Pharmacogenomics. 2023 Jan 20. doi: 10.2217/pgs-2022-0160. Online ahead of print.

ABSTRACT

Statins are among the most commonly prescribed medications worldwide. Rosuvastatin is a moderate- to high-intensity statin depending on the prescribed dose. Statin-associated muscle symptoms are the main side effects, contributing to low adherence to statins. The missense variant rs2231142 in ABCG2 affects the functionality of the ABCG2 transporter, altering the pharmacokinetics and pharmacodynamics of rosuvastatin. This special report aims to accentuate the importance of considering the ABCG2 genotype upon prescribing rosuvastatin in high cardiovascular disease risk subgroups, specifically Native Hawaiian and Pacific Islander populations. Based on the reported frequencies of rs2231142 in ABCG2, it may be justifiable to initiate low-dose rosuvastatin in Samoans relative to Marshallese or Native Hawaiians. Interpopulation differences in pharmacogenetic allele frequencies underscore the need to disaggregate broad population categories to achieve health equity in treatment outcomes.

PMID:36661065 | DOI:10.2217/pgs-2022-0160

Pharmacogenomics. 2023 Jan 20. doi: 10.2217/pgs-2022-0132. Online ahead of print.

ABSTRACT

Purpose: HLA-B*38:02 is closely related to carbimazole/methimazole-induced agranulocytosis. This study aimed to develop and validate a rapid and economical method for HLA-B*38:02 genotyping. Methods: A single-tube multiplex real-time PCR detection system comprising amplification refractory mutation system primers and TaqMan probes was established for HLA-B*38:02 genotyping. Sequence-based typing was applied to validate the accuracy of the assay. Results: The accuracy of the assay was 100% for HLA-B*38:02 genotyping. The detection limit of the new method was 0.05 ng DNA. The positive rate of HLA-B*38:02 in the Han (8%, n = 100), Bouyei (17.8%, n = 90) and Tibetan (12.7%, n = 110) populations was significantly higher than that in the Uighur population (1%, n = 100) (p < 0.05). Conclusion: The proposed method is rapid and reliable for HLA-B*38:02 screening in a clinical setting.

PMID:36661044 | DOI:10.2217/pgs-2022-0132

Pharmacogenomics. 2023 Jan 20. doi: 10.2217/pgs-2022-0140. Online ahead of print.

ABSTRACT

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of invasive non-Hodgkin lymphoma. There is great heterogeneity in its molecular biological characteristics, clinical manifestations and prognosis. The use of rituximab has greatly improved the cure rate of DLBCL, but there are still 30% of patients with poor prognosis. In the era of precision medicine, the significance of molecular biology and genetic factors on the diagnosis, treatment and prognosis of patients has been found. Among these, next-generation sequencing technology plays an important role. This paper reviews the research progress of next-generation sequencing technology in the classification, diagnosis, prognosis and molecular targeted therapy of DLBCL.

PMID:36661028 | DOI:10.2217/pgs-2022-0140

Pharmacogenomics J. 2023 Jan 19. doi: 10.1038/s41397-023-00298-8. Online ahead of print.

