Brain dopamine (DA) plays a central role in addictive disorders including nicotine addiction. Several DA-related gene variants have been studied to identify predictors of pharmacotherapy response for smoking cessation. Genetic variants in DRD2, DRD4, ANKK1, DAT1, COMT and DBH genes show some promise in predicting response to smoking cessation pharmacotherapies. However, most of the clinical trials studying these variants had small sample sizes, used retrospective analysis, and enrolled smokers of self-identified Caucasians as study participants. In addition, future studies should also consider nicotine metabolism rate, sex or menstrual cycle phase, and epigenetic factors as potential confounding factors for treatment response of smokers. Future work addressing these limitations may uncover the potential impact of DA genetic variation on smoking cessation pharmacotherapies.
Pharmacogenetics; Nicotine; Dopamine; Smoking Cessation; Genetic; Addiction
The enzyme NADPH–P450 oxidoreductase (POR) is the main electron donor to all microsomal CYPs. The possible contribution of common POR variants to inter- and intra-individual variability in drug metabolism is of great pharmacogenetic interest.
To search for POR polymorphic alleles and estimate their frequencies in a Jewish population.
Materials & methods
We analyzed the POR gene in 301 Ashkenazi and Moroccan Jews.
A total of 30 POR SNPs were identified, nine in the noncoding regions and 21 in the protein-coding regions (ten synonymous, 11 missense). Six of these missense variants are previously undescribed (S102P, V164M, V191M, D344N, E398A and D648N).
The data collected in this study on missense POR SNPs, interpreted in light of the crystallographic structure of human POR, indicate that some POR missense variants may be potential biomarkers for future POR pharmacogenetic screening.
allele frequencies; CYP oxidoreductase; haplotype; Jewish; populations; pharmacogenetics; POR
Pharmacogenetics as a tool to aid clinicians implement individualized pharmacotherapy is utilized in some areas of medicine. Pharmacogenetics in pregnancy is still a developing field. However, there are several areas of obstetric therapeutics where data are emerging that give glimpses into future therapeutic possibilities. These include opioid pain management, antihypertensive therapy, antidepressant medications, preterm labor tocolytics, antenatal corticosteroids and drugs for nausea and vomiting of pregnancy, to name a few. More data are needed to populate the therapeutic models and to truly determine if pharmacogenetics will aid in individualizing pharmacotherapy in pregnancy. The objective of this review is to summarize current data and highlight research needs.
pharmacogenetics; pregnancy; therapeutics
Effective perioperative analgesia is lacking for children owing to interindividual variations and underdosing of opioids caused by fear of adverse effects. We investigated the role of COMT SNPs on postoperative pain management in children.
One hundred and forty nine children undergoing adenotonsillectomy were enrolled. The associations of four COMT SNPs (rs6269, rs4633, rs4818 and rs4680) with postoperative pain were analyzed and outcome measures included maximum pain scores, need for postoperative opioid interventions and postoperative morphine requirements.
We detected an association of postoperative opioid intervention need with all four COMT SNPs. Minor allele carriers of COMT SNPs were approximately three-times more likely to require analgesic interventions than homozygotes of major alleles (p-value range: 0.0031–0.0127; odds ratio range: 2.6–3.1). In addition, significant association was detected between maximum Face, Leg, Activity, Consolability, Cry (FLACC) pain scores and three COMT SNPs (rs6269, rs4633 and rs4680). Haplotype 1 (ATCA: 51.3%) and Haplotype 2 (GCGG: 36.2%) are more frequent. Haplotype 2 was associated with higher odds of intravenous analgesic intervention need in postanesthesia recovery unit with an odds ratio of 2.6 (95% CI: 1.2–5.4; p-value = 0.022).
COMT SNPs may play a significant role in interindividual variation in postoperative pain perception and postoperative morphine requirements in children.
