Publications by authors named "Juan Carlos Carril"

7 Publications

  • Page 1 of 1

DNA Methylation in Neurodegenerative and Cerebrovascular Disorders.

Int J Mol Sci 2020 Mar 23;21(6). Epub 2020 Mar 23.

Euroespes Biomedical Research Center, International Center of Neuroscience and Genomic Medicine, 15165 Corunna, Spain.

DNA methylation is an epigenetic mechanism by which methyl groups are added to DNA, playing a crucial role in gene expression regulation. The aim of the present study is to compare methylation status of healthy subjects with that of patients with Alzheimer's, Parkinson's or Cerebrovascular diseases. We also analyze methylation status of a transgenic Alzheimer's disease mouse model (3xTg-AD). Our results show that both global methylation ( = 141) and hydroxymethylation ( = 131) levels are reduced in DNA samples from buffy coats of patients with neurodegenerative disorders and age-related cerebrovascular disease. The importance of methylation and hydroxymethylation reduction is stressed by the finding that DNMT3a mRNA levels are also downregulated in buffy coats of patients with Dementia ( = 25). Global methylation is also reduced in brain, liver and serum samples of 3xTg-AD vs. wild type mice, such as DNMT3a mRNA levels that are also decreased in the brain of 3xTg-AD ( = 10). These results suggest that the use of global methylation and hydroxymethylation levels, together with the study of DNMT3a expression, could be useful as a new diagnostic biomarker for these prevalent disorders.
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http://dx.doi.org/10.3390/ijms21062220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139499PMC
March 2020

Optimization of Antidepressant use with Pharmacogenetic Strategies.

Curr Genomics 2017 Oct;18(5):442-449

EuroEspes Biomedical Research Center, Institute of Medical Sciences and Genomic Medicine, 15165-Bergondo, Corunna, Spain.

Background: The response rate in the pharmacological treatment of depression has been estimated to be around 50%, achieving a remission in symptomatology in only one third of the patients. Suboptimal prescription of antidepressants has been proposed as a significant explanatory factor for this therapeutic inefficacy. The use of pharmacogenetic testing might favor the optimization of pharmacotherapy in emotional disorders. However, its implementation in the clinical routine requires studies which prove its efficacy.

Objective: The aim is to explore the clinical effects obtained by means of the personalization of antidepressant treatment derived from the pharmacogenetic profile of the individual.

Method: A sample of 291 patients under antidepressant treatment was selected, and these patients were genotyped for the most common polymorphisms of the CYP2D6, CYP2C9, CYP2C19 and CYP3A4/5 genes using RT-PCR and TaqMan® technology. 30 of them were subjected to psycho-affective assessment using the HDRS scale before and after a process of individualization of their psychopharmacological treatment in accordance with the genotype obtained.

Results: 70% of the individuals treated using the traditional criterion of trial-and-error were not taking the active ingredient most suited to their pharmacogenetic profile. The inclusion of this genetic information in the choice of drug and its dosage entailed a significant, progressive reduction in depressive symptomatology, with an efficacy ratio of 80% and a remission of the pathology in almost 30% of the cases.

Conclusion: These results suggest that the prescription of pharmacogenetic profile-based strategies has a positive effect on the therapeutic response to antidepressants.
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http://dx.doi.org/10.2174/1389202918666170426164940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5635649PMC
October 2017

Population-based Study of Risk Polymorphisms Associated with Vascular Disorders and Dementia.

Curr Genomics 2017 Oct;18(5):430-441

EuroEspes Biomedical Research Center, Institute of Medical Science and Genomic Medicine, 15165-Bergondo, Corunna, Spain.

Introduction: Cardiovascular and neurodegenerative disorders are among the major causes of mortality in the developed countries. Population studies evaluate the genetic risk, i.e. the probability of an individual carrying a specific disease-associated polymorphism. Identification of risk polymorphisms is essential for an accurate diagnosis or prognosis of a number of pathologies.

