A Genome-Wide Association Study of Oxypurinol Concentrations in Patients Treated with Allopurinol.

Cohort studies have identified several genetic determinants that could predict the clinical response to allopurinol. However, they have not been commonly used for genome-wide investigations to identify genetic determinants on allopurinol metabolism and concentrations. We conducted a genome-wide association study of a prior cross-sectional investigation of patients from the Montreal Heart Institute Biobank undergoing allopurinol therapy. Four endpoints were investigated, namely plasma concentrations of oxypurinol, the active metabolite of allopurinol, allopurinol, and allopurinol-riboside, as well as allopurinol daily dosing. A total of 439 participants (mean age 69.4 years; 86.4% male) taking allopurinol (mean daily dose 194.5 mg) and who had quantifiable oxypurinol concentrations were included in the genome-wide analyses. Participants presented with multiple comorbidities and received concomitant cardiovascular medications. No association achieved the predefined genome-wide threshold values for any of the endpoints (all p > 5 × 10-8). Our results are consistent with prior findings regarding the difficulty in identifying genetic determinants of drug concentrations or pharmacokinetics of allopurinol and its metabolites, as well as allopurinol daily dosing. Given the size of this genome-wide study, collaborative investigations involving larger and diverse cohorts may be required to further identify pharmacogenomic determinants of allopurinol and measure their clinical relevance to personalize allopurinol therapy.

A dataset of proteomic changes during human heat stress and heat acclimation.

Hotter climates have important impacts on human health and performance. Yet, the cellular and molecular responses involved in human heat stress and acclimation remain understudied. This dataset includes physiological measurements and the plasma concentration of 2,938 proteins collected from 10 healthy adults, before and during passive heat stress that was performed both prior to and after a 7-day heat acclimation protocol. Physiological measurements included body temperatures, sweat rate, cutaneous vascular conductance, blood pressure, and skin sympathetic nerve activity. The proteomic dataset was generated using the Olink Explore 3072 assay, enabling a high-multiplex antibody-based assessment of protein changes based on proximity extension assay technology. The data need to be interpreted in the context of the moderate level of body hyperthermia attained and the specific demographic of young, healthy adults. We have made this dataset publicly available to facilitate research into the cellular and molecular mechanisms involved in human heat stress and acclimation, crucial for addressing the health and performance challenges posed by rising temperatures.

Impact of amiodarone use on metoprolol concentrations, α-OH-metoprolol concentrations, metoprolol dosing and heart rate: A cross-sectional study.

Small studies suggest that amiodarone is a weak inhibitor of cytochrome P450 (CYP) 2D6. Inhibition of CYP2D6 leads to increases in concentrations of drugs metabolized by the enzyme, such as metoprolol. Considering that both metoprolol and amiodarone have ß-adrenergic blocking properties and that the modest interaction between the two drugs would result in increased metoprolol concentrations, this could lead to a higher risk of bradycardia and atrioventricular block. The primary objective of this study was to evaluate whether metoprolol plasma concentrations collected at random timepoints from patients enrolled in the Montreal Heart Institute Hospital Cohort could be useful in identifying the modest pharmacokinetic interaction between amiodarone and metoprolol. We performed an analysis of a cross-sectional study, conducted as part of the Montreal Heart Institute Hospital Cohort. All participants were self-described "White" adults with metoprolol being a part of their daily pharmacotherapy regimen. Of the 999 patients being treated with metoprolol, 36 were also taking amiodarone. Amiodarone use was associated with higher metoprolol concentrations following adjustment for different covariates (p = .0132). Consistently, the association between amiodarone use and lower heart rate was apparent and significant after adjustment for all covariates under study (p = .0001). Our results highlight that single randomly collected blood samples can be leveraged to detect modest pharmacokinetic interactions.

Pharmacogenomic markers of metoprolol and α-OH-metoprolol concentrations: a genome-wide association study.

Aim: Few genome-wide association studies (GWASs) have been conducted to identify predictors of drug concentrations. The authors therefore sought to discover the pharmacogenomic markers involved in metoprolol pharmacokinetics. Patients & methods: The authors performed a GWAS of a cross-sectional study of 993 patients from the Montreal Heart Institute Biobank taking metoprolol. Results: A total of 391 and 444 SNPs reached the significance threshold of 5 × 10-8 for metoprolol and α-OH-metoprolol concentrations, respectively. All were located on chromosome 22 at or near the CYP2D6 gene, encoding CYP450 2D6, metoprolol's main metabolizing enzyme. Conclusion: The results reinforce previous findings of the importance of the CYP2D6 locus for metoprolol concentrations and confirm that large biobanks can be used to identify genetic determinants of drug pharmacokinetics at a GWAS significance level.

