Genetic Determinants of Thiazide-Induced Hyperuricemia, Hyperglycemia, and Urinary Electrolyte Disturbances - A Genome-Wide Evaluation of the UK Biobank.

Thiazide diuretics, widely used in hypertension, cause a variety of adverse reactions, including hyperglycemia, hyperuricemia, and electrolyte abnormalities. In this study, we aimed to identify genetic variants that interact with thiazide-use to increase the risk of these adverse reactions. Using UK Biobank data, we first performed genomewide variance quantitative trait locus (vQTL) analysis of ~ 6.2 million SNPs on 95,493 unrelated hypertensive White British participants (24,313 on self-reported bendroflumethiazide treatment at recruitment) for 2 blood (glucose and urate) and 2 urine (potassium and sodium) biomarkers. Second, we conducted direct gene-environment interaction (GEI) tests on the significant (P < 2.5 × 10-9) vQTLs, included a second UK Biobank cohort comprising 13,647 unrelated hypertensive White British participants (3,478 on thiazides other than bendroflumethiazide) and set significance at P = 0.05 divided by the number of vQTL SNPs tested for GEIs. The vQTL analysis identified eight statistically significant SNPs for blood glucose (5 SNPs) and serum urate (3 SNPs), with none being identified for the urinary biomarkers. Two of the SNPs (1 glucose SNP: CDKAL1 intron rs35612982, GEI P = 6.24 × 10-3; and 1 serum urate SNP: SLC2A9 intron rs938564, GEI P = 4.51 × 10-4) demonstrated significant GEI effects in the first, but not the second, cohort. Both genes are biologically plausible candidates, with the SLC2A9-mediated interaction having been previously reported. In conclusion, we used a two-stage approach to detect two biologically plausible genetic loci that can interact with thiazides to increase the risk of thiazide-associated biochemical abnormalities. Understanding how environmental exposures (including medications such as thiazides) and genetics interact, is an important step toward precision medicine and improved patient outcomes.

Role of Transporters and Enzymes in Metabolism and Distribution of 4-Chlorokynurenine (AV-101).

4-Chlorokynurenine (4-Cl-KYN, AV-101) is a prodrug of a NMDA receptor antagonist and is in clinical development for potential CNS indications. We sought to further understand the distribution and metabolism of 4-Cl-KYN, as this information might provide a strategy to enhance the clinical development of this drug. We used excretion studies in rats, in vitro transporter assays, and pharmacogenetic analysis of clinical trial data to determine how 4-Cl-KYN and metabolites are distributed. Our data indicated that a novel acetylated metabolite (N-acetyl-4-Cl-KYN) did not affect the uptake of 4-Cl-KYN across the blood-brain barrier via LAT1. 4-Cl-KYN and its metabolites were found to be renally excreted in rodents. In addition, we found that N-acetyl-4-Cl-KYN inhibited renal and hepatic transporters involved in excretion. Thus, this metabolite has the potential to limit the excretion of a range of compounds. Our pharmacogenetic analysis found that a SNP in N-acetyltransferase 8 (NAT8, rs13538) was linked to levels of N-acetyl-4-Cl-KYN relative to 4-Cl-KYN found in the plasma and that a SNP in SLC7A5 (rs28582913) was associated with the plasma levels of the active metabolite, 7-Cl-KYNA. Thus, we have a pharmacogenetics-based association for plasma drug level that could aid in the drug development of 4-Cl-KYN and have investigated the interaction of a novel metabolite with drug transporters.

Role of fatty liver index in risk-stratifying comorbid disease outcomes in non-alcoholic fatty liver disease.