COMT; genetics; pain; pediatric pain; postoperative pain
The mTOR signaling pathway integrates inputs from a variety of upstream stimuli to regulate diverse cellular processes including proliferation, growth, survival, motility, autophagy, protein synthesis and metabolism. The mTOR pathway is dysregulated in a number of human pathologies including cancer, diabetes, obesity, autoimmune disorders, neurological disease and aging. Ongoing clinical trials testing mTOR-targeted treatments number in the hundreds and underscore its therapeutic potential. To date mTOR inhibitors are clinically approved to prevent organ rejection, to inhibit restenosis after angioplasty, and to treat several advanced cancers. In this review we discuss the continuously evolving field of mTOR pharmacogenomics, as well as highlight the emerging efforts in identifying diagnostic and prognostic markers, including miRNAs, in order to assess successful therapeutic responses.
biomarkers; cancer; cardiovascular disease; clinical trials; dual inhibitors; FKBP12; microRNA; mTOR; rapamycin; resistance
Pharmacogenomics is aimed at advancing our knowledge of the genetic basis of variable drug response. The Center for Personalized Therapeutics within the University of Chicago comprises basic, translational and clinical research as well as education including undergraduate, graduate, medical students, clinical/postdoctoral fellows and faculty. The Committee on Clinical Pharmacology and Pharmacogenomics is the educational arm of the Center aimed at training clinical and postdoctoral fellows in translational pharmacology and pharmacogenomics. Research runs the gamut from basic discovery and functional studies to pharmacogenomic implementation studies to evaluate physician adoption of genetic medicine. The mission of the Center is to facilitate research, education and implementation of pharmacogenomics to realize the true potential of personalized medicine and improve the lives of patients.
GWAS; eQTL; ENCODE; functional genomics; reporter gene assay; allelic expression imbalance; isogenic models; cancer genome
The increasing prevalence of Type 2 diabetes has emphasized the need to optimize treatment regimens. Metformin, the most widely used oral agent, is recommended as first-line drug therapy by multiple professional organizations. Response to metformin varies significantly at the individual level; this heterogeneity may be explained in part by genetic factors. Understanding these underlying factors may aid with tailoring treatment for individual patients as well as with designing improved Type 2 diabetes therapies. The past 10 years have seen substantial progress in the understanding of the pharmacogenetics of metformin response. The majority of this work has focused on genes involved in the pharmacokinetics of metformin. Owing to the uncertainty surrounding its mechanism of action, studies of pharmacodynamic genetics have been relatively few; genome-wide approaches have the potential to illuminate the molecular details of metformin response. In this review we summarize current knowledge about metformin pharmacogenetics and suggest directions for future investigation.
antidiabetic; biguanide; metformin; pharmacogenetics; Type 2 diabetes mellitus
Large interindividual variability in morphine disposition could contribute to unpredictable variability in morphine analgesia and adverse events. Caucasian children have more adverse effects and slower morphine clearance than African–American children. To study variations in intravenous morphine pharmacokinetics in children, we examined the influence of genetic polymorphisms in OCT1
In 146 children undergoing adenotonsillectomy, 146 concentration–time profiles (2–4 measurements per patient) were available. Population pharmacokinetic ana lysis characterized the profiles in NONMEM® and tested OCT1 variants as covariates.
Allometrically scaled post hoc Bayesian morphine clearance in homozygotes of loss-of-function OCT1 variants (n = 9, OCT1*2–*5/*2–*5 was significantly lower (20%) than in wild-type (n = 85, OCT1*1/*1) and heterozygotes (n = 52, OCT1*1/*2–*5; p < 0.05).
Besides bodyweight, OCT1 genotypes play a significant role in intravenous morphine pharmacokinetics. Relatively high allelic frequencies of defective OCT1 variants among Caucasians may explain their lower morphine clearance and possibly higher frequencies of adverse events compared with African–American children.
children; morphine; OCT1; pediatrics; pharmacogenetics; pharmacokinetics; population pharmacokinetics; surgical pain
β-adrenergic receptor blocker; genetic variant; G-protein-coupled receptor kinase; heart failure
Ribonucleotide reductase catalyzes an essential step in the cellular production of deoxyribonucleotide triphosphates and has been associated with clinical outcome in cancer patients receiving nucleoside analog-based chemotherapy.
