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Molecular Psychiatry Dec 2023Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population...
Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li was developed in the International Consortium of Lithium Genetics cohort (ConLiGen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P < 0.05. Li was positively associated with lithium treatment response in the ConLiGen cohort, in both the categorical (P = 9.8 × 10, R = 1.9%) and continuous (P = 6.4 × 10, R = 2.6%) outcomes. Compared to bipolar patients in the 1 decile of the risk distribution, individuals in the 10 decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P = 3.9 × 10, R = 0.9%), but not for the continuous outcome (P = 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.
Topics: Bipolar Disorder; Humans; Female; Male; Multifactorial Inheritance; Adult; Middle Aged; Lithium; Treatment Outcome; Bayes Theorem; Genome-Wide Association Study; Glutamic Acid; Cohort Studies; Lithium Compounds; Acetylcholine; Polymorphism, Single Nucleotide; Antimanic Agents
PubMed: 37433967
DOI: 10.1038/s41380-023-02149-1 -
Journal of Personalized Medicine May 2023duplication has important pharmacogenomic implications. Reflex testing with long-range PCR (LR-PCR) can resolve the genotype when a duplication and alleles with...
duplication has important pharmacogenomic implications. Reflex testing with long-range PCR (LR-PCR) can resolve the genotype when a duplication and alleles with differing activity scores are detected. We evaluated whether visual inspection of plots from real-time-PCR-based targeted genotyping with copy number variation (CNV) detection could reliably determine the duplicated allele. Six reviewers evaluated QuantStudio OpenArray genotyping results and the TaqMan Genotyper plots for seventy-three well-characterized cases with three copies of and two different alleles. Reviewers blinded to the final genotype visually assessed the plots to determine the duplicated allele or opt for reflex sequencing. Reviewers achieved 100% accuracy for cases with three copies that they opted to report. Reviewers did not request reflex sequencing in 49-67 (67-92%) cases (and correctly identified the duplicated allele in each case); all remaining cases (6-24) were marked by at least one reviewer for reflex sequencing. In most cases with three copies of , the duplicated allele can be determined using a combination of targeted genotyping using real-time PCR with CNV detection without need for reflex sequencing. In ambiguous cases and those with >3 copies, LR-PCR and Sanger sequencing may still be necessary for determination of the duplicated allele.
PubMed: 37373874
DOI: 10.3390/jpm13060883 -
Cells Jun 2023Monoclonal antibody (mAb) therapy directed against CD20 is an important tool in the treatment of B cell disorders. However, variable patient response and acquired...
Monoclonal antibody (mAb) therapy directed against CD20 is an important tool in the treatment of B cell disorders. However, variable patient response and acquired resistance remain important clinical challenges. To identify genetic factors that may influence sensitivity to treatment, the cytotoxic activity of three CD20 mAbs: rituximab; ofatumumab; and obinutuzumab, were screened in high-throughput assays using 680 ethnically diverse lymphoblastoid cell lines (LCLs) followed by a pharmacogenomic assessment. GWAS analysis identified several novel gene candidates. The most significant SNP, rs58600101, in the gene displayed ethnic stratification, with the variant being significantly more prevalent in the African cohort and resulting in reduced transcript levels as measured by qPCR. Functional validation of by shRNA-mediated knockdown of MKL1 resulted in a more resistant phenotype. Gene expression analysis identified the developmentally associated as the most significant gene associated with sensitivity. qPCR among a panel of sensitive and resistant LCLs revealed immunoglobulin class-switching as well as differences in the expression of B cell activation markers. Flow cytometry showed heterogeneity within some cell lines relative to surface Ig isotype with a shift to more IgG cells among the resistant lines. Pretreatment with prednisolone could partly reverse the resistant phenotype. Results suggest that the efficacy of anti-CD20 mAb therapy may be influenced by B cell developmental status as well as polymorphism in the gene. A clinical benefit may be achieved by pretreatment with corticosteroids such as prednisolone followed by mAb therapy.
Topics: Antibodies, Monoclonal; Antigens, CD20; Antineoplastic Agents; Pharmacogenomic Testing; Prednisolone; Humans
PubMed: 37371044
DOI: 10.3390/cells12121574 -
Frontiers in Pharmacology 2023Pharmacogenomics, which is defined as the study of changes in the properties of DNA and RNA associated with drug response, enables the prediction of the efficacy and...