Background & Aims: Population screening for non-alcoholic fatty liver disease (NAFLD) and associated comorbidities remains an unaddressed clinical need. We aimed to assess the utility of the fatty liver index (FLI) for risk stratification of NAFLD and related comorbidities using the UK Biobank. Methods: Electronic health records and liver MRI-proton density fat fraction (PDFF) were used to define NAFLD cases. FLI was calculated and individuals with high alcohol intake and other liver diseases were excluded. Using listwise deletion analysis, the area under receiver-operating characteristic curve (AUROC) of FLI for NAFLD risk was determined. Thereafter, time-dependent covariate-adjusted Cox regression models were used to estimate FLI's risk stratification potential for comorbidities of interest. Results: FLI was derived for 327,800 individuals with a median age of 58 (IQR 51.5-64.5), of whom 59.8% were females. Using Perspectum Diagnostics and AMRA protocols as references, FLI identified the risk of NAFLD with AUROCs (95% CI, n) of 0.858 (0.848-0.867, n = 7,566) and 0.851 (0.844-0.856, n = 10,777), respectively. Intermediate and high-risk FLI was associated with increased cardiometabolic and malignant disease. In the first 3 years, high-risk FLI conferred an increased risk (adjusted hazard ratio, 95% CI) of ischaemic heart disease (2.14, 1.94-2.36), hypertension (2.84, 2.70-2.98), type 2 diabetes mellitus (4.55, 4.04-5.12), dyslipidaemia (2.48, 2.32-2.64), ischaemic stroke (1.31, 1.20-1.42) and hepatic malignancy (1.69, 1.23-2.30). FLI was not associated with risk of extrahepatic malignancy but was associated with a higher risk of specific cancers (colon, upper gastrointestinal and breast). All-cause mortality was similarly stratified by FLI, independently of non-invasive fibrosis scores. Conclusions: FLI identifies NAFLD and holds potential for the risk stratification of cardiometabolic and malignant disease outcomes (including some extrahepatic malignancies), as well as all-cause mortality. Its use in population screening for primary and secondary prevention of NAFLD should be considered. Impact and implications: Our analysis using the UK Biobank study shows the potential of the fatty liver index as a risk stratification tool for identifying the risk of developing NAFLD, ischaemic heart disease, ischaemic stroke, type 2 diabetes mellitus, hypertension, hyperlipidaemia, hepatic malignancy, specific metabolism-related malignancies and all-cause mortality. These results suggest that the fatty liver index should be considered as a non-invasive steatosis score that may help guide primary prevention strategies for NAFLD and related outcomes.

A "Bundle of Care" to Improve Anticoagulation Control in Patients Receiving Warfarin in Uganda and South Africa: Protocol for an Implementation Study.

BACKGROUND: The quality of warfarin anticoagulation among Sub-Saharan African patients is suboptimal. This is due to several factors, including a lack of standardized dosing algorithms, difficulty in providing timely international normalized ratio (INR) results, a lack of patient feedback on their experiences with treatment, a lack of education on adherence, and inadequate knowledge and training of health care workers. Low quality of warfarin anticoagulation, expressed as time in therapeutic range (TTR), is associated with higher adverse event rates, including bleeding and thrombosis, and ultimately, increased morbidity and mortality. Processes and interventions that improve this situation are urgently needed. OBJECTIVE: This study aims to evaluate the implementation of the "warfarin bundle," a package of interventions to improve the quality of anticoagulation and thereby clinical outcomes. The primary outcome for this study is TTR over the initial 3 months of warfarin therapy. METHODS: Patients aged 18 years or older who are newly initiated on warfarin for venous thromboembolism, atrial fibrillation, or valvular heart disease will be enrolled and followed up for 3 months at clinics in Cape Town, South Africa, and Kampala, Uganda, where the warfarin bundle is implemented. A retrospective review of the clinical records of patients on warfarin treatment before implementation (controls) will be used for comparison. This study uses a mixed methods approach of the implementation of patient- and process-centered activities to improve the quality of anticoagulation. Patient-centered activities include the use of clinical dosing algorithms, adherence support, and root cause analysis, whereas process-centered activities include point-of-care INR testing, staff training, and patient education and training. We will assess the impact of these interventions by comparing the TTR and safety outcomes across the 2 groups, as well as the cost-effectiveness and acceptability of the package. RESULTS: We started recruitment in June 2021 and stopped in August 2022, having recruited 167 participants. We obtained ethics approval from the University of Cape Town Faculty of Health Sciences Human Research Ethics Committee, the Provincial Health Research Committees in South Africa, the Joint Clinical Research Centre Institutional Review Board, Kampala, and the University of Liverpool Research Ethics Committee. As of February 2023, data cleaning and formal analysis are underway. We expect to publish the full results by December 2023. CONCLUSIONS: We anticipate that the "bundle of care," which includes a clinical algorithm to guide individualized dosing of warfarin, will improve INR control and TTR of patients in Uganda and South Africa. We will use these findings to design a larger, multisite clinical trial across several Sub-Saharan African countries. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/46710.

A genome-wide association study of plasma concentrations of warfarin enantiomers and metabolites in sub-Saharan black-African patients.

