Gene. 2022 Nov 7:147021. doi: 10.1016/j.gene.2022.147021. Online ahead of print.

ABSTRACT

The expression level of mRNA and also the function of P-gp are strictly connected with the polymorphic nature of the ABCB1 gene. In this study, we evaluated the association between promoter SNP, i.e. T-129C, three other SNPs investigated earlier and ABCB1 expression in the depression group. To assess the additive significance of these SNPs on clinicopathological features a mathematical model was also built. 102 patients suffering from recurrent depressive disorder (rDD) and 94 healthy individuals from a local blood bank were enrolled in this study. ABCB1 gene polymorphism was identified by the RFLP method. The relative level of ABCB1 expression was measured by real-time PCR. For SNP T-129C no statistically significant differences in allele and genotype frequencies between depression and control groups were found (p=0.3176). There was no statistically significant association between the expression value and 4 studied SNPs in ABCB1 (T-129C, C1236T, G2677T/A and C3435T) or the investigated clinicopathological features. Furthermore, a correlation between the initial HDRS score (lower than 23) and presence of at least 1236T allele was observed, in particular in combination with 3435T or 2677T/A. Mutated allele of each SNP was also significantly associated with declined response to antidepressant therapy, both individually and in combination with others. Results of this study suggest that T-129C does not play an important role in the rDD development. The influence of the studied SNPs on ABCB1 gene expression is still unknown. However, the additive impact of 3 most frequently studied SNPs of ABCB1 on the course of depression and effectiveness of its treatment was confirmed.

PMID:36356904 | DOI:10.1016/j.gene.2022.147021

JCO Precis Oncol. 2022 Nov;6:e2200244. doi: 10.1200/PO.22.00244.

ABSTRACT

PURPOSE: Prognostic tools to estimate the risk of relapse for patients with liver-limited metastatic colorectal cancer (LL-mCRC) undergoing resection with curative intent are needed. Circulating tumor DNA (ctDNA) as a surrogate of postsurgical minimal residual disease is a promising marker in localized CRC. We explored the role of postoperative ctDNA as a marker of minimal residual disease in patients with radically resected LL-mCRC.

MATERIALS AND METHODS: Seventy-six patients with LL-mCRC were retrospectively included. DNA from tumor tissue was sequenced, and one somatic mutation was then assessed by digital droplet polymerase chain reaction in plasma samples collected after surgery to identify the persistence of ctDNA. Relapse-free survival and postresection overall survival were compared between patients with positive vs negative postoperative ctDNA.

RESULTS: ctDNA was found in 39 (51%) of 76 patients with LL-mCRC. At a median follow-up of 77 months, 33 of 39 ctDNA-positive patients and 20 of 37 ctDNA-negative patients experienced disease relapse (P = .008). ctDNA-positive patients reported significantly shorter RFS than ctDNA-negative ones (median RFS 12.7 v 27.4 months hazard ratio, 2.09, P = .008). In the multivariable model including other prognostic covariates, this association was still significant (P = .046) and a trend toward shorter overall survival among ctDNA-positive patients was reported (hazard ratio, 1.65, P = .183).

CONCLUSION: The detection of postsurgical ctDNA is an independent negative prognostic marker and identifies patients at high risk of relapse after liver metastases resection.

PMID:36356286 | DOI:10.1200/PO.22.00244

J Neurol. 2022 Nov 10. doi: 10.1007/s00415-022-11478-0. Online ahead of print.

ABSTRACT

Neuropathic pain is difficult to treat, and an understanding of the risk factors for its onset and resolution is warranted. This study aimed to develop and externally validate two clinical risk models to predict onset and resolution of chronic neuropathic pain. Participants of Generation Scotland: Scottish Family Health Study (GS; general Scottish population; n = 20,221) and Genetic of Diabetes Audit and Research in Tayside Scotland (GoDARTS; n = 5236) were sent a questionnaire on neuropathic pain and followed- -up 18 months later. Chronic neuropathic pain was defined using DN4 scores (≥ 3/7) and pain for 3 months or more. The models were developed in GS using logistic regression with backward elimination based on the Akaike information criterion. External validation was conducted in GoDARTS and assessed model discrimination (ROC and Precision-Recall curves), calibration and clinical utility (decision curve analysis [DCA]). Analysis revealed incidences of neuropathic pain onset (6.0% in GS [236/3903] and 10.7% in GoDARTS [61/571]) and resolution (42.6% in GS [230/540] and 23.7% in GoDARTS [56/236]). Psychosocial and lifestyle factors were included in both onset and resolved prediction models. In GoDARTS, these models showed adequate discrimination (ROC = 0.636 and 0.699), but there was evidence of miscalibration (Intercept = - 0.511 and - 0.424; slope = 0.623 and 0.999). The DCA indicated that the models would provide clinical benefit over a range of possible risk thresholds. To our knowledge, these are the first externally validated risk models for neuropathic pain. The findings are of interest to patients and clinicians in the community, who may take preventative or remedial measures.