Pharmacogenomics, which is defined as the study of changes in the properties of DNA and RNA associated with drug response, enables the prediction of the efficacy and adverse effects of drugs based on patients' specific genetic mutations. For the safe and effective use of drugs, it is important that pharmacogenomic information is easily accessible to clinical experts and patients. Therefore, we examined the pharmacogenomic information provided on drug labels in Korea, Europe, Japan, and the United States (US). The selection of drugs that include pharmacogenomic information was based on the drug list that includes genetic information from the Korea Ministry of Food and Drug Safety (MFDS) and US Food and Drug Administration (FDA) websites. Drug labels were retrieved from the sites of MFDS, FDA, European Medicines Agency, and Japanese Pharmaceuticals and Medical Devices Agency. Drugs were classified as per the Anatomical Therapeutic Chemical code, and the biomarkers, labeling sections, and necessity of genetic tests were determined. In total, 348 drugs were selected from 380 drugs with available pharmacogenomic information in Korea and the US after applying the inclusion and exclusion criteria. Of these drugs, 137, 324, 169, and 126 were with pharmacogenomics information in Korea, the US, Europe, and Japan, respectively. The most commonly represented drug class was antineoplastic and immunomodulating agents. Regarding the classification as per the mentioned biomarkers, the cytochrome P450 enzyme was the most frequently mentioned information, and the targeted anticancer drugs most commonly required genetic biomarker testing. The reasons for differences in drug labeling information based on country include differences in mutant alleles according to ethnicity, frequencies at which drug lists are updated, and pharmacogenomics-related guidelines. Clinical experts must continuously strive to identify and report mutations that can explain drug efficacy or side effects for safe drug use.
PubMed: 37361213
DOI: 10.3389/fphar.2023.1205624 -
Frontiers in Genetics 2023Genomic studies of Legacy African Americans have a tangled and convoluted history in western science. In this review paper, core issues affecting African American...
Genomic studies of Legacy African Americans have a tangled and convoluted history in western science. In this review paper, core issues affecting African American genomic studies are addressed and two case studies, the New York African Burial Ground and the Gullah Geechee peoples, are presented to highlight the current status of genomic research among Africa Americans. To investigate our target population's core issues, a metadatabase derived from 22 publicly accessible databases were reviewed, evaluated, and synthesized to identify the core bioethical issues prevalent during the centuries of the African American presence in North America. The sequence of metadatabase development included 5 steps: identification of information, record screening and retention of topic relevant information, identification of eligibility via synthesis for concept identifications, and inclusion of studies used for conceptual summaries and studies used for genetic and genomic summaries. To these data we added our emic perspectives and specific insights from our case studies. Overall, there is a paucity of existing research on underrepresent African American genomic diversity. In every category of genomic testing (i.e., diagnostic, clinical predictive, pharmacogenomic, direct-to-consumer, and tumor testing), African Americans are disproportionately underrepresented compared to European Americans. The first of our case studies is from the New York African Burial Ground Project where genomic studies of grave soil derived aDNA yields insights into the causes of death of 17 and 18 Century African Americans. In the second of our case studies, research among the Gullah Geechee people of the Carolina Lowcountry reveals a connection between genomic studies and health disparities. African Americans have historically borne the brunt of the earliest biomedical studies used to generate and refine primitive concepts in genetics. As exploited victims these investigations, African American men, women, and children were subjected to an ethics-free western science. Now that bioethical safeguards have been added, underrepresented and marginalized people who were once the convenient targets of western science, are now excluded from its health-related benefits. Recommendations to enhance the inclusion of African Americans in global genomic databases and clinical trials should include the following: emphasis on the connection of inclusion to advances in precision medicine, emphasis on the relevance of inclusion to fundamental questions in human evolutionary biology, emphasis on the historical relevance of inclusion for Legacy African Americans, emphasis on the ability of inclusion to foster expanded scientific expertise in the target population, ethical engagement with their descendants, and increase the number of science researchers from these communities.
PubMed: 37359364
DOI: 10.3389/fgene.2023.843209 -
International Journal of Clinical... Dec 2023Pharmacogenetic (PGx) testing and counselling (short: PGx service) in the community pharmacy is not routinely practiced. We propose a comprehensive pharmacist-led...
BACKGROUND
Pharmacogenetic (PGx) testing and counselling (short: PGx service) in the community pharmacy is not routinely practiced. We propose a comprehensive pharmacist-led service where PGx information is integrated into medication reviews.
AIM
To evaluate the pharmacist-led service comprising PGx testing and counselling (PGx service) from the perspective of patients.
METHOD
For this mixed-methods study, we conducted two follow-up interviews F1 and F2 with patients recruited for the PGx service in a community pharmacy after 1st of January 2020. The semi-structured interviews were held by phone call and covered understanding of PGx, the implementation of recommendations, handling of PGx documents (list of concerned substances and PGx recommendation), gain in medication knowledge, and willingness to pay for the PGx service.
RESULTS
We interviewed 25 patients in F1 and 42 patients in F2. Patients were generally able to understand and use results of the PGx service. At least one PGx recommendation was implemented for 69% of the patients. Handling of PGx documents ranged from patients having forgotten about the PGx results to patients consulting the list for every medication-related decision; the latter often expecting negative effects. Finally, 62% of the patients were willing to pay for the PGx service.
CONCLUSION
For future PGx testing and counselling, HCPs should consider the patients' health literacy in a standardized way and use adequate communication skills to enhance the patient's understanding in PGx and to attenuate potential negative expectations.