Diversity in pharmacogenomic studies is poor, especially in relation to the inclusion of black African patients. Lack of funding and difficulties in recruitment, together with the requirement for large sample sizes because of the extensive genetic diversity in Africa, are amongst the factors which have hampered pharmacogenomic studies in Africa. Warfarin is widely used in sub-Saharan Africa, but as in other populations, dosing is highly variable due to genetic and non-genetic factors. In order to identify genetic factors determining warfarin response variability, we have conducted a genome-wide association study (GWAS) of plasma concentrations of warfarin enantiomers/metabolites in sub-Saharan black-Africans. This overcomes the issue of non-adherence and may have greater sensitivity at genome-wide level, to identify pharmacokinetic gene variants than focusing on mean weekly dose, the usual end-point used in previous studies. Participants recruited at 12 outpatient sites in Uganda and South Africa on stable warfarin dose were genotyped using the Illumina Infinium H3Africa Consortium Array v2. Imputation was conducted using the 1,000 Genomes Project phase III reference panel. Warfarin/metabolite plasma concentrations were determined by high-performance liquid chromatography with tandem mass spectrometry. Multivariable linear regression was undertaken, with adjustment made for five non-genetic covariates and ten principal components of genetic ancestry. After quality control procedures, 548 participants and 17,268,054 SNPs were retained. CYP2C9*8, CYP2C9*9, CYP2C9*11, and the CYP2C cluster SNP rs12777823 passed the Bonferroni-adjusted replication significance threshold (p < 3.21E-04) for warfarin/metabolite ratios. In an exploratory GWAS analysis, 373 unique SNPs in 13 genes, including CYP2C9*8, passed the Bonferroni-adjusted genome-wide significance threshold (p < 3.846E-9), with 325 (87%, all located on chromosome 10) SNPs being associated with the S-warfarin/R-warfarin outcome (top SNP rs11188082, CYP2C19 intron variant, p = 1.55E-17). Approximately 69% of these SNPs were in linkage disequilibrium (r 2 > 0.8) with CYP2C9*8 (n = 216) and rs12777823 (n = 8). Using a pharmacokinetic approach, we have shown that variants other than CYP2C9*2 and CYP2C9*3 are more important in sub-Saharan black-Africans, mainly due to the allele frequencies. In exploratory work, we conducted the first warfarin pharmacokinetics-related GWAS in sub-Saharan Africans and identified novel SNPs that will require external replication and functional characterization before they can be considered for inclusion in warfarin dosing algorithms.

Factors Associated With Diabetic Ketoacidosis at Onset of Type 1 Diabetes Among Pediatric Patients: A Systematic Review.

Importance: Presenting with diabetic ketoacidosis (DKA) at onset of type 1 diabetes (T1D) remains a risk. Following a 2011 systematic review, considerable additional articles have been published, and the review required updating. Objective: To evaluate factors associated with DKA at the onset of T1D among pediatric patients. Evidence Review: In this systematic review, PubMed, Embase, Scopus, CINAHL, Web of Science, and article reference lists were searched using the population, intervention, comparison, outcome search strategy for primary research studies on DKA and T1D onset among individuals younger than 18 years that were published from January 2011 to November 2021. These studies were combined with a 2011 systematic review on the same topic. Data were pooled using a random-effects model. Findings: A total of 2565 articles were identified; 149 were included, along with 46 from the previous review (total 195 articles). Thirty-eight factors were identified and examined for their association with DKA at T1D onset. Factors associated with increased risk of DKA were younger age at T1D onset (<2 years vs ≥2 years; odds ratio [OR], 3.51; 95% CI, 2.85-4.32; P < .001), belonging to an ethnic minority population (OR, 0.40; 95% CI, 0.21-0.74; P = .004), and family history of T1D (OR, 0.46; 95% CI, 0.37-0.57; P < .001), consistent with the 2011 systematic review. Some factors that were not associated with DKA in the 2011 systematic review were associated with DKA in the present review (eg, delayed diagnosis: OR, 2.27; 95% CI, 1.72-3.01; P < .001). Additional factors associated with risk of DKA among patients with new-onset T1D included participation in screening programs (OR, 0.35; 95% CI, 0.21-0.59; P < .001) and presentation during the COVID-19 pandemic (OR, 2.32; 95% CI, 1.76-3.06; P < .001). Conclusions and Relevance: In this study, age younger than 2 years at T1D onset, belonging to an ethnic minority population, delayed diagnosis or misdiagnosis, and presenting during the COVID-19 pandemic were associated with increased risk of DKA. Factors associated with decreased risk of DKA included greater knowledge of key signs or symptoms of DKA, such as a family history of T1D or participation in screening programs. Future work should focus on identifying and implementing strategies related to these factors to reduce risk of DKA among new patients with T1D.

Multi-ancestry genome-wide association study of asthma exacerbations.