Aims: The aim of this study was to characterize the influence of risk polymorphisms associated with lipid metabolism, hypertension, thrombosis, and dementia, in a large population of Spanish individuals affected by a variety of brain and vascular disorders as well as metabolic syndrome.

Material & Method: We performed a cross-sectional study on 4415 individuals from a widespread regional distribution in Spain (48.15% males and 51.85% females), with mental, neurodegenerative, cerebrovascular, and metabolic disorders. We evaluated polymorphisms in 20 genes involved in obesity, vascular and cardiovascular risk, and dementia in our population and compared it with representative Spanish and European populations. Risk polymorphisms in ACE, AGT(235), IL6(573), PSEN1, and APOE (specially the APOE-ε4 allele) are representative of our population as compared to the reference data of Spanish and European individuals.

Conclusion: The significantly higher distribution of risk polymorphisms in PSEN1 and APOE-ε4 is characteristic of a representative number of patients with Alzheimer's disease; whereas polymorphisms in ACE, AGT(235), and IL6(573), are most probably related with the high number of patients with metabolic syndrome or cerebrovascular damage.
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http://dx.doi.org/10.2174/1389202918666170608093833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5635648PMC
October 2017

ACTN3 genotype influences exercise-induced muscle damage during a marathon competition.

Eur J Appl Physiol 2017 Mar 2;117(3):409-416. Epub 2017 Feb 2.

Chair of Genomic Medicine, Camilo José Cela University, Madrid, Spain.

Purpose: Exercise-induced muscle damage has been identified as one of the main causes of the progressive decrease in running and muscular performance in marathoners. The aim of this investigation was to determine the influence of the ACTN3 genotype on exercise-induced muscle damage produced during a marathon.

Methods: Seventy-one experienced runners competed in a marathon race. Before and after the race, a sample of venous blood was obtained and maximal voluntary leg muscle power was measured during a countermovement jump. In the blood samples, the ACTN3 genotype (R577X) and the changes in serum creatine kinase and myoglobin concentrations were measured. Data from RX heterozygotes and XX mutant homozygotes were grouped as X allele carriers and compared to RR homozygotes.

Results: At the end of the race, X allele carriers presented higher serum myoglobin (774 ± 852 vs 487 ± 367 U L; P = 0.02) and creatine kinase concentrations (508 ± 346 vs 359 ± 170 ng mL; P = 0.04) than RR homozygotes. Pre-to-post-race maximal voluntary leg muscle power reduction was more pronounced in X allele carriers than RR homozygotes (-34.4 ± 16.1 vs -27.3 ± 15.4%; P = 0.05). X allele carriers self-reported higher levels of lower limb muscle pain (7 ± 2 vs 6 ± 2 cm; P = 0.02) than RR homozygotes at the end of the race.

Conclusions: In comparison to RR homozygotes, X allele carriers for the R577X polymorphism of the ACTN3 gene presented higher values for typical markers of exercise-induced muscle damage during a competitive marathon. Thus, the absence of a functional α-actinin-3 produced by the X allele might induce higher levels of muscle breakdown during prolonged running events.
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http://dx.doi.org/10.1007/s00421-017-3542-zDOI Listing
March 2017

Pharmacogenetic considerations in the treatment of Alzheimer's disease.

Pharmacogenomics 2016 06 13;17(9):1041-74. Epub 2016 Jun 13.

EuroEspes Biomedical Research Center, Institute of Medical Science and Genomic Medicine, Corunna, Spain.

