Genetic investigation into the broad health implications of caffeine: evidence from phenome-wide, proteome-wide and metabolome-wide Mendelian randomization.

BACKGROUND: Caffeine is one of the most utilized drugs in the world, yet its clinical effects are not fully understood. Circulating caffeine levels are influenced by the interplay between consumption behaviour and metabolism. This study aimed to investigate the effects of circulating caffeine levels by considering genetically predicted variation in caffeine metabolism. METHODS: Leveraging genetic variants related to caffeine metabolism that affect its circulating levels, we investigated the clinical effects of plasma caffeine in a phenome-wide association study (PheWAS). We validated novel findings using a two-sample Mendelian randomization framework and explored the potential mechanisms underlying these effects in proteome-wide and metabolome-wide Mendelian randomization. RESULTS: Higher levels of genetically predicted circulating caffeine among caffeine consumers were associated with a lower risk of obesity (odds ratio (OR) per standard deviation increase in caffeine = 0.97, 95% confidence interval (CI) CI: 0.95-0.98, p = 2.47 × 10-4), osteoarthrosis (OR = 0.97, 95% CI: 0.96-0.98, P=1.10 × 10-8) and osteoarthritis (OR: 0.97, 95% CI: 0.96 to 0.98, P = 1.09 × 10-6). Approximately one third of the protective effect of plasma caffeine on osteoarthritis risk was estimated to be mediated through lower bodyweight. Proteomic and metabolomic perturbations indicated lower chronic inflammation, improved lipid profiles, and altered protein and glycogen metabolism as potential biological mechanisms underlying these effects. CONCLUSIONS: We report novel evidence suggesting that long-term increases in circulating caffeine may reduce bodyweight and the risk of osteoarthrosis and osteoarthritis. We confirm prior genetic evidence of a protective effect of plasma caffeine on risk of overweight and obesity. Further clinical study is warranted to understand the translational relevance of these findings before clinical practice or lifestyle interventions related to caffeine consumption are introduced.

Cannabis use and atherosclerotic cardiovascular disease: a Mendelian randomization study.

BACKGROUND: Association between cannabis use and development of atherosclerotic cardiovascular disease (ASCVD) is inconsistent and challenging to interpret, given existing study limitations. METHODS: Sixty five independent single-nucleotide polymorphisms (SNPs), obtained from a genome-wide association study on lifetime cannabis use, were employed as genetic instruments to estimate the effects of genetically indexed cannabis use on risk of coronary artery disease (CAD) and acute ischemic stroke (IS) using a two-sample Mendelian randomization (MR) approach. Summary statistics on CAD (CARDIoGRAMplusC4D; 60,801 cases and 123,504 controls) and IS (MEGASTROKE; 34,217 cases and 406,111 controls) were obtained separately. A comprehensive review of the observational literature on cannabis use and CAD or IS was also performed and contrasted with MR results. RESULTS: There was no causal effect of cannabis use on the risk of CAD (odds ratio (OR) per ever-users vs. never-users 0.93; 95% confidence interval (CI), 0.83 to 1.03) or IS (OR 1.05; 95%CI, 0.93 to 1.19). Sensitivity analyses yielded similar results, and no heterogeneity and directional pleiotropy was observed. Our meta-analysis of observational studies showed no significant association between ever use of cannabis with risk of CAD (k = 6 studies; ORpooled = 1.23, 95%CI 0.78 to 1.69), nor with IS (k = 6 studies; ORpooled = 1.22, 95%CI 0.95 to 1.50). CONCLUSION: Using a genetic approach approximating a clinical trial does not provide evidence consistent with a causal effect of genetic predisposition to cannabis use on CAD or IS development. Further studies are needed to replicate our findinds, an to investigate more precisely the risk of ASCVD in relation to the quantity, type, route of administration, or the age at exposure to cannabis.

[The year 2022 placed in perspective by hospital internists]. / Année 2022 mise en perspective par les internistes hospitaliers.

According to PubMed statistics when writing this review, the year 2022 is expected to mark the first dip in the number of articles published in relation to the Covid-19 pandemic. This review, without any mention to Sars-CoV-2, highlight this transition and addresses many topics in internal medicine: gastroenterology, cardiology, endocrinology, respiratory medicine, infectious diseases and venous access. Each year, the chief residents of the internal medicine ward in Lausanne university hospital (CHUV) in Switzerland meet up to share their readings: here is a selection of ten articles that have caught our attention, summarized and commented for you, which should change our daily practice.