BACKGROUND: Asthma exacerbations are a serious public health concern due to high healthcare resource utilization, work/school productivity loss, impact on quality of life, and risk of mortality. The genetic basis of asthma exacerbations has been studied in several populations, but no prior study has performed a multi-ancestry meta-analysis of genome-wide association studies (meta-GWAS) for this trait. We aimed to identify common genetic loci associated with asthma exacerbations across diverse populations and to assess their functional role in regulating DNA methylation and gene expression. METHODS: A meta-GWAS of asthma exacerbations in 4989 Europeans, 2181 Hispanics/Latinos, 1250 Singaporean Chinese, and 972 African Americans analyzed 9.6 million genetic variants. Suggestively associated variants (p ≤ 5 × 10-5 ) were assessed for replication in 36,477 European and 1078 non-European asthma patients. Functional effects on DNA methylation were assessed in 595 Hispanic/Latino and African American asthma patients and in publicly available databases. The effect on gene expression was evaluated in silico. RESULTS: One hundred and twenty-six independent variants were suggestively associated with asthma exacerbations in the discovery phase. Two variants independently replicated: rs12091010 located at vascular cell adhesion molecule-1/exostosin like glycosyltransferase-2 (VCAM1/EXTL2) (discovery: odds ratio (ORT allele ) = 0.82, p = 9.05 × 10-6 and replication: ORT allele  = 0.89, p = 5.35 × 10-3 ) and rs943126 from pantothenate kinase 1 (PANK1) (discovery: ORC allele  = 0.85, p = 3.10 × 10-5 and replication: ORC allele  = 0.89, p = 1.30 × 10-2 ). Both variants regulate gene expression of genes where they locate and DNA methylation levels of nearby genes in whole blood. CONCLUSIONS: This multi-ancestry study revealed novel suggestive regulatory loci for asthma exacerbations located in genomic regions participating in inflammation and host defense.

Real world treatment of juvenile-onset systemic lupus erythematosus: Data from the UK JSLE cohort study.

BACKGROUND: In the absence of clinical trials evidence, Juvenile-onset Systemic Lupus Erythematosus (JSLE) treatment plans vary. AIM: To explore 'real world' treatment utilising longitudinal UK JSLE Cohort Study data. METHODS: Data collected between 07/2009-05/2020 was used to explore the choice/sequence of immunomodulating drugs from diagnosis. Multivariate logistic regression determined how organ-domain involvement (pBILAG-2004) impacted treatment choice. RESULT: 349 patients met inclusion criteria, median follow-up 4-years (IQR:2,6). Mycophenolate mofetil (MMF) was most commonly used for the majority of organ-domains, and significantly associated with renal involvement (OR:1.99, 95% CI:1.65-2.41, pc < 0.01). Analyses assessing the sequence of immunomodulators focused on 197/349 patients (meeting relevant inclusion/exclusion criteria). 10/197 (5%) solely recieved hydroxychloroquine/prednisolone, 62/197 (31%) received a single-immunomodulator, 69/197 (36%) received two, and 36/197 patients (28%) received ≥three immunomodulators. The most common first and second line immunomodulator was MMF. Rituximab was the most common third-line immunomodulator. CONCLUSIONS: Most UK JSLE patients required ≥two immunomodulators, with MMF used most commonly.

Cardiovascular drugs and COVID-19 clinical outcomes: a systematic review and meta-analysis of randomized controlled trials.

AIMS: To update our previously reported systematic review and meta-analysis of observational studies on cardiovascular drug exposure and COVID-19 clinical outcomes by focusing on newly published randomized controlled trials (RCTs). METHODS: More than 500 databases were searched between 1 November 2020 and 2 October 2021 to identify RCTs that were published after our baseline review. One reviewer extracted data with other reviewers verifying the extracted data for accuracy and completeness. RESULTS: After screening 22 414 records, we included 24 and 21 RCTs in the qualitative and quantitative syntheses, respectively. The most investigated drug classes were angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blocker (ARBs) and anticoagulants, investigated by 10 and 11 studies respectively. In meta-analyses, ACEI/ARBs did not affect hospitalization length (mean difference -0.42, 95% confidence interval [CI] -1.83; 0.98 d, n = 1183), COVID-19 severity (risk ratio/RR 0.90, 95% CI 0.71; 1.15, n = 1661) or mortality (risk ratio [RR] 0.92, 95% CI 0.58; 1.47, n = 1646). Therapeutic anticoagulation also had no effect (hospitalization length mean difference -0.29, 95% CI -1.13 to 0.56 d, n = 1449; severity RR 0.86, 95% CI 0.70; 1.04, n = 2696; and, mortality RR 0.93, 95% CI 0.77; 1.13, n = 5689). Other investigated drug classes were antiplatelets (aspirin, 2 trials), antithrombotics (sulodexide, 1 trial), calcium channel blockers (amlodipine, 1 trial) and lipid-modifying drugs (atorvastatin, 1 trial). CONCLUSION: Moderate- to high-certainty RCT evidence suggests that cardiovascular drugs such as ACEIs/ARBs are not associated with poor COVID-19 outcomes, and should therefore not be discontinued. These cardiovascular drugs should also not be initiated to treat or prevent COVID-19 unless they are needed for an underlying currently approved therapeutic indication.

Stable warfarin dose prediction in sub-Saharan African patients: A machine-learning approach and external validation of a clinical dose-initiation algorithm.