Materials & methods
In the current study, we sequenced the genes RRM1 and RRM2 in genomic DNA from HapMap cell lines with European (Utah residents with northern and western European ancestry [CEU]; n = 90) or African (Yoruba people in Ibadan, Nigeria [YRI]; n = 90) ancestry.
We identified 44 genetic variants including eight coding SNPs in RRM1 and 15 SNPs including one coding SNP in RRM2. RRM1 and RRM2 mRNA expression levels were significantly correlated with each other in both CEU and YRI lymphoblast cell lines, and in leukemic blasts from acute myeloid leukemia (AML) patients (AML97, n = 89; AML02, n = 187). Additionally, RRM1 expression was higher among patient features indicative of a high relapse hazard. We evaluated SNPs within the RRM1 and RRM2 genes in the HapMap lymphoblast cell lines from CEU and YRI panels for association with expression and cytarabine chemosensitivity. SNPs of potential significance were further evaluated in AML patients. RRM1 SNPs rs1042919 (which occurs in linkage disequilbrium with multiple other SNPs) and promoter SNP rs1561876 were associated with intracellular 1-β-D-arabinofuranosyl-CTP levels, response after remission induction therapy, risk of relapse and overall survival in AML patients receiving cytarabine and cladribine.
These results suggest that SNPs within ribonucleotide reductase might be helpful predictive markers of response to nucleoside analogs and should be further validated in larger cohorts.
cytarabine; HapMap; leukemia; nucleoside analogs; pharmacogenomics; ribonucleotide reductase
Since previous functional studies of short haplotypes and polymorphic sites of SLC6A3 have shown variant-dependent and drug-sensitive promoter activity, this study aimed to understand whether a large SLC6A3 regulatory region, containing these small haplotypes and polymorphic sites, can display haplotype-dependent promoter activity in a drug-sensitive and pathway-related manner.
Materials & methods
By creating and using a single copy number luciferase-reporter vector, we examined regulation of two different SLC6A3 haplotypes (A and B) of the 5′ 18-kb promoter and two known downstream regulatory variable number tandem repeats by 17 drugs in four different cellular models.
The two regulatory haplotypes displayed up to 3.2-fold difference in promoter activity. The regulations were drug selective (37.5% of the drugs showed effects), and both haplotype and cell type dependent. Pathway analysis revealed at least 13 main signaling hubs targeting SLC6A3, including histone deacetylation, AKT, PKC and CK2 α-chains.
SLC6A3 may be regulated via either its promoter or the variable number tandem repeats independently by specific signaling pathways and in a haplotype-dependent manner. Furthermore, we have developed the first pathway map for SLC6A3 regulation. These findings provide a framework for understanding complex and variant-dependent regulations of SLC6A3.
DAT; epigenetics; haplotypic activity; promoter; signaling regulation; single copy number reporter vector
PON1 is a key component of high-density lipoproteins (HDLs) and is at least partially responsible for HDL's antioxidant/atheroprotective properties. PON1 is also associated with numerous human diseases, including cardiovascular disease, Parkinson's disease and cancer. In addition, PON1 metabolizes a broad variety of substrates, including toxic organophosphorous compounds, statin adducts, glucocorticoids, the likely atherogenic l-homocysteine thiolactone and the quorum-sensing factor of Pseudomonas aeruginosa. Numerous cardiovascular and antidiabetic pharmacologic agents, dietary macronutrients, lifestyle factors and antioxidant supplements affect PON1 expression and enzyme activity levels. Owing to the importance of PON1 to HDL function and its individual association with diverse human diseases, pharmacogenomic interactions between PON1 and the various factors that alter its expression and activity may represent an important therapeutic target for future investigation.
antioxidants; cardiovascular disease; drug interactions; gene-by-environment interactions; oxidative stress; paraoxonase; pharmacogenetics; pharmacogenomics; PON1; statins
LCLs are widely used in pharmacogenomic studies and the applicability of LCLs for various clinical phenotypes is emerging. Early studies have yielded promising results for LCLs as a proxy for genetic variants for treatment outcome for a number of cancers as well as toxicity in varying tissue types including taxane-induced neuropathy. Although LCLs have demonstrated utility in the elucidation of functional mechanisms for results of clinical genotype-drug phenotype studies, there are more relevant cell-based models developing.
