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Background: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. Methods: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. Results: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20–1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01–1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59–0.67) to 0.65 (95% CI, 0.62–0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=−4.82×10 −3 per year [95% CI, −6.49×10 −3 to −3.14×10 −3 ]; P =1.82×10 −8 ), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86–0.98]; P =0.0041). Conclusions: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH.

Bromazolam is a designer benzodiazepine that was first detected in British Columbia in January 2021. Postmortem cases were analyzed using a comprehensive blood drug screening procedure by liquid chromatography–high-resolution mass spectrometry before being retrospectively analyzed using an in-house novel psychoactive substances data processing method. Bromazolam was detected in 41 postmortem cases in 2021 and quantitatively confirmed by standard addition, using liquid chromatography–tandem mass spectrometry. The mean bromazolam concentration observed was 11.4 ± 53.7 ng/mL (median concentration: 1.6 ng/mL), with a range from 0.5 to 319.3 ng/mL and the majority of cases co-occurring with fentanyl. These low concentrations may be indicative of a presumed enhancement of opioid effects, rather than being used as a stand-alone drug. Bromazolam was always detected with opioids (fentanyl and carfentanil), stimulants (methamphetamine) and/or other benzodiazepines (etizolam and flualprazolam). To our knowledge, this is the first report to provide concentrations of bromazolam in postmortem blood samples in Canada.

Aims Elevated lipoprotein(a) [Lp(a)] levels are associated with the risk of coronary artery disease (CAD) and calcific aortic valve stenosis (CAVS). Observational studies revealed that Lp(a) and C-reactive protein (CRP) levels, a biomarker of systemic inflammation, may jointly predict CAD risk. Whether Lp(a) and CRP levels also jointly predict CAVS incidence and progression is unknown. Methods and results We investigated the association of Lp(a) with CAVS according to CRP levels in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk study (n = 18 226, 406 incident cases) and the UK Biobank (n = 438 260, 4582 incident cases), as well as in the ASTRONOMER study (n = 220), which assessed the haemodynamic progression rate of pre-existing mild-to-moderate aortic stenosis. In EPIC-Norfolk, in comparison to individuals with low Lp(a) levels (50 mg/dL) and low CRP levels (50 mg/dL) and elevated CRP levels (>2.0 mg/L) had a higher CAVS risk [hazard ratio (HR) = 1.86 (95% confidence intervals, 1.30–2.67) and 2.08 (1.44–2.99), respectively]. A comparable predictive value of Lp(a) in patients with vs. without elevated CRP levels was also noted in the UK Biobank. In ASTRONOMER, CAVS progression was comparable in patients with elevated Lp(a) levels with or without elevated CRP levels. Conclusion Lp(a) predicts the incidence and possibly progression of CAVS regardless of plasma CRP levels. Lowering Lp(a) levels may warrant further investigation in the prevention and treatment of CAVS, regardless of systemic inflammation.

Genetic predisposition is a risk factor for office hypertension. We tested whether genetic background could identify individuals with ambulatory daytime hypertension in a sample of white Europeans from Liechtenstein. We evaluated two measures of predisposition to hypertension: family history and polygenic risk scores (PRS). Our analytic sample contained 1444 participants aged 25 to 41. Of the participants, 12% had office hypertension, while 37% had out-of-office hypertension. The correlation between blood pressure PRS and family history of hypertension was low (R2= 4.96×10−3), but both were strongly associated with ambulatory blood pressure (2.2 mmHg per 1 SD increase [95% CI: 1.6, 2.7] & 2.4 mmHg increase with positive family history [95% CI: 1.3, 3.4], respectively). The PRS provides incremental improvement in predicting ambulatory systolic blood pressure beyond a validated blood pressure prediction score (ΔAIC = - 33), whereas family history does not (ΔAIC = 1). However, the difference in performance between a baseline prediction algorithm for identifying ambulatory systolic daytime hypertension (positive likelihood ratio of 6.87 [95% CI: 5.56, 8.49]; negative likelihood ratio of 0.45 [95% CI: 0.39, 0.51]) and the same model with PRS integrated (positive likelihood ratio of 7.69 [95% CI: 6.18, 9.57]; negative likelihood ratio of 0.43 [95% CI: 0.37, 0.49]) was modest. In conclusion, in a white European sample from Liechtenstein, PRS and family history are distinct constructs that are associated with increased clinical and ambulatory blood pressure. Unlike family history, polygenic risk scores provide incremental information in the identification of individuals with ambulatory hypertension. However, these gains are modest and warrant further development to improve predictive utility at the point-of-care.