The practical pharmacogenetics of Alzheimer's disease (AD) is circumscribed to acetylcholinesterase inhibitors (AChEIs) and memantine. However, pharmacogenetic procedures should be applied to novel strategies in AD therapeutics including: novel AChEIs and neurotransmitter regulators, anti-Aβ treatments, anti-tau treatments, pleiotropic products, epigenetic drugs and combination therapies. Genes involved in the pharmacogenetic network are under the influence of the epigenetic machinery which regulates gene expression transcriptionally and post-transcriptionally, configuring the fundamentals of pharmacoepigenomics. Over 60% of AD patients present concomitant pathologies demanding additional treatments which increase the likelihood of drug-drug interactions. Lipid metabolism dysfunction is a pathogenic mechanism inherent to AD neurodegeneration. The therapeutic response to hypolipidemic compounds is influenced by the APOE and CYP genotypes. The development of novel compounds and the use of combination/multifactorial treatments require the implantation of pharmacogenomic procedures for the avoidance of ADRs and the optimization of therapeutics.
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http://dx.doi.org/10.2217/pgs-2016-0031DOI Listing
June 2016

Genomics and pharmacogenomics of brain disorders.

Curr Pharm Biotechnol 2012 Apr;13(5):674-725

EuroEspes Biomedical Research Center, Institute for CNS Disorders and Genomic Medicine, EuroEspes Chair of Biotechnology and Genomics, Camilo José Cela University, Bergondo, Corunna, Spain.

CNS disorders are the third major problem of health in developed countries, with approximately 10% of direct costs associated with a pharmacological treatment of doubtful cost-effectiveness. There is an alarming abuse of psychotropic drugs worldwide and only 20-30% of patients with CNS disorders appropriately respond to conventional drugs. The pathogenesis of most CNS disorders is the result of the interplay of genetic and epigenetic factors with environmental factors leading to post-transcriptional changes and proteomic and metabolomic dysfunctions. It is estimated that genetics accounts for 20% to 95% of variability in drug disposition and pharmacodynamics, and about 25-60% of the Western population is defective in genes responsible for drug metabolism. In the European population only 25% of subjects are pure extensive metabolizers for the trigenic cluster integrated by the CYP2D6, CYP2C19 and CYP2C9 genes. About 50% of adverse drug events in CNS disorders might be attributed to pharmacogenomic factors. The rationale for practical pharmacogenomics and personalized therapeutics based on individual genomic profiles implies the management of different types of genes and their products including (i) genes associated with the mechanism of action of psychotropic drugs (neurotransmitters, receptors, transporters), (ii) genes encoding enzymes responsible for drug metabolism (phase I, phase II reactions), (iii) disease-specific genes associated with a particular pathogenic cascade, and (iv) pleiotropic genes with multilocative effects in metabolomic networks. The incorporation of genomic medicine procedures and pharmacogenomics into clinical practice, together with educational programs for the correct use of medication, must help to optimize therapeutics in CNS disorders.
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http://dx.doi.org/10.2174/138920112799857576DOI Listing
April 2012

Mitochondrial DNA error prophylaxis: assessing the causes of errors in the GEP'02-03 proficiency testing trial.

Forensic Sci Int 2005 Mar;148(2-3):191-8

Unidad de Genética, Facultad de Medicina de la Universidad de Santiago de Compostela, Instituto de Medicina Legal, A Coruña, Galicia-Spain.

We report the results of the Spanish and Portuguese working group (GEP) of the International Society for Forensic Genetics (ISFG) Collaborative Exercise 2002-2003 on mitochondrial DNA (mtDNA) analysis. Six different samples were submitted to the participating laboratories: four blood stains (M1-M2-M3-M4), one mixture blood sample (M5), and two hair shaft fragments (M6). Most of the labs reported consensus results for the blood stains, slightly improving the results of previous collaborative exercises. Although hair shaft analysis is still carried out by a small number of laboratories, this analysis yielded a high rate of success. On the contrary, the analysis of the mixture blood stain (M5) yielded a lower rate of success; in spite of this, the whole results on M5 typing demonstrated the suitability of mtDNA analysis in mixture samples. We have found that edition errors are among the most common mistakes reported by the different labs. In addition, we have detected contamination events as well as other minor problems, i.e. lack of standarization in nomenclature for punctual and length heteroplasmies, and indels. In the present edition of the GEP-ISFG exercise we have paid special attention to the visual phylogenetic inspection for detecting common sequencing errors.
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http://dx.doi.org/10.1016/j.forsciint.2004.06.008DOI Listing
March 2005