated tests, and used a Bonferroni corrected α-level of 5 × 10−4 to determine system-wide significance. Four SNPs (rs12021667, rs12027267, rs6702335, rs12039988; r2>0.98) in erythrocyte membrane protein band 4.1 (EPB41) had a significant male-specific marginal association with smoking abstinence (OR=0.5; 95% CI 0.3–0.6) at end of treatment (adjusted P<6 × 10−5). rs806365 in cannabinoid receptor 1 (CNR1) had a significant male-specific gene-treatment interaction at 6-month follow-up (adjusted P=3.9 × 10−5); within males using nasal spray, rs806365 was associated with a decrease in odds of abstinence (OR=0.04; 95% CI 0.01–0.2). While the role of CNR1 in substance abuse has been well studied, we report EPB41 for the first time in the nicotine literature.
Genetic association studies; heterogeneity; smoking cessation
The catechol-o-methyl transferase (COMT) 158Val/Met variant has been suggested to play a role in COMT function. Epigenetic regulation of COMT may further influence the prevalence of metabolic syndrome in these patient populations. This study examined the correlation between COMT promoter methylation and metabolic syndrome in schizophrenia patients receiving atypical antipsychotic (AAP) therapy. DNA was extracted from peripheral blood samples of schizophrenia subjects screened for metabolic syndrome. Pyrosequencing was used to analyze two methylation sites of the COMT-s promoter region. Associations between AAP use, lifestyle variables, metabolic syndrome, and COMT genotype with peak methylation values were analyzed. Data are reported in 85 subjects. Methylation on CpG site 1 had a mean of 79.08% (± 4.71) and 12.43% (±1.19) on site 2. COMT genotype proved to be an indicator of COMT methylation status on site 1 (F(2,84) = 5.78, p=0.0044) and site 2 (F(2,84), p=0.027). A significant negative correlation between physical activity and COMT promoter region methylation was found in Val/Val homozygous patients (Site 1: p=0.013 and Site 2: p=0.019). Those homozygous for Met/Met showed a positive correlation between promoter site methylation and physical activity (Site 1: p=0.027, Site 2: p=0.005), and between CpG site methylation and metabolic syndrome (Site 1: p=0.002; Site 2: p=0.001). The results of this study suggest COMT promoter region methylation is largely influenced by COMT genotype and that physical activity plays a significant role in epigenetic modulation of COMT.
COMT; Metabolic Syndrome; Methylation; Schizophrenia; Activity; Genotype
The risk of venous thromboembolism (VTE) is higher after total hip or knee replacement surgery than after almost any other surgical procedure; warfarin sodium is commonly prescribed to reduce this peri-operative risk. Warfarin has a narrow therapeutic window with high inter-individual dose variability and can cause hemorrhage. The Genetics-InFormatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis (DVT) is a 2×2 factorial-design, randomized controlled trial designed to compare the safety and effectiveness of warfarin-dosing strategies. GIFT will answer two questions: (1) Does pharmacogenetic (PGx) dosing reduce the rate of adverse events in orthopedic patients; and (2) Is a lower target International Normalized Ratio (INR) non-inferior to a higher target INR in orthopedic participants? The composite primary endpoint of the trial is symptomatic and asymptomatic VTE (identified on screening ultrasonography), major hemorrhage, INR ≥ 4, and death.
pharmacogenetics; warfarin; randomized controlled trial; dosing algorithm
Children with autism spectrum disorders (ASD) often have severe behavioral problems. Not all children with these problems respond to atypical antipsychotic medications; therefore, we investigated whether peripheral blood gene expression before treatment with risperidone, an atypical antipsychotic, was associated with improvements in severe behavioral disturbances 8 weeks following risperidone treatment in 42 ASD subjects (age 112.7±51.2 months). Exon expression levels in blood prior to risperidone treatment were compared with pre-post risperidone change in Aberrant Behavior Checklist-Irritability (ABC-I) scores. Expression of exons within 5 genes was correlated with change in ABC-I scores across all risperidone-treated subjects: GBP6, RABL5, RNF213, NFKBID, and RNF40 (α<0.001). RNF40 is located at 16p11.2, a region implicated in autism and schizophrenia. Thus, these genes expressed prior to treatment were associated with subsequent clinical response. Future studies will be needed to confirm these results and determine whether this expression profile is associated with risperidone response in other disorders, or alternative antipsychotic response within ASD.