Background: Lipoprotein(a) (Lp[a]), which consists of a low-density lipoprotein (LDL) bound to apolipoprotein(a), is one of the strongest genetic risk factors for atherosclerotic cardiovascular diseases. Few studies have performed hypothesis-free direct comparisons of the Lp(a) and the LDL proteomes. Our objectives were to compare the Lp(a) and the LDL proteomic profiles and to evaluate the effect of lifelong exposure to elevated Lp(a) or LDL cholesterol levels on the plasma proteomic profile. Methods: We performed a label-free analysis of the Lp(a) and LDL proteomic profiles of healthy volunteers in a discovery (n = 6) and a replication (n = 9) phase. We performed inverse variance weighted Mendelian randomization to document the effect of lifelong exposure to elevated Lp(a) or LDL cholesterol levels on the plasma proteomic profile of participants of the INTERVAL study. Results: We identified 15 proteins that were more abundant on Lp(a) compared with LDL (serping1, pi16, itih1, itih2, itih3, pon1, podxl, cd44, cp, ptprg, vtn, pcsk9, igfals, vcam1, and ttr). We found no proteins that were more abundant on LDL compared with Lp(a). After correction for multiple testing, lifelong exposure to elevated LDL cholesterol levels was associated with the variation of 18 plasma proteins whereas Lp(a) did not appear to influence the plasma proteome. Conclusions: Results of this study highlight marked differences in the proteome of Lp(a) and LDL as well as in the effect of lifelong exposure to elevated LDL cholesterol or Lp(a) on the plasma proteomic profile. Résumé: Contexte: La lipoprotéine(a) (Lp[a]), qui est constituée d’une lipoprotéine de basse densité (LDL) liée à une apolipoprotéine(a), est l’un des plus importants facteurs de risque génétiques de survenue d’une maladie cardiovasculaire athéroscléreuse. Peu d’études comparatives directes sans hypothèse ont porté sur le protéome de la Lp(a) et celui des LDL. Nos objectifs étaient de comparer les profils protéomiques de la Lp(a) et des LDL et d’évaluer l’effet d’une exposition à vie à un taux élevé de Lp(a) ou de cholestérol LDL sur le profil protéomique plasmatique. Méthodologie: Nous avons réalisé une analyse sans marquage des profils protéomiques de la Lp(a) et des LDL chez des volontaires en bonne santé dans le cadre d’une phase de découverte (n = 6) et d’une phase de réplication (n = 9). Pour rendre compte de l’effet d’une exposition à vie à un taux élevé de Lp(a) ou de cholestérol des LDL sur le profil protéomique plasmatique des participants de l’étude INTERVAL, nous avons utilisé une analyse de randomisation Mendélienne avec pondération par l’inverse de la variance. Résultats: Nous avons relevé 15 protéines associées en plus grande abondance à la Lp(a) qu’aux LDL (serping1, pi16, itih1, itih2, itih3, pon1, podxl, cd44, cp, ptprg, vtn, pcsk9, igfals, vcam1 et ttr). Nous n’avons noté aucune protéine associée en plus grande abondance aux LDL qu’à la Lp(a). Après correction pour tenir compte de la multiplicité des tests, l’exposition à vie à un taux élevé de cholestérol LDL a été associée à la variation de 18 protéines plasmatiques, tandis que le taux de Lp(a) ne semblait pas influencer le protéome plasmatique. Conclusions: Les résultats de notre étude font ressortir les différences marquées entre le protéome de la Lp(a) et celui des LDL, ainsi qu’entre l’effet sur le profil protéomique plasmatique de l’exposition à vie à un taux élevé de cholestérol LDL et celui de l’exposition à vie à un taux élevé de Lp(a).

