Precision Medicine Genomics: Pharmacogenomics

A special issue of Journal of Personalized Medicine (ISSN 2075-4426). This special issue belongs to the section "Omics/Informatics".

Deadline for manuscript submissions: closed (15 September 2023) | Viewed by 14679

Special Issue Editors

Servicio de Farmacia, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, 28007 Madrid, Spain
Interests: pharmacogenomics; pharmacogenetics; fluoropyrimidines; anti-TNFs; cancer; inflammatory bowel disease; multiple sclerosis; dual pathology
Special Issues, Collections and Topics in MDPI journals
Servicio de Farmacia, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, 28007 Madrid, Spain
Interests: pharmacogenomics; pharmacogenetics; personalized medicine; fluoropyrimidines; anti-TNFs; cancer; inflammatory bowel disease; multiple sclerosis; dual pathology
Institute for Anthropological Research, 10000 Zagreb, Croatia
Interests: candidate genes for cardiovascular diseases (CVD); impact of environment factors on CVD; hypertension; longevity; obesity; secular trend

Special Issue Information

Dear Colleagues,

The history of healthcare is going through a period of transformation. The concept of "precision medicine" concerns the prevention, diagnosis and treatment of diseases by taking into account the genomic and molecular characteristics of each patient.

Traditionally, the selection of a particular drug for pharmacological prescription has been decided by trial and error. However, an increasing amount of information is becoming available to increase efficacy and prevent adverse drug reactions based on pharmacogenomics. Pharmacogenomics is the main tool of precision medicine that uses genetic/omics information to individualize prescriptions in order to optimize drug response. In this way, the efficacy of these therapies would be maximized, reducing side effects and also the unnecessary costs associated with treatment failure and hospitalizations due to adverse drug reactions, thus improving patients' quality of life.

However, since precision medicine remains a challenge, the aim of this issue is to collect solid articles from any field of personalized medicine or genomics that will increase the knowledge of precision medicine.

Dr. Luis Andrés López-Fernández
Dr. Sara Salvador-Martín
Dr. Matea Zajc Petranović
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Personalized Medicine is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • personalized medicine
  • individualized treatment
  • pharmacogenomics
  • genomics
  • adverse drug reactions
  • biomarkers
  • effectiveness

Published Papers (8 papers)