PMID:36355188 | DOI:10.1007/s00415-022-11478-0

Curr Issues Mol Biol. 2022 Nov 4;44(11):5498-5515. doi: 10.3390/cimb44110372.

ABSTRACT

The WD repeat containing antisense to TP53 (WRAP53) gene codifies an antisense transcript for tumor protein p53 (TP53), stabilization (WRAP53α), and a functional protein (WRAP53β, WDR79, or TCAB1). The WRAP53β protein functions as a scaffolding protein that is important for telomerase localization, telomere assembly, Cajal body integrity, and DNA double-strand break repair. WRAP53β is one of many proteins known for containing WD40 domains, which are responsible for mediating a variety of cell interactions. Currently, WRAP53 overexpression is considered a biomarker for a diverse subset of cancer types, and in this study, we describe what is known about WRAP53β's multiple interactions in cell protein trafficking, Cajal body formation, and DNA double-strand break repair and its current perspectives as a biomarker for cancer.

PMID:36354684 | DOI:10.3390/cimb44110372

Psychiatr Genet. 2022 Dec 1;32(6):246-248. doi: 10.1097/YPG.0000000000000324. Epub 2022 Oct 20.

ABSTRACT

A considerable group of patients suffering from mental health disorders do not respond adequately to pharmacological treatment. For the purposes of precision and personalized medicine, pharmacogenomics has been developed as a valuable and promising tool. The technology of identifying single nucleotide polymorphisms and genotyping supplies clinicians, and therefore their patients, with the opportunity of avoiding long-lasting 'trial and error' periods, reducing the risk of manifesting disturbing adverse effects during treatment. Consequently, better adherence to treatment and clinical response can be achieved, contributing to personalized treatment planning, according to a person's genetic profile and needs. In the present report, we present a case of an individual diagnosed with bipolar affective disorder type I, who showed resistance to pharmacological treatment and underwent through pharmacogenomic investigations, in order to identify the appropriate medication for the best possible clinical response.

PMID:36354139 | DOI:10.1097/YPG.0000000000000324

Pharmgenomics Pers Med. 2022 Nov 2;15:879-911. doi: 10.2147/PGPM.S338601. eCollection 2022.

ABSTRACT

Cardiovascular disease remains a leading cause of both morbidity and mortality worldwide. It is widely accepted that both concomitant medications (drug-drug interactions, DDIs) and genomic factors (drug-gene interactions, DGIs) can influence cardiovascular drug-related efficacy and safety outcomes. Although thousands of DDI and DGI (aka pharmacogenomic) studies have been published to date, the literature on drug-drug-gene interactions (DDGIs, cumulative effects of DDIs and DGIs) remains scarce. Moreover, multimorbidity is common in cardiovascular disease patients and is often associated with polypharmacy, which increases the likelihood of clinically relevant drug-related interactions. These, in turn, can lead to reduced drug efficacy, medication-related harm (adverse drug reactions, longer hospitalizations, mortality) and increased healthcare costs. To examine the extent to which DDGIs and other interactions influence efficacy and safety outcomes in the field of cardiovascular medicine, we review current evidence in the field. We describe the different categories of DDIs and DGIs before illustrating how these two interact to produce DDGIs and other complex interactions. We provide examples of studies that have reported the prevalence of clinically relevant interactions and the most implicated cardiovascular medicines before outlining the challenges associated with dealing with these interactions in clinical practice. Finally, we provide recommendations on how to manage the challenges including but not limited to expanding the scope of drug information compendia, interaction databases and clinical implementation guidelines (to include clinically relevant DDGIs and other complex interactions) and work towards their harmonization; better use of electronic decision support tools; using big data and novel computational techniques; using clinically relevant endpoints, preemptive genotyping; ensuring ethnic diversity; and upskilling of clinicians in pharmacogenomics and personalized medicine.