ABSTRACT

Major depressive disorder (MDD) is associated with high heterogeneity in clinical presentation. In addition, response to treatment with selective serotonin reuptake inhibitors (SSRIs) varies considerably among patients. Therefore, identifying genetic variants that may contribute to SSRI treatment responses in MDD is essential. In this study, we analyzed the syndromal factor structures of the Hamilton Depression Rating Scale in 479 patients with MDD by using exploratory factor analysis. All patients were followed up biweekly for 8 weeks. Treatment response was defined for all syndromal factors and total scores. In addition, a genome-wide association study was performed to investigate the treatment outcomes at week 4 and repeatedly assess all visits during follow-up by using mixed models adjusted for age, gender, and population substructure. Moreover, the role of genetic variants in suicidal and sexual side effects was explored, and five syndromal factors for depression were derived: core, insomnia, somatic anxiety, psychomotor-insight, and anorexia. Subsequently, several known genes were mapped to suggestive signals for treatment outcomes, including single-nucleotide polymorphisms (SNPs) in PRF1, UTP20, MGAM, and ENSG00000286536 for psychomotor-insight and in C4orf51 for anorexia. In total, 33 independent SNPs for treatment responses were tested in a mixed model, 12 of which demonstrated a p value <0.05. The most significant SNP was rs2182717 in the ENSR00000803469 gene located on chromosome 6 for the core syndromal factor (β = -0.638, p = 1.8 × 10-4) in terms of symptom improvement over time. Patients with a GG or GA genotype with the rs2182717 SNP also exhibited a treatment response (β = 0.089, p = 2.0 × 10-6) at week 4. Moreover, rs1836075352 was associated with sexual side effects (p = 3.2 × 10-8). Pathway and network analyses using the identified SNPs revealed potential biological functions involved in treatment response, such as neurodevelopment-related functions and immune processes. In conclusion, we identified loci that may affect the clinical response to treatment with antidepressants in the context of empirically defined depressive syndromal factors and side effects among the Taiwanese Han population, thus providing novel biological targets for further investigation.

PMID:36658263 | DOI:10.1038/s41397-023-00298-8

Genome Res. 2023 Jan 19. doi: 10.1101/gr.277075.122. Online ahead of print.

ABSTRACT

High-throughput sequencing provides sufficient means for determining genotypes of clinically important pharmacogenes that can be used to tailor medical decisions to individual patients. However, pharmacogene genotyping, also known as star-allele calling, is a challenging problem that requires accurate copy number calling, structural variation identification, variant calling, and phasing within each pharmacogene copy present in the sample. Here we introduce Aldy 4, a fast and efficient tool for genotyping pharmacogenes that uses combinatorial optimization for accurate star-allele calling across different sequencing technologies. Aldy 4 adds support for long reads and uses a novel phasing model and improved copy number and variant calling models. We compare Aldy 4 against the current state-of-the-art star-allele callers on a large and diverse set of samples and genes sequenced by various sequencing technologies, such as whole-genome and targeted Illumina sequencing, barcoded 10x Genomics, and Pacific Biosciences (PacBio) HiFi. We show that Aldy 4 is the most accurate star-allele caller with near-perfect accuracy in all evaluated contexts, and hope that Aldy remains an invaluable tool in the clinical toolbox even with the advent of long-read sequencing technologies.

PMID:36657977 | DOI:10.1101/gr.277075.122

Clin Chem Lab Med. 2023 Jan 19. doi: 10.1515/cclm-2022-1293. Online ahead of print.

ABSTRACT

Precision Medicine is a reality in selected medical areas, as oncology, or in excellent healthcare structures, but it is still far to reach million patients who could benefit from this medical concept. Here, we sought to highlight how the time is ripe to achieve horizontal delivery to a significant larger audience of patients, represented by the poly-treated patients. Combination therapies are frequent (especially in the elderly, to treat comorbidities) and are related to decreased drug safety and efficacy, disease's exacerbation, additional treatments, hospitalization. But the recent development and validation of bioinformatic tools, aimed to automatic evaluation and optimization of poly-therapies, according to the unique individual characteristics (including genotype), is ready to change the daily approach to pharmacological prescription.

PMID:36656995 | DOI:10.1515/cclm-2022-1293

Int J Neuropsychopharmacol. 2023 Jan 19:pyad001. doi: 10.1093/ijnp/pyad001. Online ahead of print.

ABSTRACT

BACKGROUND: The clinical heterogeneity in major depressive disorder (MDD), variable treatment response and conflicting findings limit the ability of genomics towards the discovery of evidence-based diagnosis and treatment regimen. This study attempts to curate all genetic association findings to evaluate potential variants for clinical translation.

METHODS: We systematically reviewed all candidate and genome-wide association studies for both MDD susceptibility and antidepressant response, independently, using MEDLINE, particularly to identify replicated findings. These variants were evaluated for functional consequences using different in silico tools and further estimated their diagnostic predictability by calculating positive predictive values (PPV).