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Research

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13 pages, 283 KiB  
Article
Preemptive TPMT Genotyping and Adherence to Genotype-Based Therapeutic Recommendations Reduces the Healthcare Cost in Patients Receiving Azathioprine or 6-Mercaptopurine for Autoimmune Diseases
by Sarahí Valdez-Acosta, Pablo Zubiaur, Miguel Angel Casado, Jesús Novalbos, Ana Casajús, Diana Campodónico, Itziar Oyagüez and Francisco Abad-Santos
J. Pers. Med. 2023, 13(8), 1208; https://doi.org/10.3390/jpm13081208 - 29 Jul 2023
Cited by 2 | Viewed by 1011
Abstract
A cost analysis of thiopurine treatment was carried out in 257 patients, with 153 preemptively genotyped for TPMT and 104 retrospectively genotyped in a Spanish setting. The healthcare cost was significantly higher in patients retrospectively genotyped compared to those who were preemptively genotyped [...] Read more.
A cost analysis of thiopurine treatment was carried out in 257 patients, with 153 preemptively genotyped for TPMT and 104 retrospectively genotyped in a Spanish setting. The healthcare cost was significantly higher in patients retrospectively genotyped compared to those who were preemptively genotyped (p < 0.001). TPMT intermediate metabolizers (IMs) (n = 23) showed a 3.3-fold higher healthcare cost when compared to normal metabolizers (NMs) (p < 0.001). The healthcare cost in patients with a TPMT IM phenotype whose physician adhered to the genotype-informed recommendation was similar than the cost in TPMT NMs and was significantly lower than IMs whose physician did not adhere to the therapeutic recommendation (3.8-fold, p = 0.016). Myelotoxicity occurrence was significantly lower in patients preemptively vs. retrospectively genotyped (2.0% and 21.2%, respectively, p < 0.001). Patients who developed myelotoxicity showed a significantly higher healthcare cost than those who did not (4.10-fold, p < 0.001). Overall, 87% of patients whose dose was not adjusted despite being TPMT IMs suffered myelotoxicity, while only one of the eight patients (13%) whose dose was adjusted suffered myelotoxicity (p < 0.001). In conclusion, TPMT preemptive genotyping and physician adherence to genotype-informed therapeutic recommendations prevents myelotoxicity and significantly reduces the healthcare cost, and it is therefore essential for the sustainability of the Spanish healthcare system. Full article
(This article belongs to the Special Issue Precision Medicine Genomics: Pharmacogenomics)
13 pages, 318 KiB  
Article
Identification of Transporter Polymorphisms Influencing Metformin Pharmacokinetics in Healthy Volunteers
by Miriam Saiz-Rodríguez, Dolores Ochoa, Pablo Zubiaur, Marcos Navares-Gómez, Manuel Román, Paola Camargo-Mamani, Sergio Luquero-Bueno, Gonzalo Villapalos-García, Raquel Alcaraz, Gina Mejía-Abril, Estefanía Santos-Mazo and Francisco Abad-Santos
J. Pers. Med. 2023, 13(3), 489; https://doi.org/10.3390/jpm13030489 - 08 Mar 2023
Cited by 4 | Viewed by 1570
Abstract
For patients with type 2 diabetes, metformin is the most often recommended drug. However, there are substantial individual differences in the pharmacological response to metformin. To investigate the effect of transporter polymorphisms on metformin pharmacokinetics in an environment free of confounding variables, we [...] Read more.
For patients with type 2 diabetes, metformin is the most often recommended drug. However, there are substantial individual differences in the pharmacological response to metformin. To investigate the effect of transporter polymorphisms on metformin pharmacokinetics in an environment free of confounding variables, we conducted our study on healthy participants. This is the first investigation to consider demographic characteristics alongside all transporters involved in metformin distribution. Pharmacokinetic parameters of metformin were found to be affected by age, sex, ethnicity, and several polymorphisms. Age and SLC22A4 and SLC47A2 polymorphisms affected the area under the concentration-time curve (AUC). However, after adjusting for dose-to-weight ratio (dW), sex, age, and ethnicity, along with SLC22A3 and SLC22A4, influenced AUC. The maximum concentration was affected by age and SLC22A1, but after adjusting for dW, it was affected by sex, age, ethnicity, ABCG2, and SLC22A4. The time to reach the maximum concentration was influenced by sex, like half-life, which was also affected by SLC22A3. The volume of distribution and clearance was affected by sex, age, ethnicity and SLC22A3. Alternatively, the pharmacokinetics of metformin was unaffected by polymorphisms in ABCB1, SLC2A2, SLC22A2, or SLC47A1. Therefore, our study demonstrates that a multifactorial approach to all patient characteristics is necessary for better individualization. Full article
(This article belongs to the Special Issue Precision Medicine Genomics: Pharmacogenomics)