Warfarin remains the most widely prescribed oral anticoagulant in sub-Saharan Africa. However, because of its narrow therapeutic index, dosing can be challenging. We have therefore (a) evaluated and compared the performance of 21 machine-learning techniques in predicting stable warfarin dose in sub-Saharan Black-African patients and (b) externally validated a previously developed Warfarin Anticoagulation in Patients in Sub-Saharan Africa (War-PATH) clinical dose-initiation algorithm. The development cohort included 364 patients recruited from eight outpatient clinics and hospital departments in Uganda and South Africa (June 2018-July 2019). Validation was conducted using an external validation cohort (270 patients recruited from August 2019 to March 2020 in 12 outpatient clinics and hospital departments). Based on the mean absolute error (MAE; mean of absolute differences between the actual and predicted doses), random forest regression (12.07 mg/week; 95% confidence interval [CI], 10.39-13.76) was the best performing machine-learning technique in the external validation cohort, whereas the worst performing technique was model trees (17.59 mg/week; 95% CI, 15.75-19.43). By comparison, the simple, commonly used regression technique (ordinary least squares) performed similarly to more complex supervised machine-learning techniques and achieved an MAE of 13.01 mg/week (95% CI, 11.45-14.58). In summary, we have demonstrated that simpler regression techniques perform similarly to more complex supervised machine-learning techniques. We have also externally validated our previously developed clinical dose-initiation algorithm, which is being prospectively tested for clinical utility.

Genome-wide analyses of platinum-induced ototoxicity in childhood cancer patients: Results of GO-CAT and United Kingdom MAGIC consortia.

Hearing loss (ototoxicity) is a major adverse effect of cisplatin and carboplatin chemotherapy. The aim of this study is to identify novel genetic variants that play a role in platinum-induced ototoxicity. Therefore, a genome-wide association study was performed in the Genetics of Childhood Cancer Treatment (GO-CAT) cohort (n = 261) and the United Kingdom Molecular Genetics of Adverse Drug Reactions in Children Study (United Kingdom MAGIC) cohort (n = 248). Results of both cohorts were combined in a meta-analysis. In primary analysis, patients with SIOP Boston Ototoxicity Scale grade ≥1 were considered cases, and patients with grade 0 were controls. Variants with a p-value <10-5 were replicated in previously published data by the PanCareLIFE cohort (n = 390). No genome-wide significant associations were found, but variants in TSPAN5, RBBP4P5, AC010090.1 and RNU6-38P were suggestively associated with platinum-induced ototoxicity. The lowest p-value was found for rs7671702 in TSPAN5 (odds ratio 2.0 (95% confidence interval 1.5-2.7), p-value 5.0 × 10-7). None of the associations were significant in the replication cohort, although the effect directions were consistent among all cohorts. Validation and functional understanding of these genetic variants could lead to more insights in the development of platinum-induced ototoxicity.

Genome-Wide association between EYA1 and Aspirin-induced peptic ulceration.

BACKGROUND: Low-dose aspirin can cause gastric and duodenal ulceration, hereafter called peptic ulcer disease (PUD). Predisposition is thought to be related to clinical and genetic factors; our aim was to identify genetic risk factors associated with aspirin-induced PUD. METHODS: Patients (n=1478) were recruited from 15 UK hospitals. Cases (n=505) were defined as patients with endoscopically confirmed PUD within 2 weeks of using aspirin and non-aspirin Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). They were compared to two control groups: patients with endoscopically confirmed PUD without any history of NSAID use within 3 months of diagnosis (n=495), and patients with no PUD on endoscopy (n=478). A genome-wide association study (GWAS) of aspirin-induced cases (n=247) was compared to 476 controls. The results were validated by replication in another 84 cases and 162 controls. FINDINGS: The GWAS identified one variant, rs12678747 (p=1·65×10-7) located in the last intron of EYA1 on chromosome 8. The association was replicated in another sample of 84 PUD patients receiving aspirin (p=0·002). Meta-analysis of discovery and replication cohort data for rs12678747, yielded a genome-wide significant association (p=3·12×10-11; OR=2·03; 95% CI 1·65-2·50). Expression of EYA1 was lower at the gastric ulcer edge when compared with the antrum. INTERPRETATION: Genetic variation in an intron of the EYA1 gene increases the risk of endoscopically confirmed aspirin-induced PUD. Reduced EYA1 expression in the upper gastrointestinal epithelium may modulate risk, but the functional basis of this association will need mechanistic evaluation. FUNDING: Department of Health Chair in Pharmacogenetics, MRC Centre for Drug Safety Science and the Barts Cardiovascular NIHR Biomedical Research Centre, British Heart Foundation (BHF).

Cardiovascular drugs and COVID-19 clinical outcomes: A living systematic review and meta-analysis.