RESULTS: A total of 217 significantly associated studies comprising 1200 variants across 545 genes and 128 studies including 921 variants across 412 genes were included with MDD susceptibility and antidepressant response, respectively. Although, majority of associations were confirmed by single study, we identified 31 and 18 replicated variants (in atleast 2 studies) for MDD and antidepressant response. Functional annotation of these 31 variants predicted 20% coding variants as deleterious/damaging and 80.6% variants with regulatory effect. Similarly, for the response-related 18 variants revealed 25% coding variant as damaging and 88.2% with substantial regulatory potential. Finally, we could calculate the diagnostic predictability of 19 and 5 variants whose PPV ranges between 0.49 to 0.66 for MDD and 0.36 to 0.66 for response.

CONCLUSIONS: The replicated variants presented in our data are promising for disease diagnosis and improve response outcomes. Though, these quantitative assessment measures are solely directive of available observational evidence, robust homogenous validation studies are required to strengthen these variants for molecular diagnostic application.

PMID:36655406 | DOI:10.1093/ijnp/pyad001

Comput Biol Med. 2023 Jan 13;153:106548. doi: 10.1016/j.compbiomed.2023.106548. Online ahead of print.

ABSTRACT

Existing warfarin dose prediction algorithms based on pharmacogenetics and clinical parameters have not been used clinically due to the absence of external validation, lack of assessment for clinical utility, and high risk of bias. Moreover, given the high degree of heterogeneity across different datasets used to develop these algorithms, it is unsurprising that prediction errors remain high, and dosing accuracy is dependent on specific ethnic populations. To circumvent these challenges, deep neural models are increasingly used to improve the precision and accuracy of warfarin dose predictions. Hence, this study sought to develop a deep learning-based model using a well-established curated dataset of over 6000 patients from the International Warfarin Pharmacogenomics Consortium (IWPC). Clinically-relevant input data such as physical attributes, medical conditions, concomitant medications, genotype status of functional warfarin genetic polymorphisms, and therapeutic INR were entered followed by applying a unique and robust training and validation method. The deep model yielded a low average mean absolute error (MAE) of 7.6 mg/week and a relatively low mean percentage of error of 40.9% in Asians, 14.2 mg/week MAE and 36.9% in African Americans, and 12.7 mg/week MAE and 45.4% mean percentage of error in White Caucasians. This model also resulted in 36.4% of all patients with a predicted dose within 20% of the administered dose. Hence, our proposed deep model provides an alternative to predicting warfarin dose in the clinical setting upon validation in ethnically-similar datasets.

PMID:36652867 | DOI:10.1016/j.compbiomed.2023.106548

Pharmacogenomics. 2023 Jan 18. doi: 10.2217/pgs-2022-0155. Online ahead of print.

ABSTRACT

Statins are widely used medications for the primary and secondary prevention of cardiovascular diseases. Statin-induced musculoskeletal symptoms are the primary adverse drug events contributing to poor adherence to lipid-lowering therapy. Rosuvastatin is characterized by interindividual differences in systemic exposure among different patient population subgroups. The missense variant Q141K within ABCG2, highly prevalent in some Asian subgroups, results in decreased transporter efflux function and increased exposure to rosuvastatin. We aim to highlight the implications of ABCG2 genotype in prescribing rosuvastatin and the ramifications of interpopulation differences in Q141K frequencies in the starting dose of rosuvastatin in major Asian subgroups, using the most recent genetic-based guidelines. The high frequency of Q141K in Filipinos could warrant a lower starting rosuvastatin dose versus non-Filipinos. The Q141K genotype frequencies in Asian subgroups suggest significant interpopulation differences, reinforcing the need to move beyond race-based to genotype-based rosuvastatin dosing.

PMID:36651271 | DOI:10.2217/pgs-2022-0155

Pharmacogenomics. 2023 Jan 17. doi: 10.2217/pgs-2022-0170. Online ahead of print.