9 pages, 283 KiB  
Article
Clinical Value of IL6R Gene Variants as Predictive Biomarkers for Toxicity to Tocilizumab in Patients with Rheumatoid Arthritis
by Luis Sainz, Pau Riera, Patricia Moya, Sara Bernal, Jordi Casademont, Cesar Díaz-Torné, Ana Milena Millán, Hye Sang Park, Adriana Lasa and Héctor Corominas
J. Pers. Med. 2023, 13(1), 61; https://doi.org/10.3390/jpm13010061 - 28 Dec 2022
Cited by 1 | Viewed by 1895
Abstract
Tocilizumab is a first-line biologic disease-modifying anti-rheumatic drug (bDMARD) that inhibits the interleukin-6 (IL-6) pathway by antagonizing the IL-6 receptor (IL-6R). Tocilizumab is widely used to treat rheumatoid arthritis (RA), a prevalent autoimmune disease that can cause irreversible joint damage and disability. Although [...] Read more.
Tocilizumab is a first-line biologic disease-modifying anti-rheumatic drug (bDMARD) that inhibits the interleukin-6 (IL-6) pathway by antagonizing the IL-6 receptor (IL-6R). Tocilizumab is widely used to treat rheumatoid arthritis (RA), a prevalent autoimmune disease that can cause irreversible joint damage and disability. Although many bDMARDs have been developed for RA, there is a lack of validated biomarkers which could guide personalized medicine strategies. To evaluate whether single-nucleotide polymorphisms (SNPs) in the IL6R gene could predict tocilizumab toxicity in patients with RA, we conducted a retrospective cohort study of 88 patients treated with tocilizumab. Six SNPs previously described in the IL6R gene were genotyped (rs12083537, rs11265618, rs4329505, rs2228145, rs4537545, and rs4845625). Using parametric tests, we studied the association between the SNPs and hepatotoxicity, infection, hypersensitivity, gastrointestinal, hematological, and dyslipidemia adverse events (AEs). We found associations between dyslipidemia and rs4845625 and between hematological AEs and rs11265618 and rs4329505. No further associations were found for the remaining SNPs and other AEs. Our findings support the potential clinical value of SNPs in the IL6R gene as predictive biomarkers for toxicity to tocilizumab in patients with RA. Full article
(This article belongs to the Special Issue Precision Medicine Genomics: Pharmacogenomics)
15 pages, 6695 KiB  
Article
Pharmacogenetics of CYP2A6, CYP2B6, and UGT2B7 in the Context of HIV Treatments in African Populations
by Graeme R. Ford, Antoinette Niehaus, Fourie Joubert and Michael S. Pepper
J. Pers. Med. 2022, 12(12), 2013; https://doi.org/10.3390/jpm12122013 - 05 Dec 2022
Viewed by 1611
Abstract
Objectives: This study focuses on identifying variations in selected CYP genes related to treatment responses in patients with HIV in African populations by investigating variant characteristics and effects in African cohorts. Design: Cytochrome P450 (CYP) 2A6, 2B6, and Uridine 5’-diphospho-glucuronosyltransferase (UGT) 2B7 allele [...] Read more.
Objectives: This study focuses on identifying variations in selected CYP genes related to treatment responses in patients with HIV in African populations by investigating variant characteristics and effects in African cohorts. Design: Cytochrome P450 (CYP) 2A6, 2B6, and Uridine 5’-diphospho-glucuronosyltransferase (UGT) 2B7 allele frequencies were studied using public-domain datasets obtained from the 1000 Genomes Phase 3 project, the African Genome Variation Project (AGVP), and the South African Human Genome Programme (SAHGP). Methods: Variant annotations were performed using self-identified ethnicities to conduct allele frequency analysis in a population-stratification-sensitive manner. The NCBI DB-SNP database was used to identify documented variants and standard frequencies, and the E! Ensembl Variant Effect Predictor tool was used to perform the prediction of possible deleterious variants. Results: A total of 4468 variants were identified across 3676 individuals following pre-filtering. Seventy-one variants were identified at an allelic frequency (1% or more in at least one population), which were predicted to be linked to existing disease associations and, in some cases, linked to drug metabolisms. This list was further studied to identify 23 alleles with disease considerations found at significantly different frequencies in one or more populations. Conclusions: This study describes allele frequencies observed in African populations at significantly different frequencies relative to at least one other reference population and identifies a subset of variants of clinical interest. Despite the inclusion of mixed sequence coverage datasets, the variants identified pose notable avenues for future inquiries. A subset of variants of clinical interest with statistically significant inter-population frequency differences was identified for further inspection, which provides evidence of an African population-specific variant frequency profile. This study highlights the need for additional research and African genetics data given the presence of this unique frequency profile to better facilitate the genetic pre-screening of patients as a standard of practice in HIV care, particularly on the African continent where HIV is highly prevalent. Full article