PMID:36353710 | PMC:PMC9639705 | DOI:10.2147/PGPM.S338601

Front Pharmacol. 2022 Oct 24;13:1029073. doi: 10.3389/fphar.2022.1029073. eCollection 2022.

ABSTRACT

The cytochrome P450 2D6 (CYP2D6) is a key xenobiotic-metabolizing enzyme involved in the clearance of many drugs. Genetic polymorphisms in CYP2D6 contribute to the large inter-individual variability in drug metabolism and could affect metabolic phenotyping of CYP2D6 probe substances such as dextromethorphan (DXM). To study this question, we (i) established an extensive pharmacokinetics dataset for DXM; and (ii) developed and validated a physiologically based pharmacokinetic (PBPK) model of DXM and its metabolites dextrorphan (DXO) and dextrorphan O-glucuronide (DXO-Glu) based on the data. Drug-gene interactions (DGI) were introduced by accounting for changes in CYP2D6 enzyme kinetics depending on activity score (AS), which in combination with AS for individual polymorphisms allowed us to model CYP2D6 gene variants. Variability in CYP3A4 and CYP2D6 activity was modeled based on in vitro data from human liver microsomes. Model predictions are in very good agreement with pharmacokinetics data for CYP2D6 polymorphisms, CYP2D6 activity as described by the AS system, and CYP2D6 metabolic phenotypes (UM, EM, IM, PM). The model was applied to investigate the genotype-phenotype association and the role of CYP2D6 polymorphisms for metabolic phenotyping using the urinary cumulative metabolic ratio (UCMR), DXM/(DXO + DXO-Glu). The effect of parameters on UCMR was studied via sensitivity analysis. Model predictions indicate very good robustness against the intervention protocol (i.e. application form, dosing amount, dissolution rate, and sampling time) and good robustness against physiological variation. The model is capable of estimating the UCMR dispersion within and across populations depending on activity scores. Moreover, the distribution of UCMR and the risk of genotype-phenotype mismatch could be estimated for populations with known CYP2D6 genotype frequencies. The model can be applied for individual prediction of UCMR and metabolic phenotype based on CYP2D6 genotype. Both, model and database are freely available for reuse.

PMID:36353484 | PMC:PMC9637881 | DOI:10.3389/fphar.2022.1029073

Biomark Res. 2022 Nov 9;10(1):78. doi: 10.1186/s40364-022-00430-z.

ABSTRACT

Tobacco smoking is associated with increased risks of nearly 20 types of cancer. Although the association between smoking and gliomas, the most prevalent type of adult brain tumor, is still unconclusive, here, we found that the frequency of NF1 mutations was significantly increased in the glioma patients with smoking history compared to non-smoking patients (24% vs. 10%, P = 0.021). NF1 acts as a tumor suppressor gene is highly mutated in gliomas. The TCGA data analysis indicated that glioma patients carrying NF1 somatic mutations have worse overall survival (median survival time: smoking 19.9 months vs. non-smoking 36.8 month; P = 0.0018). In addition, we revealed that the NF1 and IDH1 mutations were mutually exclusive suggesting NF1 mutation has independent molecular mechanism involved in glioma biology.

PMID:36352461 | DOI:10.1186/s40364-022-00430-z

Rinsho Ketsueki. 2022;63(10):1353-1362. doi: 10.11406/rinketsu.63.1353.

ABSTRACT

Therapeutic response and drug-induced toxicity have been reported to be associated with genetic variants of drug-metabolizing enzymes and transporters. Recently, new causative variants associated with drug response have been reported by genome-wide association studies (GWASs). Additionally, therapeutic response has been predicted using a model of multiple single-nucleotide polymorphisms. In acute lymphoblastic leukemia (ALL), the genetic variants of NUDT15 associated with therapeutic response to 6-mercaptopurine (6-MP) have been reported by GWASs, and the frequency of NUDT15 variants was higher in Asians. Then, several reports on NUDT15 genetic variants associated with 6-MP-induced toxicities and the tolerable doses and outcomes of 6-MP therapy for ALL have been published in Asian countries. The drugs used in treating hematological malignancies have reported new genetic variants associated with its therapeutic response. However, the association between these genetic variants has not been validated in other populations. Here, we reviewed recent reports on the association between the genetic variants and response to drugs used in treating hematological malignancies, such as 6-MP, cytarabine, methotrexate, and vincristine.