NO ABSTRACT

PMID:36648355 | DOI:10.2217/pgs-2022-0170

Pharmacogenomics. 2023 Jan 17. doi: 10.2217/pgs-2022-0189. Online ahead of print.

NO ABSTRACT

PMID:36647900 | DOI:10.2217/pgs-2022-0189

Eur J Clin Pharmacol. 2023 Jan 16. doi: 10.1007/s00228-022-03449-1. Online ahead of print.

ABSTRACT

PURPOSE: There is marked heterogeneity in treatment response of atomoxetine in patients with attention deficit/hyperactivity disorder (ADHD), especially for the pediatric population. This review aims to evaluate current evidence to characterize the dose-exposure relationship, establish clinically relevant metrics for systemic exposure to atomoxetine, define a therapeutic exposure range, and to provide a dose-adaptation strategy before implementing personalized dosing for atomoxetine in children with ADHD.

METHODS: A comprehensive search was performed across electronic databases (PubMed and Embase) covering the period of January 1, 1985 to July 10, 2022, to summarize recent advances in the pharmacokinetics, pharmacogenomics/pharmacogenetics (PGx), therapeutic drug monitoring (TDM), physiologically based pharmacokinetics (PBPK), and population pharmacokinetics (PPK) of atomoxetine in children with ADHD.

RESULTS: Some factors affecting the pharmacokinetics of atomoxetine were summarized, including food, CYP2D6 and CYP2C19 phenotypes, and drug‒drug interactions (DDIs). The association between treatment response and genetic polymorphisms of genes encoding pharmacological targets, such as norepinephrine transporter (NET/SLC6A2) and dopamine β hydroxylase (DBH), was also discussed. Based on well-developed and validated assays for monitoring plasma concentrations of atomoxetine, the therapeutic reference range in pediatric patients with ADHD proposed by several studies was summarized. However, supporting evidence on the relationship between systemic atomoxetine exposure levels and clinical response was far from sufficient.

CONCLUSION: Personalizing atomoxetine dosage may be even more complex than anticipated thus far, but elucidating the best way to tailor the non-stimulant to a patient's individual need will be achieved by combining two strategies: detailed research in linking the pharmacokinetics and pharmacodynamics in pediatric patients, and better understanding in nature and causes of ADHD, as well as environmental stressors.

PMID:36645468 | DOI:10.1007/s00228-022-03449-1

Hosp Pharm. 2023 Feb;58(1):98-105. doi: 10.1177/00185787221134693. Epub 2022 Nov 9.

ABSTRACT

This study was designed to examine the use of pharmacogenomics (PGx) testing in a community-based facility, the adoption of the PGx recommendations by providers, and assess challenges and opportunities for pharmacists in using PGx testing in a real-world setting. This was a retrospective study involving chart reviews of 137 patients with mood disorders who underwent PGx testing between September 2017 and December 2017. Eighty-seven patients who met inclusion and exclusion criteria were analyzed to evaluate the impact of PGx testing on psychotropic medication treatment and to evaluate the PGx test process. PGx test results were used by providers to guide their therapeutic modifications based on the gene-drug interactions identified. Patient medication use increased from 125 to 190 (P < .001) prescriptions. Patient medication belonging to no gene-drug interaction significantly increased from 46.4% to 87.4% (P < .001), medications belonging to moderate and significant gene-drug interaction decreased from 32.8% to 7.9% (P < .001) and 11.2% to 2.1% (P = .012), respectively. 88.5% of patients' psychotropic medication treatment after PGx testing was consistent with the PGx test report recommendations. The PGx test lengths of time analysis indicated that patient follow-up exceeded the standard time set by guidelines at multiple steps in the test process. There are multiple opportunities for pharmacists to become involved in the PGx testing process to improve patient care.

PMID:36644742 | PMC:PMC9837320 | DOI:10.1177/00185787221134693

JHEP Rep. 2022 Sep 22;5(1):100596. doi: 10.1016/j.jhepr.2022.100596. eCollection 2023 Jan.