Females present higher dose-adjusted drug concentrations of metoprolol and allopurinol/oxypurinol than males.

Females present a higher risk of adverse drug reactions. Sex-related differences in drug concentrations may contribute to these observations but they remain understudied given the underrepresentation of females in clinical trials. The aim of this study was to investigate whether anthropometric and socioeconomic factors and comorbidities could explain sex-related differences in concentrations and dosing for metoprolol and oxypurinol, the active metabolite of allopurinol. We conducted an analysis of two cross-sectional studies. Participants were self-described "White" adults taking metoprolol or allopurinol selected from the Montreal Heart Institute Hospital Cohort. A total of 1007 participants were included in the metoprolol subpopulation and 459 participants in the allopurinol subpopulation; 73% and 86% of the participants from the metoprolol and allopurinol subpopulations were males, respectively. Females presented higher age- and dose-adjusted concentrations of both metoprolol and oxypurinol (both p < 0.03). Accordingly, females presented higher unadjusted and age-adjusted concentration:dose ratio of both metoprolol and allopurinol/oxypurinol compared to males (all p < 3.0 × 10-4 ). Sex remained an independent predictor of metoprolol concentrations (p < 0.01), but not of oxypurinol concentrations, after adjusting for other predictors. In addition to sex, age, daily dose, use of moderate to strong CYP2D6 inhibitors, weight, and CYP2D6 genotype-inferred phenotype were associated with concentrations of metoprolol (all p < 0.01). Daily dose, weight, estimated glomerular filtration rate (eGFR), and employment status were associated with oxypurinol concentrations (all p < 0.01). Females present higher dose-adjusted concentrations of metoprolol and oxypurinol than males. This suggests the need for sex-specific dosing requirements for these drugs, although this hypothesis should be validated in prospective studies.

An association study of ABCG2 rs2231142 on the concentrations of allopurinol and its metabolites.

ABCG2 is a gene that codes for the human breast cancer resistance protein (BCRP). It is established that rs2231142 G>T, a single nucleotide polymorphism of the ABCG2 gene, is associated with gout and poor response to allopurinol, a uric acid-lowering agent used to treat this condition. It has also been suggested that oxypurinol, the primary active metabolite of allopurinol, is a substrate of the BCRP. We thus hypothesized that carrying the rs2231142 variant would be associated with decreased oxypurinol concentrations, which would explain the lower reduction in uric acid. We performed a cross-sectional study to investigate the association between the ABCG2 rs2231142 variant and oxypurinol, allopurinol, and allopurinol riboside concentrations in 459 participants from the Montreal Heart Institute Hospital Cohort. Age, sex, weight, use of diuretics, and estimated glomerular filtration rate were all significantly associated with oxypurinol plasma concentration. No association was found between rs2231142 and oxypurinol, allopurinol and allopurinol riboside plasma concentrations. Rs2231142 was not significantly associated with daily allopurinol dose in the overall population, but an association was observed in men, with T carriers receiving higher doses. Our results do not support a major role of ABCG2 in the pharmacokinetics of allopurinol or its metabolites. The underlying mechanism of the association between rs2231142 and allopurinol efficacy requires further investigation.

Leveraging large observational studies to discover genetic determinants of drug concentrations: A proof-of-concept study.