Non-alcoholic fatty liver disease (NAFLD) is a complex cardiometabolic disease associated with premature mortality. The diagnosis of NAFLD is challenging and the identification of biomarkers causally influenced by NAFLD may be clinically useful. We aimed at identifying blood metabolites causally impacted by NAFLD using two-sample Mendelian randomization (MR) with validation in a population-based biobank and a cohort of patients undergoing bariatric surgery. Our instrument for genetically-predicted NAFLD (the study exposure) included all independent genetic variants (n=7 SNPs) from a recent genome-wide association study on NAFLD. The study outcomes included 123 blood lipids, lipoproteins and metabolites measured in 24,925 individuals from 10 European cohorts. After correction for multiple testing, we identified a positive effect of NAFLD on plasma tyrosine levels but not on other metabolites. The association between NAFLD and tyrosine levels was consistent across MR methods and robust to outliers and pleiotropy. In observational analyses performed in the Estonian Biobank (10,809 individuals including 359 patients with NAFLD), after multivariable adjustment, tyrosine levels were positively associated with the presence of NAFLD (odds ratio per 1-SD increment = 1.23 (95% confidence interval = 1.12-1.36, p = 2.19e-05). In a sample of 138 patients undergoing bariatric surgery, compared to patients without NAFLD, blood tyrosine levels were higher in those with NAFLD, but were comparable among patients with or without non-alcoholic steatohepatitis. This analysis revealed a potentially causal effect of NAFLD on blood tyrosine levels, suggesting that blood tyrosine levels may represent a new biomarker of NAFLD.Graphical abstract

Canada's Food Guide (CFG) was profoundly revised in 2019, but the extent to which adherence to recommendations on healthy food choices reduces the risk of cardiovascular disease (CVD) is unknown.The aim of this study was to examine how greater adherence to the 2019 CFG's recommendations on healthy food choices influences the risk of incident CVD.Participants were a sample of adults without history of CVD, diabetes, or cancer from the UK Biobank prospective cohort study. Usual dietary intakes were estimated by modeling data from repeated Web-based 24-h dietary recalls using the National Cancer Institute multivariate method. Adherence to key CFG recommendations on healthy food choices was assessed using the Healthy Eating Food Index (HEFI)-2019, which has a maximum of 80 points. The CVD outcome was a composite of fatal and nonfatal myocardial infarction and ischemic stroke. Cox regression models adjusted via inverse probability weighting were used to estimate CVD risks. Counterfactual models were used to interpret risks of hypothetical changes in the HEFI-2019 score.A total of 136,698 participants met the eligibility criteria (55% females; mean age: 57.2 y; range: 40-75 y). During the 11-y follow-up, there were 2843 cases of incident CVD. Compared with no change in the HEFI-2019 score, increasing the HEFI-2019 score of all participants to the 90th percentile of the score distribution (58.1 points) hypothetically reduced the risk of CVD by 24% (RR: 0.76; 95% CI: 0.58, 0.94; absolute risk difference: -0.58%).These results suggest that greater adherence to the 2019 CFG recommendations on healthy food choices reduces the 11-y risk of CVD in middle-aged and older adults.

Context The impact of galectin-3 inhibitors on nonalcoholic fatty liver diseases (NAFLD)-related outcomes is currently under investigation in randomized clinical trials. Whether there is a causal association between plasma galectin-3 levels and NAFLD is unknown. Objective To evaluate the causal effect of circulating galectin-3 levels on NAFLD as well as >800 other human diseases. Design Inverse variance-weighted (IVW) Mendelian randomization (MR) and phenome-wide MR. Setting Summary statistics of genome-wide association studies. Patients Participants of the UK Biobank, Electronic Medical Records and Genomics (eMERGE), FinnGen, Prevention of Renal and Vascular End-Stage Disease (PREVEND), and IMPROVE cohorts. Intervention Identification of independent single-nucleotide polymorphisms (SNPs) associated with galectin-3 levels (P Main outcome measures Presence of NAFLD in a meta-analysis of genome-wide association study of the eMERGE, UK Biobank, and FinnGen cohorts (3042 NAFLD cases and 504 853 controls), as well as >800 other human diseases in the UK Biobank and FinnGen. Results Using IVW-MR, we found no causal association between galectin-3 levels and NAFLD in the meta-analysis of the 3 cohorts or in each individual cohort. After correction for multiple testing, we found no causal association between galectin-3 levels and >800 human disease-related traits. Conclusions This MR study revealed no causal associations between circulating galectin-3 levels and NAFLD or any other disease traits, suggesting that plasma galectin-3 levels may not be directly implicated in the pathogenesis of NAFLD or other human diseases.