ABSTRACT

BACKGROUND & AIMS: Non-invasive tests (NITs) offer a practical solution for advanced fibrosis identification in non-alcoholic fatty liver disease (NAFLD). Despite increasing implementation, their use is not standardised, which can lead to inconsistent interpretation and risk stratification. We aimed to assess the types of NITs and the corresponding cut-offs used in a range of healthcare settings.

METHODS: A survey was distributed to a convenience sample of liver health experts who participated in a global NAFLD consensus statement. Respondents provided information on the NITs used in their clinic with the corresponding cut-offs and those used in established care pathways in their areas.

RESULTS: There were 35 respondents from 24 countries, 89% of whom practised in tertiary level settings. A total of 14 different NITs were used, and each respondent reported using at least one (median = 3). Of the respondents, 80% reported using FIB-4 and liver stiffness by vibration-controlled transient elastography (Fibroscan®), followed by the NAFLD fibrosis score (49%). For FIB-4, 71% of respondents used a low cut-off of <1.3 (range <1.0 to <1.45) and 21% reported using age-specific cut-offs. For Fibroscan®, 21% of respondents used a single liver stiffness cut-off: 8 kPa in 50%, while the rest used 7.2 kPa, 7.8 kPa and 8.7 kPa. Among the 63% of respondents who used lower and upper liver stiffness cut-offs, there were variations in both values (<5 to <10 kPa and >7.5 to >20 kPa, respectively).

CONCLUSIONS: The cut-offs used for the same NITs for NAFLD risk stratification vary between clinicians. As cut-offs impact test performance, these findings underscore the heterogeneity in risk-assessment and support the importance of establishing consistent guidelines on the standardised use of NITs in NAFLD management.

LAY SUMMARY: Owing to the high prevalence of non-alcoholic fatty liver disease (NAFLD) in the general population it is important to identify those who have more advanced stages of liver fibrosis, so that they can be properly treated. Non-invasive tests (NITs) provide a practical way to assess fibrosis risk in patients. However, we found that the cut-offs used for the same NITs vary between clinicians. As cut-offs impact test performance, these findings highlight the importance of establishing consistent guidelines on the standardised use of NITs to optimise clinical management of NAFLD.

PMID:36644239 | PMC:PMC9832273 | DOI:10.1016/j.jhepr.2022.100596

J Invest Dermatol. 2023 Jan 12:S0022-202X(22)02903-7. doi: 10.1016/j.jid.2022.12.009. Online ahead of print.

ABSTRACT

Terminally differentiated keratinocytes are critical for epidermal function and surrounded by involucrin (IVL). Increased IVL expression is associated with a near selective sweep in European populations compared to African. This positive selection for increased IVL in the epidermis identifies human adaptation out-of-Africa. The functional significance is unclear. We hypothesize Ivl to modulate the environmentally sensitive Vitamin D receptor (Vdr) in the epidermis. We investigated Vdr activity in Ivl -/- and wild-type (WT) mice using vitamin D agonist (MC903) treatment and comprehensively determined the inflammatory response using single-cell RNA sequencing (scRNA-seq) and associated skin microbiome changes using 16S bacterial phylotyping. Vdr activity and target gene expression were reduced in Ivl -/- mouse skin, with decreased MC903-mediated skin inflammation and significant reductions in CD4+ T cells, basophils, macrophages, monocytes, and type II basal keratinocytes and increase in suprabasal keratinocytes. Coinciding with the dampened MC903-mediated inflammation, skin microbiota of Ivl -/- mice was more stable compared to WT mice, which exhibited a MC903-responsive increase in Bacteroidetes and decrease in Firmicutes. Together, our studies in Ivl -/- mice identify a functional role for Involucrin to positively impact Vdr activity and suggest an emerging IVL/VDR paradigm for adaptation in the human epidermis.

PMID:36642403 | DOI:10.1016/j.jid.2022.12.009

Commun Biol. 2023 Jan 14;6(1):49. doi: 10.1038/s42003-023-04443-8.