Large, observational genetic studies are commonly used to identify genetic factors associated with diseases and disease-related traits. Such cohorts have not been commonly used to identify genetic predictors of drug dosing or concentrations, perhaps because of the heterogeneity in drug dosing and formulation, and the random timing of blood sampling. We hypothesized that large sample sizes relative to traditional pharmacokinetic studies would compensate for this variability and enable the identification of pharmacogenetic predictors of drug concentrations. We performed a cross-sectional, proof-of-concept association study to replicate the well-established association between metoprolol concentrations and CYP2D6 genotype-inferred metabolizer phenotypes in participants from the Montreal Heart Institute Hospital Cohort undergoing metoprolol therapy. Plasma concentrations of metoprolol and α-hydroxymetoprolol (α-OH-metoprolol) were measured in samples collected randomly regarding the previous metoprolol dose. A total of 999 individuals were included. The metoprolol daily dose ranged from 6.25 to 400 mg (mean 84.3 ± 57.1 mg). CYP2D6-inferred phenotype was significantly associated with both metoprolol and α-OH-metoprolol in unadjusted and adjusted models (all p < 10-14 ). Models for metoprolol daily dose showed consistent results. Our study suggests that randomly drawn blood samples from biobanks can serve as a new approach to discover genetic associations related to drug concentrations and dosing, with potentially broader implications for genomewide association studies on the pharmacogenomics of drug metabolism.

Genetics of symptom remission in outpatients with COVID-19.

We conducted a genome-wide association study of time to remission of COVID-19 symptoms in 1723 outpatients with at least one risk factor for disease severity from the COLCORONA clinical trial. We found a significant association at 5p13.3 (rs1173773; P = 4.94 × 10-8) near the natriuretic peptide receptor 3 gene (NPR3). By day 15 of the study, 44%, 54% and 59% of participants with 0, 1, or 2 copies of the effect allele respectively, had symptom remission. In 851 participants not treated with colchicine (placebo), there was a significant association at 9q33.1 (rs62575331; P = 2.95 × 10-8) in interaction with colchicine (P = 1.19 × 10-5) without impact on risk of hospitalisations, highlighting a possibly shared mechanistic pathway. By day 15 of the study, 46%, 62% and 64% of those with 0, 1, or 2 copies of the effect allele respectively, had symptom remission. The findings need to be replicated and could contribute to the biological understanding of COVID-19 symptom remission.

Assessing Splanchnic Compartment Using Portal Venous Doppler and Impact of Adding It to the EVEREST Score for Risk Assessment in Heart Failure.

BACKGROUND: The Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST) score has proven useful for risk prediction in acute decompensated heart failure (ADHF). However, this score does not include the characterization of the splanchnic compartment, which has been involved in worsening heart failure. Refining this score by integrating an assessment of the splanchnic compartment would allow for a better risk assessment. Therefore, we aimed to characterize the patterns of portal vein pulsatility (PVP), an ultrasound metric used for the assessment of splanchnic compartment and their determinants in patients with ADHF, to explore the relationships between abnormal patterns of PVP and outcomes, and to evaluate the added value of PVP to the EVEREST score for risk assessment in ADHF. METHODS: Portal vein flow was assessed prospectively on admission and at discharge in 95 patients with ADHF using pulsed-wave Doppler. Abnormal PVP was defined for values ≥ 50%. Cox proportional hazards models were used for the assessment of the relationship between PVP and outcomes. RESULTS: Overall, 64% of patients on admission and 24% at discharge had abnormal PVP. PVP on admission was inversely correlated with right ventricular function (tricuspid annular plane systolic excursion, ρ = -0.434) and pulmonary pressure (ρ = 0.346), P < 0.05. Although PVP was associated with all-cause mortality (hazard ratio, 1.028, P < 0.001), the addition of this metric to the EVEREST score had little effect on its C-index (0.813 vs 0.818) for risk assessment. CONCLUSIONS: Abnormal PVP is frequent and associated with right ventricular dysfunction in ADHF. Although abnormal PVP identifies higher-risk patients, this metric does not improve the performance of the EVEREST score for risk assessment.