Background: Observational studies have linked obesity and especially abdominal obesity to non-alcoholic fatty liver disease (NAFLD). These traits are also associated with type 2 diabetes (T2D) and coronary artery disease (CAD) but the causal factor(s) underlying these associations remain unexplored. Multivariable Mendelian randomization (MVMR) is a method that uses multiple genetic variants associated with traits of interest to simultaneously estimate the causal effect of each of these traits on outcomes of interest. Methods: We used a MVMR study design to determine whether obesity (defined using body mass index [BMI]) and abdominal obesity (defined using waist circumference) were causally associated with NAFLD using publicly available genome-wide association study (GWAS) summary statistics of the UK Biobank (n>450,000) and a GWAS meta-analysis of NAFLD (8434 cases and 770,180 control). A MVMR study design was also used to determine the respective causal contributions of waist circumference and NAFLD to T2D and CAD using GWAS summary statistics of the DIAGRAM (74,124 cases and 824,006 controls) and CARDIoGRAMplusC4D (122,733 cases and 424,528 controls) consortia.Results: In univariable Mendelian randomization analyses, both BMI and waist circumference were associated with NAFLD. NAFLD was not associated with obesity or abdominal obesity. In MVMR analyses, waist circumference was associated with NAFLD when accounting for BMI (OR per 1-standard deviation increase = 2.35 95% CI=1.31-4.22, p=4.1e-03) and BMI was not associated with NAFLD when accounting for waist circumference (0.87 95% CI=0.54-1.38, p=5.5e-01). In MVMR analyses accounting for NAFLD, waist circumference remained strongly associated with both T2D (2.65 95% CI=2.32-3.04, p=5.7e-45) and CAD (1.49 95% CI=1.37-1.62, p=8.3e-21).Conclusions: These results identified abdominal obesity as a strong, independent and causal contributor to NAFLD, T2D and CAD, thereby highlighting the importance of assessing body fat distribution for the prediction and prevention of cardiometabolic diseases.

BACKGROUND: Uromodulin, the most abundant protein excreted in normal urine, plays major roles in kidney physiology and disease. The mechanisms regulating the urinary excretion of uromodulin remain essentially unknown.METHODS: We conducted a meta-analysis of genome-wide association studies for raw (uUMOD) and indexed to creatinine (uUCR) urinary levels of uromodulin in 29,315 individuals of European ancestry from 13 cohorts. We tested the distribution of candidate genes in kidney segments and investigated the effects of keratin-40 (KRT40) on uromodulin processing.RESULTS: Two genome-wide significant signals were identified for uUMOD: a novel locus ( P 1.24E-08) over the KRT40 gene coding for KRT40, a type 1 keratin expressed in the kidney, and the UMOD-PDILT locus ( P 2.17E-88), with two independent sets of single nucleotide polymorphisms spread over UMOD and PDILT. Two genome-wide significant signals for uUCR were identified at the UMOD-PDILT locus and at the novel WDR72 locus previously associated with kidney function. The effect sizes for rs8067385, the index single nucleotide polymorphism in the KRT40 locus, were similar for both uUMOD and uUCR. KRT40 colocalized with uromodulin and modulating its expression in thick ascending limb (TAL) cells affected uromodulin processing and excretion. CONCLUSIONS: Common variants in KRT40, WDR72, UMOD, and PDILT associate with the levels of uromodulin in urine. The expression of KRT40 affects uromodulin processing in TAL cells. These results, although limited by lack of replication, provide insights into the biology of uromodulin, the role of keratins in the kidney, and the influence of the UMOD-PDILT locus on kidney function.

Calcific aortic valve stenosis (CAVS) is a frequent heart disease with significant morbidity and mortality. Recent genomic studies have identified a locus near the gene PALMD (palmdelphin) strongly associated with CAVS. Here, we show that genetically-determined expression of PALMD in the aortic valve is inversely associated with CAVS, with a stronger effect in women, in a meta-analysis of two large cohorts totaling 2359 cases and 350,060 controls. We further demonstrate the specificity of this relationship by showing the absence of other significant association between the genetically-determined expression of PALMD in 9 tissues and 852 phenotypes. Using genome-wide association studies meta-analyses of cardiovascular traits, we identify a significant colocalized positive association between genetically-determined expression of PALMD in four non-cardiac tissues (brain anterior cingulate cortex, esophagus muscularis, tibial nerve and subcutaneous adipose tissue) and atrial fibrillation. The present work further establishes PALMD as a promising molecular target for CAVS., Zhonglin Li et al. perform phenome-wide analyses to explore the genetic association between the locus near PALMD and calcific aortic valve stenosis (CAVS). Using previously reported aortic valve expression data and genotypes from large cohorts, they find a strong and specific association between genetically-determined PALMD expression in the aortic valve and CAVS as well as a novel association with atrial fibrillation in non-cardiac tissues.