D'après les statistiques PubMed au moment de la rédaction de cette revue, l'année 2022 devrait marquer le premier infléchissement du nombre d'articles publiés en relation avec la pandémie de Covid-19. Cette revue d'articles, sans écho au Sars-CoV-2, souligne cette transition et aborde de nombreux sujets de la médecine interne : gastroentérologie, cardiologie, endocrinologie, pneumologie, infectiologie et accès veineux. Chaque année, les cheffes et chefs de clinique du Service de médecine interne du CHUV se réunissent pour partager leurs lectures : voici une sélection de dix articles ayant retenu notre attention, revus et commentés pour vous, et qui devraient faire évoluer notre pratique quotidienne.

[Highlights of Swiss congress of internal general medicine: part 2]. / Highlights du congrès 2022 de la Société suisse de médecine interne générale : partie 2.

From June 1 to 3, 2022, Lausanne held the spring congress of the Swiss Society of General Internal Medicine: "Changes and Opportunities". In this article, chief residents in internal medicine at CHUV summarize presentations they attended. Internal general medicine is established in french-speaking Switzerland as a transversal specialty, which is reflected in this synthesis with very varied subjects. In thromboembolic disease, the duration of anticoagulation is now based on risk of recurrence. The thrombotic microangiopathy benefit nowadays from targeted therapy which improve diseases' outcomes. The new anti-viral therapy against SARS-CoV-2 (nirmatrelvir/ritonavir) is associated with numerous drug interactions. Finally, professors from Switzerland and abroad give their advices for scientific writing and academic career initiation.

Du 1er au 3 juin 2022 se tenait à Lausanne le congrès de printemps de la Société suisse de médecine interne : « Changes & Opportunities ¼. Les chefs de clinique du Service de médecine interne du CHUV vous proposent ici des résumés de quelques présentations. Cette synthèse aborde des sujets très variés reflétant la transversalité de la médecine interne générale. La durée d'anticoagulation de la maladie thromboembolique s'articule selon le risque de récidive. Les microangiopathies thrombotiques bénéficient de thérapies ciblées, qui améliorent leur pronostic. Le n­ouveau traitement antiviral contre le SARS-CoV-2 (nirmatrelvir/ritonavir) induit de multiples interactions médicamenteuses. Et pour finir, quelques conseils pour la rédaction d'un article scientifique et l'initiation d'une carrière académique.

[The Internal medicine articles that struck us the most in 2021]. / Année 2021 mise en perspective par les internistes hospitaliers.

The year 2021 has seen many breakthroughs in general internal medicine, despite the ongoing COVID-19 pandemic, with multiple implications in our daily clinical practice. From shorter antibiotic treatment duration in community-acquired pneumonia, to new indications for colchicine treatment, without forgetting better targets of hemoglobin for transfusion, questioning of the interest of high dose vitamin D substitution when preventing falls in older patients and finally disappointing hopes for new indications of albumin substitution in cirrhosis, the literature is full of new evidence. Each year, the chief residents of the internal medicine ward in Lausanne university hospital (CHUV) in Switzerland meet up to share their readings: here is a selection of ten articles, chosen, summarized, and commented for you.

L'année 2021, malgré la pandémie de Covid-19, a vu de nombreux progrès en médecine interne générale, avec de multiples implications pour notre pratique quotidienne. D'une durée diminuée d'antibiothérapie pour le traitement de la pneumonie communautaire à de nouvelles indications au traitement de colchicine, en passant par des précisions sur les cibles de transfusion érythrocytaire, ainsi qu'une remise en question de l'intérêt de la vitamine D à haute dose dans la prévention des chutes chez la personne âgée, et pour finir des espoirs déçus de nouvelle indication à la substitution d'albumine dans la cirrhose, les nouveautés abondent dans la littérature. Chaque année, les cheffes et chefs de clinique du Service de médecine interne du CHUV se réunissent pour partager leurs lectures : voici une sélection de dix articles choisis, revus et commentés pour vous.

Cerebrospinal and Brain Proteins Implicated in Neuropsychiatric and Risk Factor Traits: Evidence from Mendelian Randomization.