CONTEXTE: Le score EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan) s'avère utile pour la prévision du risque dans les cas d'insuffisance cardiaque décompensée aiguë (ICDA). Cependant, ce score ne permet pas de caractériser le compartiment splanchnique, impliqué dans l'aggravation de l'insuffisance cardiaque. Affiner ce score en y intégrant une évaluation du compartiment splanchnique permettrait une meilleure évaluation du risque. Par conséquent, nous avons entrepris de caractériser les profils de la pulsatilité du flux de la veine porte (PFVP) (mesure échographique permettant d'évaluer le compartiment splanchnique et ses déterminants dans les cas d'ICDA) afin d'examiner les relations entre les profils anormaux de la PFVP et les résultats, et afin d'évaluer la valeur ajoutée de la PFVP dans l'évaluation du risque faisant appel au score EVEREST chez des patients atteints d'ICDA. MÉTHODOLOGIE: Le flux de la veine porte a été évalué prospectivement par échographie Doppler pulsée à l'admission et à la sortie de 95 patients atteints d'ICDA. La définition d'une PFVP anormale ciblait des valeurs de 50 % ou plus. Des modèles à risques proportionnels de Cox ont servi à évaluer la relation entre la PFVP et les résultats. RÉSULTATS: Globalement, la PFVP était anormale à l'admission chez 64 % des patients et à la sortie chez 24 % des patients. Une corrélation inverse a été notée entre la PFVP à l'admission et la fonction ventriculaire droite (excursion annulaire horizontale systolique de la tricuspide, ρ = -0,434) ainsi que la pression pulmonaire (ρ = -0,346), p < 0,05. Bien que la PFVP ait été associée à la mortalité toutes causes confondues (rapport des risques instantanés de 1,028, p < 0,001), l'ajout de cette mesure au score EVEREST a eu peu d'effet sur son indice C (0,813 vs 0,818) pour l'évaluation du risque. CONCLUSIONS: Une PFVP anormale est d'observation courante et se trouve associée à une dysfonctionn ventriculaire droite dans les cas d'ICDA. Bien qu'une PFVP anormale permette de déceler les patients qui présentent un risque plus élevé, son objectivation n'améliore pas la précision du score EVEREST dans l'évaluation du risque.

A genetic association study of heart failure: more evidence for the role of BAG3 in idiopathic dilated cardiomyopathy.

AIMS: Few investigations have been conducted to identify genetic determinants of common, polygenetic forms of heart failure (HF), and only a limited number of these genetic associations have been validated by multiple groups. METHODS AND RESULTS: We performed a case-control study to further investigate the potential impact of 14 previously reported candidate genes on the risk of HF and specific HF sub-types. We also performed an exploratory genome-wide study. We included 799 patients with HF and 1529 controls. After adjusting for age, sex, and genetic ancestry, we found that the C allele of rs2234962 in BAG3 was associated with a decreased risk of idiopathic dilated cardiomyopathy (odds ratio 0.42, 95% confidence interval 0.25-0.68, P = 0.0005), consistent with a previous report. No association for the other primary variants or exploratory genome-wide study was found. CONCLUSIONS: Our findings provide independent replication for the association between a common coding variant (rs2234962) in BAG3 and the risk of idiopathic dilated cardiomyopathy.

Spironolactone metabolite concentrations in decompensated heart failure: insights from the ATHENA-HF trial.

AIMS: In Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure (ATHENA-HF), high-dose spironolactone (100 mg daily) did not improve efficacy endpoints over usual care [placebo or continued low-dose spironolactone (25 mg daily) in patients already receiving spironolactone] in the treatment of acute heart failure (HF). We hypothesized that low concentrations of the long-acting active metabolites of spironolactone [canrenone and 7α-thiomethylspironolactone (7α-TMS)] in the high-dose group could have contributed to these neutral results. METHODS AND RESULTS: In patients randomized to high-dose spironolactone not previously treated with spironolactone (high-dose-naïve, n = 112), concentrations of canrenone and 7α-TMS increased at 48 and 96 h compared to baseline, and between 48 and 96 h (all P < 0.005), indicating that steady-state concentrations had not been reached by 48 h. In patients previously on low-dose, high-dose spironolactone (high-dose-previous, n = 37), concentrations of canrenone increased at 48 and 96 h compared to baseline (both P < 0.0005), with a marginal increase between 48 and 96 h (P = 0.0507). At 48 h, both high-dose groups had higher concentrations of both metabolites than the low-dose spironolactone group (P < 0.0001). Moreover, concentrations of both metabolites were higher in high-dose-previous vs. high-dose-naïve patients (P < 0.01), indicating that previous spironolactone use was significant, and that steady-state has not been reached in high-dose-naïve patients at 48 h. We found limited and inconsistent evidence of correlation between metabolite concentrations and endpoints. CONCLUSIONS: Lower-than-anticipated concentrations of spironolactone active metabolites were observed for at least 48 h in the high-dose spironolactone group and may have contributed to the absence of pharmacological effects of spironolactone in the ATHENA-HF trial.

Anticoagulants in Older Patients with Nonvalvular Atrial Fibrillation after Intracranial Hemorrhage.

