Future Trends in the Pharmacogenomics of Brain Disorders and Dementia: Influence of APOE and CYP2D6 Variants
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SUBMITTER: Cacabelos R
PROVIDER: S-EPMC4034082 | biostudies-literature | 2010 Sep
REPOSITORIES: biostudies-literature
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Project description:Dementia is a major problem of health in developed societies. Alzheimer's disease (AD), vascular dementia, and mixed dementia account for over 90% of the most prevalent forms of dementia. Both genetic and environmental factors are determinant for the phenotypic expression of dementia. AD is a complex disorder in which many different gene clusters may be involved. Most genes screened to date belong to different proteomic and metabolomic pathways potentially affecting AD pathogenesis. The ε4 variant of the APOE gene seems to be a major risk factor for both degenerative and vascular dementia. Metabolic factors, cerebrovascular disorders, and epigenetic phenomena also contribute to neurodegeneration. Five categories of genes are mainly involved in pharmacogenomics: genes associated with disease pathogenesis, genes associated with the mechanism of action of a particular drug, genes associated with phase I and phase II metabolic reactions, genes associated with transporters, and pleiotropic genes and/or genes associated with concomitant pathologies. The APOE and CYP2D6 genes have been extensively studied in AD. The therapeutic response to conventional drugs in patients with AD is genotype specific, with CYP2D6-PMs, CYP2D6-UMs, and APOE-4/4 carriers acting as the worst responders. APOE and CYP2D6 may cooperate, as pleiotropic genes, in the metabolism of drugs and hepatic function. The introduction of pharmacogenetic procedures into AD pharmacological treatment may help to optimize therapeutics.
| S-EPMC3312254 | biostudies-literature
Project description:Symptomatic interventions for patients with dementia involve anti-dementia drugs to improve cognition, psychotropic drugs for the treatment of behavioral disorders (BDs), and different categories of drugs for concomitant disorders. Demented patients may take >6-10 drugs/day with the consequent risk for drug-drug interactions and adverse drug reactions (ADRs >80%) which accelerate cognitive decline. The pharmacoepigenetic machinery is integrated by pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes redundantly and promiscuously regulated by epigenetic mechanisms. CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5 geno-phenotypes are involved in the metabolism of over 90% of drugs currently used in patients with dementia, and only 20% of the population is an extensive metabolizer for this tetragenic cluster. ADRs associated with anti-dementia drugs, antipsychotics, antidepressants, anxiolytics, hypnotics, sedatives, and antiepileptic drugs can be minimized by means of pharmacogenetic screening prior to treatment. These drugs are substrates, inhibitors, or inducers of 58, 37, and 42 enzyme/protein gene products, respectively, and are transported by 40 different protein transporters. APOE is the reference gene in most pharmacogenetic studies. APOE-3 carriers are the best responders and APOE-4 carriers are the worst responders; likewise, CYP2D6-normal metabolizers are the best responders and CYP2D6-poor metabolizers are the worst responders. The incorporation of pharmacogenomic strategies for a personalized treatment in dementia is an effective option to optimize limited therapeutic resources and to reduce unwanted side-effects.
| S-EPMC7246738 | biostudies-literature
Project description:PurposeThis study aims to evaluate the influence of genetic polymorphisms of CYP2D6, CYP3A5, ABCB1, and APOE genes and nongenetic factors on steady-state plasma concentrations (Cpss) of donepezil and therapeutic outcomes in Thai patients with Alzheimer's disease (AD) and vascular dementia (VAD).Patients and methodsEighty-five dementia patients who received donepezil for at least six months were recruited. CYP2D6, CYP3A5, ABCB1, and APOE polymorphisms were genotyped. Cpss of donepezil was measured. Association of genetic and non-genetic factors with Cpss and clinical outcomes of donepezil (cognitive function as measured by the Thai Mental State Examination score; TMSE) were determined by using univariate and multivariate analysis.ResultsBoth univariate and multiple linear regression analysis indicated that only CYP2D6*10 allele was associated with higher Cpss (p-value =0.029 and B =0.478, p-value =0.032, respectively) that might influence the clinical outcomes of donepezil. ie, TMSE (p-value =0.010 and B =4.527, p-value =0.001) and ΔTMSE (p-value =0.023 and B =4.107, p-value =0.002), especially in patients with AD. Interestingly, concomitant use of memantine was found to be associated with increased Cpss of donepezil (p-value =0.007 and B =0.511, p-value =0.014). Whereas, co-medication with antidepressant drugs attenuated clinical responses in patients with AD (TMSE: B =-2.719, p-value =0.013 and ΔTMSE: B =-2.348, p-value =0.028). Age was a significant predictor of donepezil response in VAD patients. No significant association of CYP3A5*3, ABCB1 3435C>T or ABCB1 1236C>T, and APOE ε4 genotypes with Cpss or clinical outcomes of donepezil was found in this study.ConclusionOur results suggests that CYP2D6*10 strongly influences Cpss and there is a trend toward better outcomes of donepezil in patients with AD. Nongenetic factors including concomitant drugs treatment might alter Cpss of donepezil or clinical outcomes.