PMID:36351640 | DOI:10.11406/rinketsu.63.1353

Clin Pharmacol Ther. 2022 Nov 9. doi: 10.1002/cpt.2790. Online ahead of print.

ABSTRACT

Pharmacogenomics (PGx) investigates the genetic influence on drug response and is an integral part of precision medicine. While PGx testing is becoming more common in clinical practice and may be reimbursed by Medicare/Medicaid and commercial insurance, interpreting PGx testing results for clinical decision support is still a challenge. The Pharmacogenomics Clinical Annotation Tool (PharmCAT) has been designed to tackle the need for transparent, automatic interpretations of patient genetic data. PharmCAT incorporates a patient's genotypes, annotates PGx information (allele, genotype, and phenotype), and generates a report with PGx guideline recommendations from the Clinical Pharmacogenetics Implementation Consortium (CPIC) and/or the Dutch Pharmacogenetics Working Group (DPWG). PharmCAT has introduced new features in the last two years, including a VCF preprocessor, the inclusion of DPWG guidelines, and functionalities for PGx research. For example, researchers can use the VCF preprocessor to prepare biobank-scale data for PharmCAT. In addition, PharmCAT enables the assessment of novel partial and combination alleles that are composed of known PGx variants and can call CYP2D6 genotypes based on SNPs and INDELs in the input VCF file. This tutorial provides materials and detailed step-by-step instructions for how to use PharmCAT in a versatile way that can be tailored to users' individual needs.

PMID:36350094 | DOI:10.1002/cpt.2790

Pharmacogenomics J. 2022 Nov 8. doi: 10.1038/s41397-022-00296-2. Online ahead of print.

ABSTRACT

Head and neck squamous cell carcinomas (HNSCCs) are introduced as the sixth most common cancer in the world. Detection of predictive biomarkers improve early diagnosis and prognosis. Recent cancer researches provide a new avenue for organoids, known as "mini-organs" in a dish, such as patient-derived organoids (PDOs), for cancer modeling. HNSCC burden, heterogeneity, mutations, and organoid give opportunities for the evaluation of drug sensitivity/resistance response according to the unique genetic profile signature. The Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) nucleases, as an efficient genome engineering technology, can be used for genetic manipulation in three-dimensional (3D) organoids for cancer modeling by targeting oncogenes/tumor suppressor genes. Moreover, single-cell analysis of circulating tumor cells (CTCs) improved understanding of molecular angiogenesis, distance metastasis, and drug screening without the need for tissue biopsy. Organoids allow us to investigate the biopathogenesis of cancer, tumor cell behavior, and drug screening in a living biobank according to the specific genetic profile of patients.

PMID:36347937 | DOI:10.1038/s41397-022-00296-2

Epilepsy Behav Rep. 2022 Oct 19;20:100568. doi: 10.1016/j.ebr.2022.100568. eCollection 2022.

ABSTRACT

Pediatric acute liver failure (PALF) is a rare and life-threatening clinical syndrome for which drug-induced liver injury is a cause. Lamotrigine (LTG) is generally a safe and effective antiseizure medication, and PALF related to LTG has rarely been reported. Here, we describe two cases of PALF associated with LTG in children with epilepsy. In both patients, LTG was used in combination with valproic acid at an initial dose exceeding the recommended dose, which increased the risk of adverse reactions. In addition, single nucleotide polymorphisms of genes associated with the pharmacokinetics and pharmacodynamics of LTG were selected for pharmacogenomic testing. However, the results revealed that genotypes of the patients had variable effects on the serum concentration and therapeutic responsiveness of LTG and therefore did not explain the clinical manifestations well. The findings of this case report caution clinicians to be aware of the risk of liver failure when using antiseizure medication in polytherapy, especially LTG in combination with valproic acid. When administered to children, the recommended dosage of LTG should be strictly followed. Further pharmacogenomic studies are needed to help improve the efficacy and safety of epilepsy treatment in the future.