BACKGROUND AND PURPOSE: Patients with nonvalvular atrial fibrillation (NVAF) who survive an intracranial hemorrhage (ICH) have an increased risk of ischemic stroke and systemic embolism (IS/ SE). We investigated whether starting oral anticoagulants (OACs) among older NVAF patients after an ICH was associated with a lower risk of IS/SE and mortality but offset by an increase in major bleeding. METHODS: We assembled a patient cohort from the Quebec Régie de l'Assurance Maladie du Québec (RAMQ) and Med-Echo administrative databases. We identified older adults with NVAF from 1995 to 2015. All patients with incident ICH and discharged in community were included. Patients were categorized according to OAC exposure. Outcomes included IS/SE, all-cause mortality, recurrent ICH and major bleeding after a quarantine period of 6 weeks. Crude event rates were calculated at 1-year of follow-up, and Cox proportional hazard models with a time-dependent binary exposure were used to assess adjusted hazard ratios (AHRs). RESULTS: The cohort of 683 NVAF patients with ICH aged 83 years on average. The rates (per 100 person-years) for IS/SE, death, ICH and major bleeding were 3.3, 40.6, 11.4, and 2.7 for the no OAC group; and 2.6, 16.3, 5.2, and 5.2 for OAC group, respectively. The AHR for IS/SE and death was 0.10 (95% confidence interval [CI], 0.05 to 0.21), 0.43 (95% CI, 0.19 to 0.97) for recurrent ICH and 1.73 (95% CI, 0.71 to 4.20) for major extracranial bleeding comparing OAC exposure to non-exposed. CONCLUSIONS: Initiating OAC after ICH in older individuals with NVAF is associated with a reduction of IS/SE and mortality and a trend in recurrent ICH supporting its use after ICH.

Cumulative childhood trauma, emotion regulation, dissociation, and behavior problems in school-aged sexual abuse victims.

BACKGROUND: Child sexual abuse is associated with a plethora of devastating repercussions. A significant number of sexually abused children are likely to experience other forms of maltreatment that can seriously affect their emotion regulation abilities and impede on their development. The aim of the study was to test emotion regulation and dissociation as mediators in the association between cumulative childhood trauma and internalized and externalized behavior problems in child victims of sexual abuse. METHODS: Participants were 309 sexually abused children (203 girls and 106 boys; Mean age = 9.07) and their non-offending parent. Medical and clinical files were coded for cumulative childhood trauma. At initial evaluation (T1), parents completed measures assessing children's emotion regulation abilities and dissociation. At Time 2 (T2), parents completed a measure assessing children's behavior problems. Mediation analyses were conducted with emotion regulation and dissociation as sequential mediators using Mplus software. RESULTS: Findings revealed that cumulative childhood trauma affects both internalized and externalized behavior problems through three mediation paths: emotion regulation alone, dissociation alone, and through a path combining emotion regulation and dissociation. LIMITATIONS: Both emotion regulation and dissociation were assessed at T1 and thus the temporal sequencing of mediators remains to be ascertained through a longitudinal design. All measures were completed by the parents. CONCLUSIONS: Clinicians should routinely screen for other childhood trauma in vulnerable clienteles. In order to tackle behavior problems, clinical interventions for sexually abused youth need to address emotion regulation competencies and dissociation.

Alexithymia as a mediator of the relationship between child sexual abuse and psychological distress in adolescence: A short-term longitudinal study.

BACKGROUND: Understanding factors influencing mental health of sexually abused teenagers is essential to orient treatment with this vulnerable population. The purpose of this study was to explore alexithymia as a mediator of the relationship between child sexual abuse and psychological distress using a representative sample of teenagers, while considering gender as a potential moderator. METHODS: Teenagers participating in the Quebec Youths' Romantic Relationships Survey completed measures evaluating a history of child sexual abuse and alexithymia at baseline while psychological distress was evaluated 6 months later. RESULTS: A moderated mediated model revealed a partial mediation effect of alexithymia in the relationship between child sexual abuse and psychological distress. Gender acted as a moderator as the conditional indirect effects of child sexual abuse on mental health via alexithymia were stronger for boys. CONCLUSION: Findings underscore the relevance of assessing and targeting sexually abused victims' capacity to identify and communicate emotions to promote well-being.