Neuropsychiatric disorders present a global health challenge, necessitating an understanding of their molecular mechanisms for therapeutic development. Using Mendelian randomization (MR) analysis, this study explored associations between genetically predicted levels of 173 proteins in cerebrospinal fluid (CSF) and 25 in the brain with 14 neuropsychiatric disorders and risk factors. Follow-up analyses assessed consistency across plasma protein levels and gene expression in various brain regions. Proteins were instrumented using tissue-specific genetic variants, and colocalization analysis confirmed unbiased gene variants. Consistent MR and colocalization evidence revealed that lower cortical expression of low-density lipoprotein receptor-related protein 8, coupled higher abundance in the CSF and plasma, associated with lower fluid intelligence scores and decreased bipolar disorder risk. Additionally, elevated apolipoprotein-E2 and hepatocyte growth factor-like protein in the CSF and brain were related to reduced leisure screen time and lower odds of physical activity, respectively. Furthermore, elevated CSF soluble tyrosine-protein kinase receptor 1 level increased liability to attention deficit hyperactivity disorder and schizophrenia alongside lower fluid intelligence scores. This research provides genetic evidence supporting novel tissue-specific proteomic targets for neuropsychiatric disorders and their risk factors. Further exploration is necessary to understand the underlying biological mechanisms and assess their potential for therapeutic intervention.

Adherence to 2020 ESC recommendations on physical activity in a population with different cardiovascular risk levels: A prospective population-based study from the CoLaus/PsyCoLaus study.

Introduction: In 2020, the European Society of Cardiology (ESC) recommends 150 min of moderate or 75 min of vigorous-intensity PA per week. While general population PA adherence is suboptimal, its status among those with previous ASCVD or high ASCVD risk remains unknown. We aimed to assess objective adherence to ESC PA recommendations using accelerometer-based measurement among these populations. Methodology: We used data from the Swiss CoLaus|PsyCoLaus cohort study (2014-2016). PA was measured using a 14-day wrist accelerometer. Adherence was defined as > 80 % of recommended PA achievement. Adherence was investigated separately among participants with previous ASCVD and among cardiovascular risk groups (based on the Systematic Coronary Risk Evaluation SCORE-1 and more recent SCORE2) with simple and multivariable logistic regressions. Participants' characteristics were also evaluated as independent factors after adjustment. Results: We studied 1867 participants (median age: 61.2 years, 51.3 % female). ESC PA Adherence reached 55.5 % overall, and 37 % in those with previous ASCVD. Multivariable analysis showed no significant association between previous ASCVD or high cardiovascular risk and PA adherence (Odds ratio adjusted [ORa] 0.9, 95 % Confidence Interval [CI] 0.6-1.4 and ORa 0.7, 95 % CI 0.4-1.2, respectively). Age (≥60 years old), obesity, smoking, chronic renal disease, hypertension, diabetes and benzodiazepine use were significantly associated with lower likelihood of PA adherence in multivariable logistic regression. Conclusion: Adherence to ESC PA guidelines, particularly in participants with higher cardiovascular risk, was poor. Since PA adherence was associated with modifiable risk factors (e.g., obesity, smoking, and benzodiazepine use), maintained efforts to implement the ESC recommendations are advised.

Caffeine Intake, Plasma Caffeine Level, and Kidney Function: A Mendelian Randomization Study.

Caffeine is a psychoactive substance widely consumed worldwide, mainly via sources such as coffee and tea. The effects of caffeine on kidney function remain unclear. We leveraged the genetic variants in the CYP1A2 and AHR genes via the two-sample Mendelian randomization (MR) framework to estimate the association of genetically predicted plasma caffeine and caffeine intake on kidney traits. Genetic association summary statistics on plasma caffeine levels and caffeine intake were taken from genome-wide association study (GWAS) meta-analyses of 9876 and of >47,000 European ancestry individuals, respectively. Genetically predicted plasma caffeine levels were associated with a decrease in estimated glomerular filtration rate (eGFR) measured using either creatinine or cystatin C. In contrast, genetically predicted caffeine intake was associated with an increase in eGFR and a low risk of chronic kidney disease. The discrepancy is likely attributable to faster metabolizers of caffeine consuming more caffeine-containing beverages to achieve the same pharmacological effect. Further research is needed to distinguish whether the observed effects on kidney function are driven by the harmful effects of higher plasma caffeine levels or the protective effects of greater intake of caffeine-containing beverages, particularly given the widespread use of drinks containing caffeine and the increasing burden of kidney disease.