autism; risperidone; gene expression; atypical antipsychotic
Opioid addiction is a chronic disease with high genetic contribution and a large inter-individual variability in therapeutic response. The goal of this study was to identify pharmacodynamic factors that modulate methadone dose requirement. The neurotrophin family is involved in neural plasticity, learning memory and behavior and deregulated neural plasticity may underlie the pathophysiology of drug addiction. BDNF was shown to affect the response to methadone maintenance treatment. This study explores the effects of polymorphisms in the nerve growth factor (beta polypeptide) gene, NGFB, on the methadone doses required for successful maintenance treatment for heroin addiction. Genotypes of 14 NGFB polymorphisms were analyzed for association with the stabilizing methadone dose in 72 former severe heroin addicts with no major co-medications. There was significant difference in methadone doses required by subjects with different genotypes of the NGFB intronic SNP rs2239622 (P = 0.0002). These results may have clinical importance.
methadone; opioid addiction; nerve growth factor; NGFB; heroin addiction
The overall neurobiological mechanisms by which lithium and valproate stabilize mood in bipolar disorder patients have yet to be fully defined. The therapeutic efficacy and dissimilar chemical structures of these medications suggest that they perturb both shared and disparate cellular processes. To investigate key pathways and functional clusters involved in the global action of lithium and valproate, we generated interaction networks formed by well-supported drug targets. Striking functional similarities emerged. Intersecting nodes in lithium and valproate networks highlighted a strong enrichment of apoptosis clusters and neurotrophin signaling. Other enriched pathways included MAPK, ErbB, insulin, VEGF, Wnt and long-term potentiation indicating a widespread effect of both drugs on diverse signaling systems. MAPK1/3 and AKT1/2 were the most preponderant nodes across pathways suggesting a central role in mediating pathway interactions. The convergence of biological responses unveils a functional signature for lithium and valproate that could be key modulators of their therapeutic efficacy.
Expression; pathways; AKT1/2; MAPK1/3; Cytoscape; MiMI; DAVID; GLay
We introduce a method for detecting variants in several genes of related function with small effect on a phenotype of interest. Our method uses logistic regression to test whether multiple alleles within a functional set have significantly higher than expected predictive value, even though none individually may have strong individual effects. We illustrate this method by testing seven gene sets (including 48 genes), from a study with1350 single nucleotide polymorphisms in 130 addiction candidate genes studied in a sample of 575 alcohol dependence (AD) cases and 530 controls. We conclude that AD is related to variation in genes participating in Glutamate and GABA signaling, as has been reported elsewhere, and in stress response pathways, but not with genes in several other systems implicated in other drugs of abuse.
alcohol dependence; GABA; glutamate; CRH; logistic regression; neurotransmitter system
This study evaluated association between common and rare sequence variants in 10 nicotinic acetylcholine receptor subunit genes and the severity of nausea 21 days after initiating the standard, FDA-approved varenicline regimen for smoking cessation. Included in the analysis were 397 participants from a randomized clinical effectiveness trial with complete clinical and DNA resequencing data (mean age = 49.2 years; 68.0% female). Evidence for significant association between common sequence variants in CHRNB2 and nausea severity was obtained after adjusting for age, gender, and correlated tests (all PACT<.05). Individuals with the minor allele of CHRNB2 variants experienced less nausea than did those without the minor allele, consistent with previously reported findings for CHRNB2 and the occurrence of nausea and dizziness as a consequence of first smoking attempt in adolescents, and with the known neurophysiology of nausea. As nausea is the most common reason for discontinuance of varenicline, further pharmacogenetic investigations are warranted.
varenicline; nausea; smoking cessation; adherence
ATP-Binding Cassette (ABC) membrane transporters determine the disposition of many drugs, metabolites and endogenous compounds. Coding region variation in ABC transporters is the cause of many genetic disorders, but much less is known about the genetic basis and functional outcome of ABC transporter expression level variation. We used genotype and mRNA transcript level data from human lymphoblastoid cell lines to assess population and gender differences in ABC transporter expression, and to guide the discovery of genomic regions involved in transcriptional regulation. Nineteen of 49 ABC genes were differentially expressed between individuals of African, Asian and European descent suggesting an important influence of race on expression level of ABC transporters. Twenty-four significant associations were found between transporter transcript levels and proximally located genetic variants. Several of the associations were experimentally validated in reporter assays. Through influencing ABC expression levels, these SNPs may affect disease susceptibility and response to drugs.