(This article belongs to the Special Issue Precision Medicine Genomics: Pharmacogenomics)
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14 pages, 1523 KiB  
Article
From Croatian Roma to 1000 Genomes: The Story of the CYP2D6 Gene Promoter and Enhancer SNPs
by Anita Stojanović Marković, Željka Celinšćak, Maja Šetinc, Tatjana Škarić-Jurić, Marijana Peričić Salihović and Matea Zajc Petranović
J. Pers. Med. 2022, 12(8), 1353; https://doi.org/10.3390/jpm12081353 - 22 Aug 2022
Viewed by 1362
Abstract
The CYP2D6 gene encodes an enzyme responsible for the metabolism of ~20% of clinically prescribed drugs. In this study, 18 SNPs from the enhancer and promoter regions of CYP2D6 in 323 Roma from Croatia were genotyped, to find out whether the demographic history [...] Read more.
The CYP2D6 gene encodes an enzyme responsible for the metabolism of ~20% of clinically prescribed drugs. In this study, 18 SNPs from the enhancer and promoter regions of CYP2D6 in 323 Roma from Croatia were genotyped, to find out whether the demographic history of Roma affected the distribution of the studied SNPs and their linkage disequilibrium (LD) values, with the major SNPs defining the CYP2D6 star alleles. No differences were found between the three Roma groups in allele and genotype frequencies. The distribution of LD values of Roma was compared with LD values of European and Asian populations. Regulatory CYP2D6 SNPs (rs5758550, rs28624811, rs1080985 and rs1080983) showed similar distribution and the highest LDs with rs16947 from the gene-coding region in all populations. In the promoter region, a complete LD between rs1080989 and rs28588594, and between rs1080983 and rs28624811, was found in Croatian Roma and investigated populations from 1000 genomes. A high LD was also found between rs1080985 from the promoter and rs5758550 from the enhancer region. SNP rs28735595 from the gene promoter region had the highest LD, with two gene region SNPs, rs1058164 and rs1135840. To conclude, the Croatian Roma population shows an LD pattern of the CYP2D6 gene region similar to the 1000 Genomes European and Asian populations. Full article
(This article belongs to the Special Issue Precision Medicine Genomics: Pharmacogenomics)
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16 pages, 347 KiB  
Article
Pharmacogenetics of Donepezil and Memantine in Healthy Subjects
by María C. Ovejero-Benito, Dolores Ochoa, Teresa Enrique-Benedito, Miriam del Peso-Casado, Pablo Zubiaur, Marcos Navares, Manuel Román and Francisco Abad-Santos
J. Pers. Med. 2022, 12(5), 788; https://doi.org/10.3390/jpm12050788 - 13 May 2022
Cited by 3 | Viewed by 2435
Abstract
Donepezil and memantine are the most common drugs used for Alzheimer’s disease. Their low effectiveness could partly be explained by genetic factors. Thus, we aim to identify Single Nucleotide Polymorphisms (SNPs) associated with pharmacokinetics, pharmacodynamics, and the safety of donepezil and memantine. For [...] Read more.
Donepezil and memantine are the most common drugs used for Alzheimer’s disease. Their low effectiveness could partly be explained by genetic factors. Thus, we aim to identify Single Nucleotide Polymorphisms (SNPs) associated with pharmacokinetics, pharmacodynamics, and the safety of donepezil and memantine. For this regard, 25 volunteers enrolled in a bioequivalence clinical trial were genotyped for 67 SNPs in 21 genes with a ThermoFisher QuantStudio 12K Flex OpenArray. The statistical strategy included a univariate analysis that analyzed the association of these SNPs with pharmacokinetic parameters or the development of adverse drug reactions (ADRs) followed by a Bonferroni-corrected multivariate regression. Statistical analyses were performed with SPSS software v.21 and R commander (version v3.6.3). In the univariate analysis, fourteen and sixteen SNPs showed a significant association with memantine’s and donepezil’s pharmacokinetic parameters, respectively. Rs20417 (PTGS2) was associated with the development of at least one ADR. However, none of these associations reached the significance threshold in the Bonferroni-corrected multivariate analysis. In conclusion, we did not observe any significant association of the SNPs analyzed with memantine and donepezil pharmacokinetics or ADRs. Current evidence on memantine and donepezil pharmacogenetics does not justify their inclusion in pharmacogenetic guidelines. Full article
(This article belongs to the Special Issue Precision Medicine Genomics: Pharmacogenomics)
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Review