Combining European and U.S. risk prediction models with polygenic risk scores to refine cardiovascular prevention: the CoLaus|PsyCoLaus Study.

AIMS: A polygenic risk score (PRS) has the potential to improve individual atherosclerotic cardiovascular disease (ASCVD) risk assessment. To determine whether a PRS combined with two clinical risk scores, the Systematic COronary Risk Evaluation 2 (SCORE2) and the Pooled Cohort Equation (PCE) improves the prediction of ASCVD. METHODS AND RESULTS: Using a population-based European prospective cohort, with 6733 participants at the baseline (2003-2006), the PRS presenting the best predictive accuracy was combined with SCORE2 and PCE to assess their joint performances for predicting ASCVD Discrimination, calibration, Cox proportional hazard regression, and net reclassification index were assessed. : 4218 subjects (53% women; median age, 53.4 years), with 363 prevalent and incident ASCVD, were used to compare four PRSs. The metaGRS_CAD PRS presented the best predictive capacity (AUROC = 0.77) and was used in the following analyses. 3383 subjects (median follow-up of 14.4 years), with 190 first-incident ASCVD, were employed to test ASCVD risk prediction. The changes in C statistic between SCORE2 and PCE models and those combining metaGRS_CAD with SCORE2 and PCE were 0.008 (95% CI, -0.00008-0.02, P = 0.05) and 0.007 (95% CI, 0.005-0.01, P = 0.03), respectively. Reclassification was improved for people at clinically determined intermediate-risk for both clinical scores [NRI of 9.6% (95% CI, 0.3-18.8) and 12.0% (95% CI, 1.5-22.6) for SCORE2 and PCE, respectively]. CONCLUSION: Combining a PRS with clinical risk scores significantly improved the reclassification of risk for incident ASCVD for subjects in the clinically determined intermediate-risk category. Introducing PRSs in clinical practice may refine cardiovascular prevention for subgroups of patients in whom prevention strategies are uncertain.

The aim of this study is to determine whether using polygenic risk scores improves the prediction of atherosclerotic cardiovascular disease risk when combined with clinical scores currently recommended by European and US guidelines on cardiovascular prevention.

Associations of genetic and infectious risk factors with coronary heart disease.

Coronary heart disease (CHD) is one of the most pressing health problems of our time and a major cause of preventable death. CHD results from complex interactions between genetic and environmental factors. Using multiplex serological testing for persistent or frequently recurring infections and genome-wide analysis in a prospective population study, we delineate the respective and combined influences of genetic variation, infections, and low-grade inflammation on the risk of incident CHD. Study participants are enrolled in the CoLaus|PsyCoLaus study, a longitudinal, population-based cohort with baseline assessments from 2003 through 2008 and follow-up visits every 5 years. We analyzed a subgroup of 3459 individuals with available genome-wide genotyping data and immunoglobulin G levels for 22 persistent or frequently recurring pathogens. All reported CHD events were evaluated by a panel of specialists. We identified independent associations with incident CHD using univariable and multivariable stepwise Cox proportional hazards regression analyses. Of the 3459 study participants, 210 (6.07%) had at least one CHD event during the 12 years of follow-up. Multivariable stepwise Cox regression analysis, adjusted for known cardiovascular risk factors, socioeconomic status, and statin intake, revealed that high polygenic risk (hazard ratio [HR] 1.31, 95% CI 1.10-1.56, p=2.64 × 10-3) and infection with Fusobacterium nucleatum (HR 1.63, 95% CI 1.08-2.45, p=1.99 × 10-2) were independently associated with incident CHD. In a prospective, population-based cohort, high polygenic risk and infection with F. nucleatum have a small, yet independent impact on CHD risk.

Comparison of the European and US guidelines for lipid-lowering therapy in primary prevention of cardiovascular disease.