lymphoblastoid; pharmacogenetic; cell-based model; genotype-phenotype; cytotoxicity; apoptosis
Pseudogenes are junk DNA gene remnants generated by inactivating mutations or the loss of regulatory sequences, often following gene duplication or retrotransposition events. These pseudogenes have previously been considered to be molecular fossils derived from once-coding genes. In many cases, pseudogenes confer no observable selective advantage to the host organism and may be on a path towards removal from the genome. However, pseudogenes can also serve as raw material for the exaptation of novel functions, particularly in relation to the regulation of gene expression. Many pseudogenes are resurrected as noncoding RNA genes, which function in RNA-based gene regulatory circuits. As such, functional pseudogenes might simply be considered as ‘genes’. Here, we discuss the role of these pseudogene-derived RNAs as regulators of gene expression in the context of human disease. In particular, we consider the manipulation of pseudogene transcripts through the use of antisense oligonucleotides, siRNAs, aptamers or classical gene therapy approaches as novel pharmacological strategies.
epigenetics; lncRNAs; long noncoding RNAs; microRNA; miRNA; pseudogenes; therapeutics
Hypertension is a common condition associated with increased cardiovascular morbidity and mortality. In the USA only approximately a third of those who are aware of their hypertensive status successfully control their blood pressure. One reason for this is the unpredictable response individuals have to treatment. Clinicians must often rely on empirical methods to match patients with effective drug treatment. Hypertension pharmacogenetics seeks to find genetic predictors of response to drugs that lower blood pressure and to translate this knowledge into clinical practice. To date, around 60 studies have investigated associations between genetic polymorphisms and response to antihypertensive drugs. Here we review 18 studies that have been published since 2005. While consonant findings that are insufficient for clinical translation remain the norm, some consistent findings are emerging with several gene-treatment combinations. Nonetheless, differences in study designs, variable methods for assessing pharmacologic exposures, heterogeneous phenotypes (that is, response variables and outcomes ranging from blood pressure to clinical outcomes) and small sample sizes coupled with a short duration of follow-up in many studies account for a large portion of these inconsistencies. Progress in the future will depend upon our ability to launch large studies using high-fidelity phenotyping with multiple drugs and multiple ethnic groups.
antihypertensive; blood pressure; gene; pharmacogenetics; pharmacogenomics
Association mapping with lymphoblastoid cell lines (LCLs) is a promising approach in pharmacogenomics research, and in the current study we utilize this model to perform association mapping for 29 chemotherapy drugs.
Materials and Methods
Currently, we use LCLs to perform genome-wide association mapping of the cytotoxic response of 520 European Americans to 29 different anticancer drugs, the largest LCL study to date. A novel association approach using a multivariate analysis of covariance design was employed with the software program MAGWAS, testing for differences in the dose-response profiles between genotypes without making assumptions about the response curve or the biological mode of association. Additionally, by classifying 25 of the 29 drugs into 8 families according to structural and mechanistic relationships, MAGWAS was used to test for associations that were shared across each drug family. Finally, a unique algorithm using multivariate responses and multiple linear regressions across pairs of response curves was used for unsupervised clustering of drugs.
Among the single drug studies, suggestive associations were obtained for 18 loci, 12 within/near genes. Three of these, MED12L, CHN2 and MGMT, have been previously implicated in cancer pharmacogenomics. The drug family associations resulted in 4 additional suggestive loci (3 contained within/near genes). One of these genes, HDAC4, associated with the DNA alkylating agents, shows possible clinical interactions with temozolomide. For the drug clustering analysis, 18 of 25 drugs clustered into the appropriate family.