PMID:36345310 | PMC:PMC9636542 | DOI:10.1016/j.ebr.2022.100568

Pediatr Neonatol. 2022 Oct 25:S1875-9572(22)00224-8. doi: 10.1016/j.pedneo.2022.07.012. Online ahead of print.

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused the global coronavirus disease 2019 (COVID-19) pandemic. Rapid identification and isolation of patients infected with SARS-CoV-2 are critical methods for blocking COVID-19 transmission. The advantages of antigen tests, such as their relatively low cost and short turnaround time, can contribute to the prompt identification of infectious individuals. However, the diagnostic accuracy of antigen tests for COVID-19 in children remains inconclusive. This meta-analysis aimed to evaluate the diagnostic performance of antigen tests for SARS-CoV-2 in the pediatric population.

METHODS: We conducted a literature search for relevant studies in the PubMed, Embase, Google Scholar, and Biomed Central databases. Studies evaluating the diagnostic accuracy of antigen tests for SARS-CoV-2 in pediatric patients were included. In addition, we included studies that provided sufficient data to construct a 2 × 2 table on a per-patient basis. The final literature search was performed on October 10, 2021. Days after symptom onset, asymptomatic and symptomatic individuals may have been potential sources of heterogeneity. The overall sensitivity and specificity of the antigen tests were generated using a bivariate random-effects model.

RESULTS: Five studies with 4400 participants were included. The meta-analysis of antigen tests generated a pooled sensitivity of 65.9% (95% CI: 52.8%-77.0%) and pooled specificity of 99.9% (95% CI: 98.9%-100.0%). A subgroup analysis of studies reporting antigen test data for symptomatic patients showed a pooled sensitivity of 64.5% and a pooled specificity of 99.7%. The subgroup analysis of studies that included 881 asymptomatic participants generated a pooled sensitivity of 48.4% and a pooled specificity of 99.5%.

CONCLUSION: Antigen tests exhibit moderate sensitivity and high specificity for detecting SARS-CoV-2 in children. Antigen tests might have moderate sensitivity for detecting SARS-CoV-2 in symptomatic children, and serial testing might effectively prevent further SARS-CoV-2 transmission.

PMID:36344413 | DOI:10.1016/j.pedneo.2022.07.012

Cancer Lett. 2022 Nov 4:215994. doi: 10.1016/j.canlet.2022.215994. Online ahead of print.

ABSTRACT

The androgen inactivating UGT2B28 pathway emerges as a predictor of progression in prostate cancer (PCa). However, the clinical significance of UGT2B28 tumoral expression and its contribution to PCa progression remain unclear. Using the Canadian Prostate Cancer Biomarker Network biobank (CPCBN; n = 1512), we analyzed UGT2B28 tumor expression in relation to clinical outcomes in men with localized PCa. UGT2B28 was overexpressed in tumors compared to paired normal adjacent prostatic tissue and was associated with inferior outcomes. Functional analyses indicated that UGT2B28 promoted cell proliferation, and its expression was regulated by the androgen receptor (AR)/ARv7. Mechanistically, UGT2B28 was shown to be a protein partner of the endocytic adaptor protein huntingtin-interacting protein 1 (HIP1), increasing its stability and priming AR/epidermal growth factor receptor (EGFR) pathways, leading to ERK1/2 activation triggering cell proliferation and epithelial-to-mesenchymal transition (EMT). HIP1 knockdown in UGT2B28 positive cells, and dual pharmacological targeting of AR and EGFR pathways, abolished cell proliferative advantages conferred by UGT2B28. In conclusion, UGT2B28 is a prognosticator of progression in localized PCa, regulates both AR and EGFR oncogenic signaling pathways via HIP1, and therefore can be therapeutically targeted by using combination of existing AR/EGFR inhibitors.

PMID:36343786 | DOI:10.1016/j.canlet.2022.215994

J Cardiovasc Aging. 2022 Oct;2(4):45. doi: 10.20517/jca.2022.36. Epub 2022 Sep 13.

NO ABSTRACT

PMID:36340925 | PMC:PMC9624469 | DOI:10.20517/jca.2022.36

Front Pharmacol. 2022 Oct 19;13:1040591. doi: 10.3389/fphar.2022.1040591. eCollection 2022.