AIMS: Population-wide impacts of new guidelines in the primary prevention of atherosclerotic cardiovascular disease (ASCVD) should be explored in independent cohorts. Assess and compare the lipid-lowering therapy eligibility and predictive classification performance of 2016 and 2021 European Society of Cardiology (ESC), 2019 American Heart Association/American College of Cardiology (AHA/ACC), and 2022 US Preventive Services Task Force (USPSTF) guidelines. METHODS AND RESULTS: Participants from the CoLaus|PsyCoLaus study, without ASCVD and not taking lipid-lowering therapy at baseline. Derivation of 10-year risk for ASCVD using Systematic COronary Risk Evaluation (SCORE1), SCORE2 [including SCORE2-Older Persons (SCORE2-OP)], and pooled cohort equation. Computation of the number of people eligible for lipid-lowering therapy based on each guideline and assessment of discrimination and calibration metrics of the risk models using first incident ASCVD as an outcome. Among 4,092 individuals, 158 (3.9%) experienced an incident ASCVD during a median follow-up of 9 years (interquartile range, 1.1). Lipid-lowering therapy was recommended or considered in 40.2% (95% confidence interval, 38.2-42.2), 26.4% (24.6-28.2), 28.6% (26.7-30.5), and 22.6% (20.9-24.4) of women and in 62.1% (59.8-64.3), 58.7% (56.4-61.0), 52.6% (50.3-54.9), and 48.4% (46.1-50.7) of men according to the 2016 ESC, 2021 ESC, 2019 AHA/ACC, and 2022 USPSTF guidelines, respectively. 43.3 and 46.7% of women facing an incident ASCVD were not eligible for lipid-lowering therapy at baseline according to the 2021 ESC and 2022 USPSTF, compared with 21.7 and 38.3% using the 2016 ESC and 2019 AHA/ACC, respectively. CONCLUSION: Both the 2022 USPSTF and 2021 ESC guidelines particularly reduced lipid-lowering therapy eligibility in women. Nearly half of women who faced an incident ASCVD were not eligible for lipid-lowering therapy.

QUESTION: Compared with previous European and US guidelines, what are the population-wide impacts of the 2021 European Society of Cardiology (ESC) and 2022 US Preventive Services Task Force (USPSTF) guidelines for primary cardiovascular prevention in terms of lipid-lowering therapy eligibility and risk classification performance? KEY FINDINGS: In a population-based cohort study comprising 4069 adults free from cardiovascular disease and lipid-lowering treatment, the implementation of both guidelines resulted in a lower proportion of treatment-eligible individuals compared with the 2016 ESC and 2019 American Heart Association/American College of Cardiology guidelines, especially among women. In women, nearly half of 10-year incident cardiovascular events occurred in those for whom a lipid-lowering therapy was not recommended. Meanings: The 2021 ESC and 2022 USPSTF guidelines reduced overtreatment but did not improve the identification of individuals who will develop atherosclerotic cardiovascular disease. There is a need to better stratify the cardiovascular risk in women.

Risk stratification for hospital-acquired venous thromboembolism in medical patients (RISE): Protocol for a prospective cohort study.

BACKGROUND: Hospital-acquired venous thromboembolism (VTE) is one of the leading preventable causes of in-hospital mortality. However, its risk assessment in medically ill inpatients is complicated due to the patients' heterogeneity and complexity of currently available risk assessment models (RAMs). The simplified Geneva score provides simplicity but has not yet been prospectively validated. Immobility is an important predictor for VTE in RAMs, but its definition is inconsistent and based on subjective assessment by nurses or physicians. In this study, we aim to prospectively validate the simplified Geneva score and to examine the predictive performance of a novel and objective definition of in-hospital immobilization using accelerometry. METHODS AND ANALYSIS: RISE is a multicenter prospective cohort study. The goal is to recruit 1350 adult inpatients admitted for medical illness in three Swiss tertiary care hospitals. We collect data on demographics, comorbidities, VTE risk and thromboprophylaxis. Mobility from admission to discharge is objectively measured using a wrist-worn accelerometer. Participants are followed for 90 days for the occurrence of symptomatic VTE (primary outcome). Secondary outcomes are the occurrence of clinically relevant bleeding, and mortality. The evolution of autonomy in the activities of daily living, the length of stay, and the occurrence of readmission are also recorded. Time-dependent area under the curve, sensitivity, specificity, and positive and negative predictive values are calculated for each RAM (i.e. the simplified and original Geneva score, Padua, and IMPROVE score) with and without the objective mobility measures to assess their accuracy in predicting hospital-acquired VTE at 90 days. ETHICS AND EXPECTED IMPACT: The ethics committee approved the protocol and the study was registered on ClinicalTrials.gov as NCT04439383. RISE has the potential to optimize VTE risk stratification, and thus to improve the quality of care of medically hospitalized patients.