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13 pages, 646 KiB  
Review
Bortezomib Pharmacogenetic Biomarkers for the Treatment of Multiple Myeloma: Review and Future Perspectives
by Antonio Sanz-Solas, Jorge Labrador, Raquel Alcaraz, Beatriz Cuevas, Raquel Vinuesa, María Victoria Cuevas and Miriam Saiz-Rodríguez
J. Pers. Med. 2023, 13(4), 695; https://doi.org/10.3390/jpm13040695 - 20 Apr 2023
Cited by 1 | Viewed by 1390
Abstract
Multiple myeloma (MM) is a hematological neoplasm for which different chemotherapy treatments are used with several drugs in combination. One of the most frequently used drugs for the treatment of MM is the proteasome inhibitor bortezomib. Patients treated with bortezomib are at increased [...] Read more.
Multiple myeloma (MM) is a hematological neoplasm for which different chemotherapy treatments are used with several drugs in combination. One of the most frequently used drugs for the treatment of MM is the proteasome inhibitor bortezomib. Patients treated with bortezomib are at increased risk for thrombocytopenia, neutropenia, gastrointestinal toxicities, peripheral neuropathy, infection, and fatigue. This drug is almost entirely metabolized by cytochrome CYP450 isoenzymes and transported by the efflux pump P-glycoprotein. Genes encoding both enzymes and transporters involved in the bortezomib pharmacokinetic pathway are highly polymorphic. The response to bortezomib and the incidence of adverse drug reactions (ADRs) vary among patients, which could be due to interindividual variations in these possible pharmacogenetic biomarkers. In this review, we compiled all pharmacogenetic information relevant to the treatment of MM with bortezomib. In addition, we discuss possible future perspectives and the analysis of potential pharmacogenetic markers that could influence the incidence of ADR and the toxicity of bortezomib. It would be a milestone in the field of targeted therapy for MM to relate potential biomarkers to the various effects of bortezomib on patients. Full article
(This article belongs to the Special Issue Precision Medicine Genomics: Pharmacogenomics)
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18 pages, 472 KiB  
Review
Pharmacogenetics in the Treatment of Huntington’s Disease: Review and Future Perspectives
by Xandra García-González, Esther Cubo, Lucía Simón-Vicente, Natividad Mariscal, Raquel Alcaraz, Laura Aguado, Jéssica Rivadeneyra-Posadas, Antonio Sanz-Solas and Miriam Saiz-Rodríguez
J. Pers. Med. 2023, 13(3), 385; https://doi.org/10.3390/jpm13030385 - 22 Feb 2023
Cited by 4 | Viewed by 2544
Abstract
Huntington’s disease (HD) is an autosomal dominant progressive brain disorder, caused by a pathological expansion of a CAG repeat that encodes the huntingtin gene. This genetic neurodegenerative rare disease is characterized by cognitive, motor, and neuropsychiatric manifestations. The aim of the treatment is [...] Read more.
Huntington’s disease (HD) is an autosomal dominant progressive brain disorder, caused by a pathological expansion of a CAG repeat that encodes the huntingtin gene. This genetic neurodegenerative rare disease is characterized by cognitive, motor, and neuropsychiatric manifestations. The aim of the treatment is symptomatic and addresses the hyperkinetic disorders (chorea, dystonia, myoclonus, tics, etc.) and the behavioural and cognitive disturbances (depression, anxiety, psychosis, etc.) associated with the disease. HD is still a complex condition in need of innovative and efficient treatment. The long-term goal of pharmacogenetic studies is to use genotype data to predict the effective treatment response to a specific drug and, in turn, prevent potential undesirable effects of its administration. Chorea, depression, and psychotic symptoms have a substantial impact on HD patients’ quality of life and could be better controlled with the help of pharmacogenetic knowledge. We aimed to carry out a review of the available publications and evidence related to the pharmacogenetics of HD, with the objective of compiling all information that may be useful in optimizing drug administration. The impact of pharmacogenetic information on the response to antidepressants and antipsychotics is well documented in psychiatric patients, but this approach has not been investigated in HD patients. Future research should address several issues to ensure that pharmacogenetic clinical use is appropriately supported, feasible, and applicable. Full article
(This article belongs to the Special Issue Precision Medicine Genomics: Pharmacogenomics)
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