ABSTRACT

Chaihu-Shugan-San (CSS) is a traditional botanical drug formula often prescribed to treat depression in oriental countries, but its pharmacotherapeutic mechanism remains unknown. It was recently reported that CSS alters the composition of intestinal microflora and related metabolites such as bile acids (BAs). Since the intestinal microflora affects physiological functions of the brain through the gut-microbiota-brain axis, herein we investigated whether CSS altered BA levels, gut microflora, and depression-like symptoms in chronic unpredictable mild stress (CUMS) mice, a well-established mouse model of depression. Furthermore, we determined whether BA manipulation and fecal microbiota transplantation altered CSS antidepressant actions. We found that the BA chelator cholestyramine impaired the antidepressant effects of CSS, which was partially rescued by dietary cholic acid. CSS increased the relative abundance of Parabacteroides distasonis in the colon of CUMS mice, and increased serum levels of various BAs including hyocholic acid (HCA) and 7-ketodeoxycholic acid (7-ketoDCA). Furthermore, gut bacteria transplantation from CSS-treated mice into untreated or cholestyramine-treated CUMS mice restored serum levels of HCA and 7-ketoDCA, alleviating depression-like symptoms. In the hippocampus, CSS-treated mice had decreased expression of genes associated with BA transport (Bsep and Fxr) and increased expression of brain-derived neurotrophic factor and its receptor, TrkB. Overall, CSS increases intestinal P. distasonis abundance, leading to elevated levels of secondary BAs in the circulation and altered expression of hippocampal genes implicated in BA transport and neurotrophic signaling. Our data strongly suggest that the gut microbiota-brain axis contributes to the potent antidepressant action of CSS by modulating BA metabolism.

PMID:36339629 | PMC:PMC9627339 | DOI:10.3389/fphar.2022.1040591

Psychopharmacol Bull. 2022 Oct 27;52(4):52-60.

ABSTRACT

BACKGROUND: CYP2D6 subfamily isoenzymes play an important role in the biotransformation of haloperidol, and their activity may influence the efficacy and safety of haloperidol. The use of haloperidol is often associated with the occurrence of adverse drug reactions (ADRs), such as dyskinesia, acute dystonia, and orthostatic hypotension. Previous studies have demonstrated the relationship between the CYP2D6*4 genetic polymorphism and CYP2D6 activity, as well as haloperidol efficacy and safety rates.

PURPOSE: To evaluate the association of CYP2D6*4 genetic polymorphism with the steady-state concentration of haloperidol in patients with acute alcohol-induced psychotic disorders (AIPDs).

MATERIAL AND METHODS: The study involved 100 male patients with AIPD (average age 41.4 ± 14.4 years) who received haloperidol by injections in a dose of 5-10 mg/day. The efficacy profile was assessed using a validated psychometric PANSS scale (Positive and Negative Syndrome Scale). Therapy safety was assessed using the internationally validated UKU (Side-Effect Rating Scale) and SAS (Simpson-Angus Scale for Extrapyramidal Symptoms) scales. Genotyping was performed with the real-time polymerase chain reaction.

RESULTS: We revealed the statistically significant results in terms of therapy safety evaluation (dynamics of the UKU scores: (GG) 8.00 [7.00; 10.00], (GA) 15.0 [9.25; 18.0], p < 0.001; dynamics of the SAS scores: (GG) 11.0 [9.0; 14.0], (GA) 14.50 [12.0; 18.0], p < 0.001. Pharmacokinetic study showed a statistically significant difference across the groups with different genotypes: (GG) 3.13 [2.32; 3.95], (GA) 3.89 [2.92; 5.26], p = 0.010.

CONCLUSION: It can be concluded that patients with the GA genotype have a higher risk of ADRs compared to patients who carry the GG genotype. It was shown that CYP2D6*4 genetic polymorphism has a statistically significant effect on the steady-state concentration of haloperidol.

PMID:36339274 | PMC:PMC9611797

Neuroophthalmology. 2022 Aug 2;46(5):304-313. doi: 10.1080/01658107.2022.2100916. eCollection 2022.