AIMS: The aim of this study was to continually evaluate the association between cardiovascular drug exposure and COVID-19 clinical outcomes (susceptibility to infection, disease severity, hospitalization, hospitalization length, and all-cause mortality) in patients at risk of/with confirmed COVID-19. METHODS: Eligible publications were identified from more than 500 databases on 1 November 2020. One reviewer extracted data with 20% of the records independently extracted/evaluated by a second reviewer. RESULTS: Of 52 735 screened records, 429 and 390 studies were included in the qualitative and quantitative syntheses, respectively. The most-reported drugs were angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) with ACEI/ARB exposure having borderline association with confirmed COVID-19 infection (OR 1.14, 95% CI 1.00-1.31). Among COVID-19 patients, unadjusted estimates showed that ACEI/ARB exposure was associated with hospitalization (OR 1.76, 95% CI 1.34-2.32), disease severity (OR 1.40, 95% CI 1.26-1.55) and all-cause mortality (OR 1.22, 95% CI 1.12-1.33) but not hospitalization length (mean difference -0.27, 95% CI -1.36-0.82 days). After adjustment, ACEI/ARB exposure was not associated with confirmed COVID-19 infection (OR 0.92, 95% CI 0.71-1.19), hospitalization (OR 0.93, 95% CI 0.70-1.24), disease severity (OR 1.05, 95% CI 0.81-1.38) or all-cause mortality (OR 0.84, 95% CI 0.70-1.00). Similarly, subgroup analyses involving only hypertensive patients revealed that ACEI/ARB exposure was not associated with confirmed COVID-19 infection (OR 0.93, 95% CI 0.79-1.09), hospitalization (OR 0.84, 95% CI 0.58-1.22), hospitalization length (mean difference -0.14, 95% CI -1.65-1.36 days), disease severity (OR 0.92, 95% CI 0.76-1.11) while it decreased the odds of dying (OR 0.76, 95% CI 0.65-0.88). A similar trend was observed for other cardiovascular drugs. However, the validity of these findings is limited by a high level of heterogeneity and serious risk of bias. CONCLUSION: Cardiovascular drugs are not associated with poor COVID-19 outcomes in adjusted analyses. Patients should continue taking these drugs as prescribed.

ADRB2 haplotypes and asthma exacerbations in children and young adults: An individual participant data meta-analysis.

BACKGROUND: The polymorphism Arg16 in ß2 -adrenergic receptor (ADRB2) gene has been associated with an increased risk of exacerbations in asthmatic children treated with long-acting ß2 -agonists (LABA). However, it remains unclear whether this increased risk is mainly attributed to this single variant or the combined effect of the haplotypes of polymorphisms at codons 16 and 27. OBJECTIVE: We assessed whether the haplotype analysis could explain the association between the polymorphisms at codons 16 (Arg16Gly) and 27 (Gln27Glu) in ADRB2 and risk of asthma exacerbations in patients treated with inhaled corticosteroids (ICS) plus LABA. METHODS: The study was undertaken using data from 10 independent studies (n = 5903) participating in the multi-ethnic Pharmacogenomics in Childhood Asthma (PiCA) consortium. Asthma exacerbations were defined as asthma-related use of oral corticosteroids or hospitalizations/emergency department visits in the past 6 or 12 months prior to the study visit/enrolment. The association between the haplotypes and the risk of asthma exacerbations was performed per study using haplo.stats package adjusted for age and sex. Results were meta-analysed using the inverse variance weighting method assuming random-effects. RESULTS: In subjects treated with ICS and LABA (n = 832, age: 3-21 years), Arg16/Gln27 versus Gly16/Glu27 (OR: 1.40, 95% CI: 1.05-1.87, I2  = 0.0%) and Arg16/Gln27 versus Gly16/Gln27 (OR: 1.43, 95% CI: 1.05-1.94, I2  = 0.0%), but not Gly16/Gln27 versus Gly16/Glu27 (OR: 0.99, 95% CI: 0.71-1.39, I2  = 0.0%), were significantly associated with an increased risk of asthma exacerbations. The sensitivity analyses indicated no significant association between the ADRB2 haplotypes and asthma exacerbations in the other treatment categories, namely as-required short-acting ß2 -agonists (n = 973), ICS monotherapy (n = 2623), ICS plus leukotriene receptor antagonists (LTRA; n = 338), or ICS plus LABA plus LTRA (n = 686). CONCLUSION AND CLINICAL RELEVANCE: The ADRB2 Arg16 haplotype, presumably mainly driven by the Arg16, increased the risk of asthma exacerbations in patients treated with ICS plus LABA. This finding could be beneficial in ADRB2 genotype-guided treatment which might improve clinical outcomes in asthmatic patients.

Genome-wide association studies of exacerbations in children using long-acting beta2-agonists.