ABSTRACT

Pulmonary function is an indicator of well-being, and pulmonary pathologies are the third major cause of death worldwide. We analysed the UK Biobank genome-wide association summary statistics of pulmonary function for Europeans and individuals of recent African descent to identify variants associated with the trait in the two ancestries. Here, we show 627 variants in Europeans and 3 in Africans associated with three pulmonary function parameters. In addition to the 110 variants in Europeans previously reported to be associated with phenotypes related to pulmonary function, we identify 279 novel loci, including an ISX intergenic variant rs369476290 on chromosome 22 in Africans. Remarkably, we find no shared variants among Africans and Europeans. Furthermore, enrichment analyses of variants separately for each ancestry background reveal significant enrichment for terms related to pulmonary phenotypes in Europeans but not Africans. Further analysis of studies of pulmonary phenotypes reveals that individuals of European background are disproportionally overrepresented in datasets compared to Africans, with the gap widening over the past five years. Our findings extend our understanding of the different variants that modify the pulmonary function in Africans and Europeans, a promising finding for future GWASs and medical studies.

PMID:36641522 | DOI:10.1038/s42003-023-04443-8

Neuron. 2023 Jan 5:S0896-6273(22)01123-0. doi: 10.1016/j.neuron.2022.12.026. Online ahead of print.

ABSTRACT

Using machine learning (ML), we interrogated the function of all human-chimpanzee variants in 2,645 human accelerated regions (HARs), finding 43% of HARs have variants with large opposing effects on chromatin state and 14% on neurodevelopmental enhancer activity. This pattern, consistent with compensatory evolution, was confirmed using massively parallel reporter assays in chimpanzee and human neural progenitor cells. The species-specific enhancer activity of HARs was accurately predicted from the presence and absence of transcription factor footprints in each species. Despite these striking cis effects, activity of a given HAR sequence was nearly identical in human and chimpanzee cells. This suggests that HARs did not evolve to compensate for changes in the trans environment but instead altered their ability to bind factors present in both species. Thus, ML prioritized variants with functional effects on human neurodevelopment and revealed an unexpected reason why HARs may have evolved so rapidly.

PMID:36640767 | DOI:10.1016/j.neuron.2022.12.026

Br J Clin Pharmacol. 2023 Jan 14. doi: 10.1111/bcp.15662. Online ahead of print.

ABSTRACT

AIM: Diabetes mellitus affects the pharmacokinetics of cytochrome P450 3A4/5 (CYP3A4/5) substrates. We evaluated the relationship between hemoglobin A1c (HbA1c) levels and the pharmacokinetics of controlled-release tacrolimus.

METHODS: This retrospective observational cohort study included kidney transplant recipients (>18 years) with controlled-release tacrolimus orally. CYP3A5 genotypes were categorized as expressers (*1/*1 or *1/*3) and non-expressers (*3/*3). Multiple linear regression analysis determined the predictors for trough concentration/dose-normalized body weight (C/D) ratio of tacrolimus at 7 days, 6 months, and 12 months after administration. Correlations between the C/D ratio and HbA1c levels at baseline and 6 and 12 months after tacrolimus initiation were evaluated with Bonferroni correction.

RESULTS: Out of 42 patients (CYP3A5 expressers, n=17, and non-expressers, n=25), the multiple linear regression analysis showed that the C/D ratio on day 7 was marginally higher in CYP3A5 non-expressers than in CYP3A5 expressers (r=0.43, p=0.028). Factors impacting the elevation of tacrolimus C/D ratio after 6 and 12 months of treatment were male sex and CYP3A5 non-expressers (r=0.59, p<0.001) and increased HbA1c levels and CYP3A5 non-expressers (r=0.62, p<0.001), respectively. The C/D ratio and HbA1c levels after 12 months was positively correlated in CYP3A5 non-expressers (y=54.6x-194.6, r=0.63, p=0.004, Bonferroni-correction). Furthermore, intra-individual changes in the C/D ratio and HbA1c levels from 6 to 12 months were nearly correlated (y=54.5x+20.2, r=0.41, p=0.036, Bonferroni-correction).