| S-EPMC6732559 | biostudies-literature
Project description:ObjectiveWe sought to determine whether APOE genotype influences a previously observed decline in serum total cholesterol (TC) and low-density lipoprotein (LDL) levels preceding primary intracerebral hemorrhage (ICH), as a potential demonstration of nonamyloid mechanisms of APOE in ICH risk.MethodsWe performed a single-center retrospective longitudinal analysis using patients with known APOE genotype drawn from an ongoing cohort study of ICH. Serum lipid measurements for TC, triglycerides (TGs), LDL, and high-density lipoprotein (HDL) collected within 2 years before and after index ICH were extracted from electronic medical records. Piecewise linear mixed-effects models were used to compare APOE allele-specific effects on temporal serum lipid trends in ICH. Demographics, medical history, medications, and health maintenance data were included as fixed effects. Inter- and intraindividual variations in lipid levels were modeled as random effects.ResultsA total of 124 ICH cases were analyzed. APOE ε4 carriers had greater rates of decline in serum TC and LDL within 6 months preceding ICH (TC: -7.30 mg/dL/mo, p = 0.0035; LDL: -8.44 mg/dL/mo, p = 0.0001). Conversely, serum TC and LDL levels in APOE ε2 carriers were unchanged within the same time period. APOE genotype had no associations with serum HDL or TG trends.ConclusionsAPOE allele status predicts serum TC and LDL changes preceding acute ICH. Our results have implications for ongoing efforts in dissecting the role of dyslipidemia in cerebrovascular disease risk. APOE genotype-specific influence on lipid trends provides a clue for one mechanism by which APOE may influence risk of ICH. Further characterization of the metabolic roles of APOE is needed to improve the understanding of APOE biology in cerebrovascular disease risk.
| S-EPMC4936477 | biostudies-literature
Project description:Dementia is a major problem of health in developed countries, and a prototypical paradigm of chronic disability, high cost, and social-family burden. Approximately, 10-20% of direct costs in this kind of neuropathology are related to pharmacological treatment, with a moderate responder rate below 30% and questionable cost-effectiveness. Over 200 different genes have been associated with the pathogenesis of dementia. Studies on structural and functional genomics, transcriptomics, proteomics and metabolomics have revealed the paramount importance of these novel technologies for the understanding of pathogenic cascades and the prediction of therapeutic outcomes in dementia. About 10-30% of Western populations are defective in genes of the CYP superfamily. The most frequent CYP2D6 variants in the Iberian peninsula are the *1/*1 (57.84%), *1/*4 (22.78%), *1×N/*1 (6.10%), *4/*4 (2.56%), and *1/*3 (2.01%) genotypes, accounting for more than 80% of the population. The frequency of extensive (EMs), intermediate (IMs), poor (PMs), and ultra-rapid metabolizers (UMs) is about 59.51%, 29,78%, 4.46%, and 6.23%, respectively, in the general population, and 57.76, 31.05%, 5.27%, and 5.90%, respectively, in AD cases. The construction of a genetic map integrating the most prevalent CYP2D6+CYP2C19+CYP2C9 polymorphic variants in a trigenic cluster yields 82 different haplotype-like profiles, with *1*1-*1*1-*1*1 (25.70%), *1*1-*1*2-*1*2 (10.66%), *1*1-*1*1-*1*1 (10.45%), *1*4-*1*1-*1*1 (8.09%), *1*4-*1*2-*1*1 (4.91%), *1*4-*1*1-*1*2 (4.65%), and *1*1-*1*3-*1*3 (4.33%), as the most frequent genotypes. Only 26.51% of AD patients show a pure 3EM phenotype, 15.29% are 2EM1IM, 2.04% are pure 3IM, 0% are pure 3PM, and 0% are 1UM2PM. EMs and IMs are the best responders, and PMs and UMs are the worst responders to a combination therapy with cholinesterase inhibitors, neuroprotectants, and vasoactive substances. The pharmacogenetic response in AD appears to be dependent upon the networking activity of genes involved in drug metabolism and genes involved in AD pathogenesis (e.g., APOE). AD patients harboring the APOE-4/4 genotypes are the worst responders to conventional antidementia drugs. To achieve a mature discipline of pharmacogenomics in CNS disorders and dementia it would be convenient to accelerate the following processes: (i) to educate physicians and the public on the use of genetic/genomic screening in daily clinical practice; (ii) to standardize genetic testing for major categories of drugs; (iii) to validate pharmacogenomic information according to drug category and pathology; (iv) to regulate ethical, social, and economic issues; and (v) to incorporate pharmacogenomic procedures both to drugs in development and drugs on the market in order to optimize therapeutics.