BACKGROUND: Some children with asthma experience exacerbations despite long-acting beta2-agonist (LABA) treatment. While this variability is partly caused by genetic variation, no genome-wide study until now has investigated which genetic factors associated with risk of exacerbations despite LABA use in children with asthma. We aimed to assess whether genetic variation was associated with exacerbations in children treated with LABA from a global consortium. METHODS: A meta-analysis of genome-wide association studies (meta-GWAS) was performed in 1,425 children and young adults with asthma (age 6-21 years) with reported regular use of LABA from six studies within the PiCA consortium using a random effects model. The primary outcome of each study was defined as any exacerbation within the past 6 or 12 months, including at least one of the following: 1) hospital admissions for asthma, 2) a course of oral corticosteroids or 3) emergency room visits because of asthma. RESULTS: Genome-wide association results for a total of 82 996 common single nucleotide polymorphisms (SNPs, MAF ≥1%) with high imputation quality were meta-analysed. Eight independent variants were suggestively (P-value threshold ≤5 × 10-6 ) associated with exacerbations despite LABA use. CONCLUSION: No strong effects of single nucleotide polymorphisms (SNPs) on exacerbations during LABA use were identified. We identified two loci (TBX3 and EPHA7) that were previously implicated in the response to short-acting beta2-agonists (SABA). These loci merit further investigation in response to LABA and SABA use.

Developing and Validating a Clinical Warfarin Dose-Initiation Model for Black-African Patients in South Africa and Uganda.

Warfarin remains the oral anticoagulant of choice in sub-Saharan Africa. However, dosing is challenging due to a highly variable clinical response for a given dose. This study aimed to develop and validate a clinical warfarin dose-initiation model in sub-Saharan Black-African patients. For the development cohort, we used data from 364 patients who were recruited from 8 outpatient clinics and hospital departments in Uganda and South Africa (June 2018-July 2019). Validation was undertaken using the International Warfarin Pharmacogenetics Consortium (IWPC) dataset (690 black patients). Four predictors (age, weight, target International Normalized Ratio range, and HIV status) were included in the final model, which achieved mean absolute errors (MAEs; mean of absolute differences between true dose and dose predicted by the model) of 11.6 (95% confidence interval (CI) 10.4-12.8) and 12.5 (95% CI 11.6-13.4) mg/week in the development and validation cohorts, respectively. Two other clinical models, IWPC and Gage, respectively, obtained MAEs of 12.5 (95% CI 11.3-13.7) and 12.7 (95% CI 11.5-13.8) mg/week in the development cohort, and 12.1 (95% CI 11.2-13.0) and 12.2 (95% CI 11.4-13.1) mg/week in the validation cohort. Compared with fixed dose-initiation, our model decreased the percentage of patients at high risk of suboptimal anticoagulation by 7.5% (1.5-13.7%) and 11.9% (7.1-16.8%) in the development and validation cohorts, respectively. The clinical utility of this model will be tested in a prospective study. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? ☑ Warfarin dosing remains challenging due to a highly variable clinical response for a given dose. WHAT QUESTION DID THIS STUDY ADDRESS? ☑ Can a clinical dose-initiation model be developed and validated for sub-Saharan Black-African patients? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? ☑ We have developed the first warfarin dose-initiation clinical model for Black-African patients in Uganda and South Africa. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? ☑ We will be implementing and validating this model in a prospective cohort to inform future large-scale implementation. More optimized dosing should improve the quality of warfarin anticoagulation in these two developing countries.

Warfarin dosing algorithms: A systematic review.

AIMS: Numerous algorithms have been developed to guide warfarin dosing and improve clinical outcomes. We reviewed the algorithms available for various populations and the covariates, performances and risk of bias of these algorithms. METHODS: We systematically searched MEDLINE up to 20 May 2020 and selected studies describing the development, external validation or clinical utility of a multivariable warfarin dosing algorithm. Two investigators conducted data extraction and quality assessment. RESULTS: Of 10 035 screened records, 266 articles were included in the review, describing the development of 433 dosing algorithms, 481 external validations and 52 clinical utility assessments. Most developed algorithms were for dose initiation (86%), developed by multiple linear regression (65%) and mostly applicable to Asians (49%) or Whites (43%). The most common demographic/clinical/environmental covariates were age (included in 401 algorithms), concomitant medications (270 algorithms) and weight (229 algorithms) while CYP2C9 (329 algorithms), VKORC1 (319 algorithms) and CYP4F2 (92 algorithms) variants were the most common genetic covariates. Only 26% and 7% algorithms were externally validated and evaluated for clinical utility, respectively, with <2% of algorithm developments and external validations being rated as having a low risk of bias. CONCLUSION: Most warfarin dosing algorithms have been developed in Asians and Whites and may not be applicable to under-served populations. Few algorithms have been externally validated, assessed for clinical utility, and/or have a low risk of bias which makes them unreliable for clinical use. Algorithm development and assessment should follow current methodological recommendations to improve reliability and applicability, and under-represented populations should be prioritized.