ABSTRACT

Tuberculosis (TB) is a global health problem with the major brunt of disease occurring in developing countries. The cornerstone of treatment of TB is anti-tubercular therapy (ATT), which includes rifampicin, isoniazid, pyrazinamide and ethambutol. Because of emerging drug resistance, treatment failures, defaulters and increasing incidence of disseminated and extrapulmonary TB, the guidelines have been modified in some countries. Ethambutol is prescribed for longer times (in some cases >8 months) and hence the incidence of ethambutol-induced optic neuropathy (EtON) is expected to rise. The fundamental question which needs explanation is why only a small subset of patients on ethambutol are prone to develop loss of vision. This review focuses on available genetic studies which provide evidence that mitochondria are the likely substrates involved in the final pathway of reactive oxidative damage of the papillo-macular bundle. Genetic analysis of mitochondrial mutations encoding genes involved in oxidative phosphorylation pathways may help in isolating the subset of patients who are genetically susceptible. If the groups having high risk of developing EtON are recognised then prolonged duration of ethambutol treatment can be avoided in these susceptible individuals. A better understanding of the pathophysiology will also pave the way for the development of management strategies in this condition.

PMID:36337233 | PMC:PMC9635551 | DOI:10.1080/01658107.2022.2100916

Int J Infect Dis. 2022 Nov 3:S1201-9712(22)00582-3. doi: 10.1016/j.ijid.2022.10.044. Online ahead of print.

ABSTRACT

OBJECTIVE: This study reported severe respiratory syndrome coronavirus-2 (SARS-CoV-2) whole genome sequencing results from June 2021 to January 2022 from seven genome sequencing centers in Malaysia as part of the national surveillance program.

METHODS: Coronavirus disease 2019 (COVID-19) samples that tested positive by reverse transcription polymerase chain reaction and with CT values <30 were obtained throughout Malaysia. Sequencing of SARS-CoV-2 complete genomes was performed using Illumina, Oxford Nanopore, or Ion Torrent platforms. A total of 6163 SARS-CoV-2 complete genome sequences were generated over the surveillance period. All sequences were submitted to the Global Initiative on Sharing All Influenza Data (GISAID) database.

RESULTS: From June 2021 to January 2022, Malaysia experienced the fourth wave of COVID-19 dominated by the Delta variant of concern (VOC) including the original B.1.617.2 lineage and descendant AY lineages. The B.1.617.2 lineage was identified as the early dominant circulating strain throughout the country but over time was displaced by AY.59 and AY.79 lineages in Peninsular (West) Malaysia, and the AY.23 lineage in East Malaysia. In December 2021, pilgrims returning from Saudi Arabia facilitated the introduction and spread of the BA.1 lineage (Omicron VOC) in the country.

CONCLUSION: The changing trends of circulating SARS-CoV-2 lineages were identified, with differences observed between West and East Malaysia. This initiative highlighted the importance of leveraging research expertise in the country to facilitate pandemic response and preparedness.

PMID:36336246 | DOI:10.1016/j.ijid.2022.10.044

Nat Commun. 2022 Nov 5;13(1):6694. doi: 10.1038/s41467-022-34116-9.

ABSTRACT

Asian populations are under-represented in human genomics research. Here, we characterize clinically significant genetic variation in 9051 genomes representing East Asian, South Asian, and severely under-represented Austronesian-speaking Southeast Asian ancestries. We observe disparate genetic risk burden attributable to ancestry-specific recurrent variants and identify individuals with variants specific to ancestries discordant to their self-reported ethnicity, mostly due to cryptic admixture. About 27% of severe recessive disorder genes with appreciable carrier frequencies in Asians are missed by carrier screening panels, and we estimate 0.5% Asian couples at-risk of having an affected child. Prevalence of medically-actionable variant carriers is 3.4% and a further 1.6% harbour variants with potential for pathogenic classification upon additional clinical/experimental evidence. We profile 23 pharmacogenes with high-confidence gene-drug associations and find 22.4% of Asians at-risk of Centers for Disease Control and Prevention Tier 1 genetic conditions concurrently harbour pharmacogenetic variants with actionable phenotypes, highlighting the benefits of pre-emptive pharmacogenomics. Our findings illuminate the diversity in genetic disease epidemiology and opportunities for precision medicine for a large, diverse Asian population.

PMID:36335097 | DOI:10.1038/s41467-022-34116-9