CONCLUSION: HbA1c and CYP3A5 genotypes might be considered to understand the inter- and intra-individual variability in blood tacrolimus concentrations after 6 months post kidney transplantation.

PMID:36640105 | DOI:10.1111/bcp.15662

Invest New Drugs. 2023 Jan 13. doi: 10.1007/s10637-023-01328-9. Online ahead of print.

ABSTRACT

BACKGROUND: Potential novel strategies for adverse event (AE) management of osimertinib therapy, including therapeutic drug monitoring and the use of biomarkers, have not yet been fully investigated. This study aimed to evaluate (1) the relationship between exposure to osimertinib, especially its active metabolites (AZ5104 and AZ7550), and AEs, and (2) the relationship between germline polymorphisms and AEs.

METHODS: We conducted a prospective, longitudinal observational study of 53 patients with advanced non-small cell lung cancer receiving osimertinib therapy from February 2019 to April 2022. A population pharmacokinetic model was developed to estimate the area under the serum concentration-time curve from 0 to 24 h (AUC0-24) of osimertinib and its metabolites. Germline polymorphisms were analyzed using TaqMan® SNP genotyping and CycleavePCR® assays.

RESULTS: There was a significant association between the AUC0-24 of AZ7550 and grade ≥ 2 paronychia (p = 0.043) or anorexia (p = 0.011) and between that of osimertinib or AZ5104 and grade ≥ 2 diarrhea (p = 0.026 and p = 0.049, respectively). Furthermore, the AUC0-24 of AZ5104 was significantly associated with any grade ≥ 2 AEs (p = 0.046). EGFR rs2293348 and rs4947492 were associated with severe AEs (p = 0.019 and p = 0.050, respectively), and ABCG2 rs2231137 and ABCB1 rs1128503 were associated with grade ≥ 2 AEs (p = 0.008 and p = 0.038, respectively).

CONCLUSION: Higher exposures to osimertinib, AZ5104, and AZ7550 and polymorphisms in EGFR, ABCG2, and ABCB1 were related to higher severity of AEs; therefore, monitoring these may be beneficial for osimertinib AE management.

PMID:36637703 | DOI:10.1007/s10637-023-01328-9

Int J Bipolar Disord. 2023 Jan 13;11(1):3. doi: 10.1186/s40345-022-00281-5.

ABSTRACT

BACKGROUND: CACNA1C rs1006737 A allele, identified as a genetic risk variant for bipolar disorder (BD), is associated with anomalous functional connectivity in adults with and without BD. Studies have yet to investigate the association of CACNA1C rs1006737 with resting-state functional connectivity (rsFC) in youth BD.

METHODS: Participants included 139 youth with BD-I, -II, or -not otherwise specified, ages 13-20 years, including 27 BD A-carriers, 41 BD non-carriers, 32 healthy controls (HC) A-carriers, and 39 HC non-carriers. Anterior cingulate cortex (ACC), amygdala, and orbitofrontal cortex (OFC) were examined as regions-of-interest in seed-to-voxel analyses. General linear models included main effects of diagnosis and rs1006737, and an interaction term, controlling for age, sex, and race.

RESULTS: We observed a main effect of BD diagnosis on rsFC between the right amygdala and the right occipital pole (p = 0.02), and a main effect of rs1006737 genotypes on rsFC between the right OFC and bilateral occipital cortex (p < 0.001). Two significant BD diagnosis-by-CACNA1C rs1006737 interactions were also identified. The A allele was associated with positive rsFC between the right ACC and right amygdala in BD but negative rsFC in HC (p = 0.01), and negative rsFC between the left OFC and left putamen in BD but positive rsFC in HC (p = 0.01).

CONCLUSION: This study found that the rs1006737 A allele, identified as a genetic risk variant for BD in adults, was differentially associated with rsFC in youth with BD in regions relevant to emotion, executive function, and reward. Future task-based approaches are warranted to better understand brain connectivity in relation to CACNA1C in BD.

PMID:36637564 | DOI:10.1186/s40345-022-00281-5