STrengthening the Reporting Of Pharmacogenetic Studies: Development of the STROPS guideline.

BACKGROUND: Large sample sizes are often required to detect statistically significant associations between pharmacogenetic markers and treatment response. Meta-analysis may be performed to synthesize data from several studies, increasing sample size and, consequently, power to detect significant genetic effects. However, performing robust synthesis of data from pharmacogenetic studies is often challenging because of poor reporting of key data in study reports. There is currently no guideline for the reporting of pharmacogenetic studies that has been developed using a widely accepted robust methodology. The objective of this project was to develop the STrengthening the Reporting Of Pharmacogenetic Studies (STROPS) guideline. METHODS AND FINDINGS: We established a preliminary checklist of reporting items to be considered for inclusion in the guideline. We invited representatives of key stakeholder groups to participate in a 2-round Delphi survey. A total of 52 individuals participated in both rounds of the survey, scoring items with regards to their importance for inclusion in the STROPS guideline. We then held a consensus meeting, at which 8 individuals considered the results of the Delphi survey and voted on whether each item ought to be included in the final guideline. The STROPS guideline consists of 54 items and is accompanied by an explanation and elaboration document. The guideline contains items that are particularly important in the field of pharmacogenetics, such as the drug regimen of interest and whether adherence to treatment was accounted for in the conducted analyses. The guideline also requires that outcomes be clearly defined and justified, because in pharmacogenetic studies, there may be a greater number of possible outcomes than in other types of study (for example, disease-gene association studies). A limitation of this project is that our consensus meeting involved a small number of individuals, the majority of whom are based in the United Kingdom. CONCLUSIONS: Our aim is for the STROPS guideline to improve the transparency of reporting of pharmacogenetic studies and also to facilitate the conduct of high-quality systematic reviews and meta-analyses. We encourage authors to adhere to the STROPS guideline when publishing pharmacogenetic studies.

Genetic Factors Influencing Warfarin Dose in Black-African Patients: A Systematic Review and Meta-Analysis.

Warfarin is the most commonly used oral anticoagulant in sub-Saharan Africa. Dosing is challenging due to a narrow therapeutic index and high interindividual variability in dose requirements. To evaluate the genetic factors affecting warfarin dosing in black-Africans, we performed a meta-analysis of 48 studies (2,336 patients). Significant predictors for CYP2C9 and stable dose included rs1799853 (CYP2C9*2), rs1057910 (CYP2C9*3), rs28371686 (CYP2C9*5), rs9332131 (CYP2C9*6), and rs28371685 (CYP2C9*11) reducing dose by 6.8, 12.5, 13.4, 8.1, and 5.3 mg/week, respectively. VKORC1 variants rs9923231 (-1639G>A), rs9934438 (1173C>T), rs2359612 (2255C>T), rs8050894 (1542G>C), and rs2884737 (497T>G) decreased dose by 18.1, 21.6, 17.3, 11.7, and 19.6 mg/week, respectively, whereas rs7294 (3730G>A) increased dose by 6.9 mg/week. Finally, rs12777823 (CYP2C gene cluster) was associated with a dose reduction of 12.7 mg/week. Few studies were conducted in Africa, and patient numbers were small, highlighting the need for further work in black-Africans to evaluate genetic factors determining warfarin response.

Exploring the potential of BH3 mimetic therapy in squamous cell carcinoma of the head and neck.

Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common cancer worldwide, with overall survival of less than 50%. Current therapeutic strategies involving a combination of surgery, radiation, and/or chemotherapy are associated with debilitating side effects, highlighting the need for more specific and efficacious therapies. Inhibitors of BCL-2 family proteins (BH3 mimetics) are under investigation or in clinical practice for several hematological malignancies and show promise in solid tumors. In order to explore the therapeutic potential of BH3 mimetics in the treatment of SCCHN, we assessed the expression levels of BCL-2, BCL-XL, and MCL-1 via Western blots and immunohistochemistry, in cell lines, primary cells derived from SCCHN patients and in tissue microarrays containing tumor tissue from a cohort of 191 SCCHN patients. All preclinical models exhibited moderate to high levels of BCL-XL and MCL-1, with little or no BCL-2. Although expression levels of BCL-XL and MCL-1 did not correlate with patient outcome, a combination of BH3 mimetics to target these proteins resulted in decreased clonogenic potential and enhanced apoptosis in all preclinical models, including tumor tissue resected from patients, as well as a reduction of tumor volume in a zebrafish xenograft model of SCCHN. Our results show that SCCHN is dependent on both BCL-XL and MCL-1 for apoptosis evasion and combination therapy targeting both proteins may offer significant therapeutic benefits in this disease.