This study demonstrates the utility of LCLs for identifying genes having clinical importance in drug response, for assigning unclassified agents to specific drug families, and proposes new candidate genes for follow-up in a large number of chemotherapy drugs.
genome-wide association study; lymphoblastoid cell lines; chemotherapeutics
One of the basic questions in the early uses of pharmacogenetic (PGx) testing revolves around the clinical delivery of testing. Because multiple health professionals may play a role in the delivery of PGx testing, various clinical delivery models have begun to be studied. We propose that a partnership between genetic counselors and pharmacists can assist clinicians in the delivery of comprehensive PGx services. Based on their expert knowledge of pharmacokinetics and pharmacodynamics, pharmacists can facilitate the appropriate application of PGx test results to adjust medication use as warranted and act as a liaison to the healthcare team recommending changes in medication based on test results and patient input. Genetic counselors are well-trained in genetics as well as risk communication and counseling methodology, but have limited knowledge of pharmaceuticals. The complementary knowledge and skill set supports the partnership between genetic counselors and pharmacists to provide effective PGx testing services.
Pharmacogenetic testing; delivery models; team-based care
Incidental findings have long posed challenges for healthcare providers, but the scope and scale of these challenges have increased with the introduction of new technologies. This article assesses the impact of incidental findings on the introduction of prospective pharmacogenomic testing into clinical use. Focusing on the challenges of the incidentalome, the large set of incidental findings potentially generated through genotyping, the paper argues that provisional approaches to managing incidental findings may be implemented if necessary to allow benefits of pharmacogenomic testing to be realized in the clinical setting. In the longer term, approaches to returning incidental findings may need to focus on limiting the number of incidental findings to a number that can be addressed by patients and providers.
clinical pharmacogenomics; incidental findings; incidentalome; translational genomics
pharmacogenetics; health care systems; biomedical informatics; clinical decision support systems
Recent years have seen great advances in our understanding of genetic contributors to drug response. Drug discovery and development around targeted genetic (somatic) mutations has led to a number of new drugs with genetic indications, particularly for the treatment of cancers. Our knowledge of genetic contributors to variable drug response for existing drugs has also expanded dramatically, such that the evidence now supports clinical use of genetic data to guide treatment in some situations, and across a variety of therapeutic areas. Clinical implementation of pharmacogenetics has seen substantial growth in recent years and groups are working to identify the barriers and best practices for pharmacogenetic-guided treatment. The advances and challenges in these areas are described and predictions about future use of genetics in drug therapy are discussed.
clinical implementation; pharmacogenetics; pharmacogenomics
The University of Florida and Shands Hospital recently launched a genomic medicine program focused on the clinical implementation of pharmacogenetics called the Personalized Medicine Program. We focus on a preemptive, chip-based genotyping approach that is cost effective, while providing experience that will be useful as genomic medicine moves towards genome sequence data for patients becoming available. The Personalized Medicine Program includes a regulatory body that is responsible for ensuring that evidence-based examples are moved to clinical implementation, and relies on clinical decision support tools to provide healthcare providers with guidance on use of the genetic information. The pilot implementation was with CYP2C19-clopidogrel and future plans include expansion to additional pharmacogenetic examples, along with aiding in implementation in other health systems across Florida.
Patients with schizophrenia, treated with antipsychotics often develop metabolic side effects including dyslipidemia. Antipsychotics potentially upregulate gene expression of a lipid metabolism pathyway called sterol regulatory element binding protein (SREBP) via transcription factors (SREBF) and genetic variation within SREBF may contribute to dyslipidemias and lipid medication efficacy within schizophrenia.
A cross-sectional study of 157 patients were genotyped for SREBF1 (rs11868035) and SREBF2 (rs1057217) variants, and assessed for fasting lipids. The cohort’s mean age was 46.6 years, 64% male, and 86% were using atypical antipsychotics. When stratified by statin use, those receiving a statin and carrying the SREBF1 T allele exhibited higher TC levels (p=0.01), TG levels (p=0.04) and LDL levels (p=0.03). A regression analysis controlling for gender differences in lipids showed that the SREBF1 T allele and statin interaction remained only for TC levels (F(4,149)=5.8, p<0.0001).
For schizophrenia individuals with the SREBF1 rs11868035 T allele incomplete response to statin medications may be seen. Future investigations may allow for personalizing dyslipidemia treatment based on pharmacogenetics within schizophrenia.
Schizophrenia; Cholesterol; SREBF; Pharmacogenomics; Statins