Topics: Humans; Pharmacogenomic Testing; Pharmacists; Pharmacies; Pharmacogenetics; Counseling
PubMed: 37338707
DOI: 10.1007/s11096-023-01596-8 -
Asian Journal of Psychiatry Aug 2023Pharmacogenetic studies the influence of inherited characteristics on medication. While different from pharmacogenomics, which is a study of the entire genome in...
Pharmacogenetic studies the influence of inherited characteristics on medication. While different from pharmacogenomics, which is a study of the entire genome in relation to medication effect, their distinction remains inconsistent, and the two terms are used interchangeably. Although the potential of pharmacogenomics in psychiatry is apparent and its clinical utility is suboptimal, the uptake of recommendations and guidelines is minimal and research into PGx is not diverse. This article offers an overview of pharmacogenetics (PGx) in psychiatry, explores the difficulties, and provides recommendations on improving its applicability and clinical utility.
Topics: Humans; Pharmacogenomic Testing; Pharmacogenetics; Psychiatry
PubMed: 37327563
DOI: 10.1016/j.ajp.2023.103674 -
Medical Science Monitor : International... Jun 2023BACKGROUND Pharmacogenomics (PGx) has a direct influence on personalized drug therapy for various types of disorders and has been proven to have an important role in the...
BACKGROUND Pharmacogenomics (PGx) has a direct influence on personalized drug therapy for various types of disorders and has been proven to have an important role in the future of medicine. The present study evaluated the awareness of PGx testing of clinicians and healthcare workers in the Republic of Poland. To the best of our knowledge, this is the first direct assessment of Polish healthcare professionals' attitudes toward introducing PGx tests into daily clinical practice. MATERIAL AND METHODS We used a comprehensive anonymous questionnaire with queries on level of education, background knowledge of PGx tests, advantages and barriers for implementation of such tests, and clinicians' desire to order the test that was distributed online to doctors, healthcare workers, related students/Ph.D. students, and administrative staff managing healthcare units. RESULTS We gathered 315 responses. According to the answers, two-thirds of participants had heard about PGx before (64.4%). An overwhelming majority of respondents appreciated the benefits of PGx (93.3%). Indeed, prior knowledge and level of education showed significant associations with positive attitudes toward PGx clinical testing (P≤0.05). However, all participants agreed there are major challenges for including such tests as part of routine clinical practice. CONCLUSIONS While the awareness and interest in PGx clinical testing in Polish healthcare providers are rising, some main barriers for implementation of these tests still need to be addressed in Poland.
Topics: Humans; Poland; Pharmacogenetics; Health Personnel; Physicians; Educational Status
PubMed: 37303136
DOI: 10.12659/MSM.940119 -
Frontiers in Pharmacology 2023Population genomic studies of individuals of Indigenous ancestry have been extremely limited comprising <0.5% of participants in international genetic databases and...
Population genomic studies of individuals of Indigenous ancestry have been extremely limited comprising <0.5% of participants in international genetic databases and genome-wide association studies, contributing to a "genomic gap" that limits their access to personalised medicine. While Indigenous Australians face a high burden of chronic disease and associated medication exposure, corresponding genomic and drug safety datasets are sorely lacking. To address this, we conducted a pharmacogenomic study of almost 500 individuals from a founder Indigenous Tiwi population. Whole genome sequencing was performed using short-read Illumina Novaseq6000 technology. We characterised the pharmacogenomics (PGx) landscape of this population by analysing sequencing results and associated pharmacological treatment data. We observed that every individual in the cohort carry at least one actionable genotype and 77% of them carry at least three clinically actionable genotypes across 19 pharmacogenes. Overall, 41% of the Tiwi cohort were predicted to exhibit impaired CYP2D6 metabolism, with this frequency being much higher than that for other global populations. Over half of the population predicted an impaired CYP2C9, CYP2C19, and CYP2B6 metabolism with implications for the processing of commonly used analgesics, statins, anticoagulants, antiretrovirals, antidepressants, and antipsychotics. Moreover, we identified 31 potentially actionable novel variants within Very Important Pharmacogenes (VIPs), five of which were common among the Tiwi. We further detected important clinical implications for the drugs involved with cancer pharmacogenomics such as thiopurines and tamoxifen, immunosuppressants like tacrolimus and certain antivirals used in the hepatitis C treatment due to potential differences in their metabolic processing. The pharmacogenomic profiles generated in our study demonstrate the utility of pre-emptive PGx testing and have the potential to help guide the development and application of precision therapeutic strategies tailored to Tiwi Indigenous patients. Our research provides valuable insights on pre-emptive PGx testing and the feasibility of its use in ancestrally diverse populations, emphasizing the need for increased diversity and inclusivity in PGx investigations.
PubMed: 37284308
DOI: 10.3389/fphar.2023.1180640