ATP-Binding Cassette Transporters; Lymphoblastoid Cell Lines; Expression Quantitative Trait Mapping; Transcriptional Regulation; Population Differences
To assess public attitudes and interest in pharmacogenetic (PGx) testing, we conducted a random-digit-dial telephone survey of U.S. adults, achieving a response rate of 42% (n=1139). Most respondents expressed interest in PGx testing to predict mild or serious side effects (73% ±3.29% and 85% ±2.91%, respectively), guide dosing (91%) and assist with drug selection (92%). Younger individuals (ages 18–34) were more likely to be interested in PGx testing to predict serious side effects (vs. ages 55+), as well as Whites, those with a college degree, and who had experienced side effects from medications. However, most respondents (78% ±3.14%) were not likely to have a PGx test if there was a risk that their DNA sample or test result could be shared without their permission. Given differences in interest among some groups, providers should clearly discuss the purpose of testing, alternative testing options (if available), and policies to protect patient privacy and confidentiality.
Single nucleotide polymorphisms (SNPs) can be assayed using DNA isolated from archival formalin-fixed paraffin-embedded (FFPE) samples, making retrospective pharmacogenetic studies possible. Here we describe methods that significantly increase the number of SNP determinations possible using FFPE samples. Quantifying the amount of DNA amenable to PCR (amplification-quality DNA, AQ-DNA) allows a significant reduction in the amount of sample required for Taqman-based SNP assays. Optimizing AQ-DNA input increases PCR amplification efficiency and SNP determination accuracy. DNA was extracted from thirty-nine FFPE tumor sections and matched tumor and stromal cores, of the type used to generate tissue microarrays. Sections and tumor cores yielded sufficient AQ-DNA for over 1,000 SNP determinations. Seven SNPs were assessed, following individual assay optimization for minimal AQ-DNA. Genotypes from tumor cores for single SNPs were 92.3-100% concordant with those obtained from sections. Using these methods, the number of SNP genotypes that can be determined from single FFPE samples is greatly increased expanding the genetic association studies possible from limited archival specimens. The use of tumor cores is of particular importance since the harvesting of tumor cores has minimal impact on the utility of the donor blocks for other purposes.
genotyping; paraffin-embedded; tumor samples; genetic polymorphism
Pharmacogenomics is yet to fulfill its promise of manifestly altering clinical medicine. As one example, a predictive test for tardive dyskinesia (an adverse drug reaction consequent to antipsychotic exposure) could greatly improve the clinical treatment of schizophrenia but human studies are equivocal. A complementary approach is the mouse-then-human design in which a valid mouse model is used to identify susceptibility loci which are subsequently tested in human samples. We used inbred mouse strains from the Mouse Phenome Project to estimate the heritability of haloperidol-induced activity and orofacial phenotypes. 159 mice from 27 inbred strains were chronically treated with haloperidol (3 mg/kg/day via subdermal slow-release pellets) and monitored for the development of vacuous chewing movements (VCMs, the mouse analog of TD) and other movement phenotypes derived from open field activity and the inclined screen test. The test battery was assessed at 0, 30, 60, 90, and 120 days in relation to haloperidol exposure. As expected, haloperidol caused marked changes in VCMs, activity in the open field, and EPS. Unexpectedly, factor analysis demonstrated that these measures were imprecise assessments of a latent construct rather than discrete constructs. The heritability of a composite phenotype was ~0.9 after incorporation of the longitudinal nature of the design. Murine VCMs are a face valid animal model of antipsychotic-induced TD and heritability estimates from this study support the feasibility of mapping of susceptibility loci for VCMs.
Antipsychotic; haloperidol; adverse drug reaction; tardive dyskinesia; mouse model; vacuous chewing movements
QT prolongation is associated with increased risk of cardiac arrhythmias. Identifying the genetic variants that mediate antipsychotic induced prolongation may help to minimize this risk, which might prevent the removal of efficacious drugs from the market. We performed candidate gene analysis and five drug specific genome-wide association studies (GWAS) with 492K SNPs to search for genetic variation mediating antipsychotic induced QT prolongation in 738 schizophrenia patients from the Clinical Antipsychotic Trial of Intervention Effectiveness (CATIE) study.
Our candidate gene study suggests the involvement of NOS1AP and NUBPL (p-values =1.45×10−05 and 2.66×10−13, respectively). Furthermore, our top GWAS hit achieving genome-wide significance, defined as a q-value <0.10, (p-value =1.54×10−7, q-value =0.07), located in SLC22A23, mediated the effects of quetiapine on prolongation. SLC22A23 belongs to a family of organic ion transporters that shuttle a variety of compounds including drugs, environmental toxins, and endogenous metabolites across the cell membrane. This gene is expressed in the heart and is integral in mouse heart development. The genes mediating antipsychotic induced QT prolongation partially overlap with the genes affecting normal QT interval variation. However, some genes may also be unique for drug induced prolongation. This study demonstrates the potential of GWAS to discover genes and pathways that mediate antipsychotic induced QT prolongation.
candidate gene analysis; genome-wide association study; schizophrenia; adverse effects; CATIE