| S-EPMC6493895 | biostudies-literature
Project description:OBJECTIVE:Prior studies investigating the association between APOE alleles ?2/?4 and risk of intracerebral hemorrhage (ICH) have been inconsistent and limited to small sample sizes, and did not account for confounding by population stratification or determine which genetic risk model was best applied. METHODS:We performed a large-scale genetic association study of 2189 ICH cases and 4041 controls from 7 cohorts, which were analyzed using additive models for ?2 and ?4. Results were subsequently meta-analyzed using a random effects model. A proportion of the individuals (322 cases, 357 controls) had available genome-wide data to adjust for population stratification. RESULTS:Alleles ?2 and ?4 were associated with lobar ICH at genome-wide significance levels (odds ratio [OR] = 1.82, 95% confidence interval [CI] = 1.50-2.23, p = 6.6 × 10(-10); and OR = 2.20, 95%CI = 1.85-2.63, p = 2.4 × 10(-11), respectively). Restriction of analysis to definite/probable cerebral amyloid angiopathy ICH uncovered a stronger effect. Allele ?4 was also associated with increased risk for deep ICH (OR = 1.21, 95% CI = 1.08-1.36, p = 2.6 × 10(-4)). Risk prediction evaluation identified the additive model as best for describing the effect of APOE genotypes. INTERPRETATION:APOE ?2 and ?4 are independent risk factors for lobar ICH, consistent with their known associations with amyloid biology. In addition, we present preliminary findings on a novel association between APOE ?4 and deep ICH. Finally, we demonstrate that an additive model for these APOE variants is superior to other forms of genetic risk modeling previously applied.
| S-EPMC3058266 | biostudies-literature
Project description:During the last decade, the Caribbean Hispanic islands experienced accelerated demographic aging, representing the fastest aging region within Latin America. Age-related non-communicable diseases, including dementia, are now reported at high prevalence. The Caribbean islands share similar genetic ancestry, culture, migration patterns, and risk profiles, providing a unique setting to understand dementia in the Caribbean-Hispanics. This perspective article aimed to describe the impact of dementia in the Caribbean, at a local and regional level and reflect on research strategies to address dementia. We report on 10/66 project findings, described research projects and regional plans for the region. According to our results, the prevalence of dementia in the Caribbean is the highest in Latin America, with 11.7% in Dominican Republic, 11.6% in Puerto Rico, and 10.8% in Cuba. Preliminary data from new waves of the 10/66 study shows increasing numbers of dementia cases. Furthermore, dementia is expected to be one of the most serious medical and social issues confronted by Caribbean health systems. However, there is a scarcity of knowledge, awareness, and health services to deal with this public health crisis. In light of the new evidence, local and regional strategies are underway to better understand dementia trends for the region and develop policies aimed to decrease the impact of dementia. Implementation of our national plans is critical to deal with an aging population with high dementia rates. Current recommendations include emphasizing public health prevention campaigns to address modifiable risk factors and expand support to caregiver and family interventions.
| S-EPMC7848137 | biostudies-literature
Project description:Cytochrome P450 2D6 (CYP2D6) is a critical pharmacogene involved in the metabolism of ~20% of commonly used drugs across a broad spectrum of medical disciplines including psychiatry, pain management, oncology and cardiology. Nevertheless, CYP2D6 is highly polymorphic with single-nucleotide polymorphisms, small insertions/deletions and larger structural variants including multiplications, deletions, tandem arrangements, and hybridisations with non-functional CYP2D7 pseudogenes. The frequency of these variants differs across populations, and they significantly influence the drug-metabolising enzymatic function of CYP2D6. Importantly, altered CYP2D6 function has been associated with both adverse drug reactions and reduced drug efficacy, and there is growing recognition of the clinical and economic burdens associated with suboptimal drug utilisation. To date, pharmacogenomic clinical guidelines for at least 48 CYP2D6-substrate drugs have been developed by prominent pharmacogenomics societies, which contain therapeutic recommendations based on CYP2D6-predicted categories of metaboliser phenotype. Novel algorithms to interpret CYP2D6 function from sequencing data that consider structural variants, and machine learning approaches to characterise the functional impact of novel variants, are being developed. However, CYP2D6 genotyping is yet to be implemented broadly into clinical practice, and so further effort and initiatives are required to overcome the implementation challenges and deliver the potential benefits to the bedside.
| S-EPMC7692531 | biostudies-literature
Project description:Pharmacogenomics represents a potentially powerful enhancement to the current standard of care for psychiatric patients. However, a variety of biological and technical challenges must be addressed in order to provide adequate clinical decision support for personalized prescribing and dosing based on genomic data. This is particularly true in the case of CYP2D6, a key drug-metabolizing gene, which not only harbors multiple genetic variants known to affect enzyme function but also shows a broad range of copy-number and hybrid alleles in various patient populations. Here, we describe several challenges in the accurate measurement and interpretation of data from the CYP2D6 locus including the clinical consequences of increased copy number. We discuss best practices for overcoming these challenges and then explore various current and future applications of pharmacogenomic analysis of CYP2D6 in psychiatry.
| S-EPMC6595891 | biostudies-literature
Project description:Military Brain Science is a cutting-edge innovative science that uses potential military application as the guidance. It was preliminarily divided into 9 aspects by authors: understanding the brain, protecting the brain, monitoring the brain, injuring the brain, interfering with the brain, repairing the brain, enhancing the brain, simulating the brain and arming the brain. In this review, we attempt to propose the concept, content and meaning of the Military Brain Science, with the hope to provide some enlightenment and understanding of the research area.
| S-EPMC6235785 | biostudies-literature