The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization (QRS duration) and repolarization (JT interval). Abnormalities of the QT interval are associated with potentially fatal ventricular arrhythmia. We conducted genome-wide multi-ancestry analyses in >250,000 individuals and identified 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identified associations with Mendelian disease genes. Enrichments were observed in established pathways for QT and JT, with new genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast, connective tissue components and processes for cell growth and extracellular matrix interactions were significantly enriched for QRS. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlighted potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.

The study of parental lifespan has emerged as an innovative tool to advance aging biology and our understanding of the genetic architecture of human longevity and aging‐associated diseases. Here, we leveraged summary statistics of a genome‐wide association study including over one million parental lifespans to identify genetically regulated genes from the Genotype‐Tissue Expression project. Through a combination of multi‐tissue transcriptome‐wide association analyses and genetic colocalization, we identified novel genes that may be associated with parental lifespan. Mendelian randomization (MR) analyses also identified circulating proteins and metabolites causally associated with parental lifespan and chronic diseases offering new drug repositioning opportunities such as those targeting apolipoprotein‐B‐containing lipoproteins. Liver expression of HP, the gene encoding haptoglobin, and plasma haptoglobin levels were causally linked with parental lifespan. Phenome‐wide MR analyses were used to map genetically regulated genes, proteins and metabolites with other human traits as well as the disease‐related phenome in the FinnGen cohorts (n = 135,638). Altogether, this study identified new candidate genes, circulating proteins and metabolites that may influence human aging as well as potential therapeutic targets for chronic diseases that warrant further investigation., Schematic overview of the analytical framework used to identify novel biological determinants of lifespan and potential drug targets for aging‐associated diseases using genome‐wide association study summary statistics of >1 million parental lifespans.

Background: Several risk factors for coronary artery disease (CAD) have been described, some of which are genetically determined. The use of a polygenic risk score (PRS) could improve CAD risk assessment, but predictive accuracy according to age and sex is not well established. Methods: A PRS CAD including the weighted effects of >1.14 million single nucleotide polymorphisms associated with CAD was calculated in UK Biobank (n=408 422), using LDpred. Cox regressions were performed, stratified by age quartiles and sex, for incident myocardial infarction (MI) and mortality, with a median follow-up of 11.0 years. Improvement in risk prediction of MI was assessed by comparing PRS CAD to the pooled cohort equation with categorical net reclassification index using a 2% threshold (NRI 0.02 ) and continuous NRI (NRI >0 ). Results: From 7746 incident MI cases and 393 725 controls, hazard ratio for MI reached 1.53 (95% CI, 1.49–1.56; P =2.69×10 −296 ) per SD increase of PRS CAD . PRS CAD was significantly associated with MI in both sexes, with a stronger association in men (interaction P =0.002), particularly in those aged between 40 and 51 years (hazard ratio, 2.00 [95% CI, 1.86–2.16], P =1.93×10 −72 ). This group showed the highest reclassification improvement, mainly driven by the up-classification of cases (NRI 0.02 , 0.199 [95% CI, 0.157–0.248] and NRI >0 , 0.602 [95% CI, 0.525–0.683]). From 23 982 deaths, hazard ratio for mortality was 1.08 (95% CI, 1.06–1.09; P =5.46×10 −30 ) per SD increase of PRS CAD , with a stronger association in men (interaction P =1.60×10 −6 ). Conclusions: Our PRS CAD predicts MI incidence and all-cause mortality, especially in men aged between 40 and 51 years. PRS could optimize the identification and management of individuals at risk for CAD.

Coronary artery disease (CAD) is a multifactorial disorder, which is partly heritable. Herein, we implemented a mapping of CAD-associated candidate genes by using genome-wide enhancer-promoter conformation (H3K27ac-HiChIP) and expression quantitative trait loci (eQTL). Enhancer-promoter anchor loops from human coronary artery smooth muscle cells (HCASMC) explained 22% of the heritability for CAD. 3D enhancer-promoter genome mapping of CAD-genes in HCASMC was enriched in vascular eQTL genes. By using colocalization and Mendelian randomization analyses, we identified 58 causal candidate vascular genes including some druggable targets (MAP3K11, CAMK1D, PDGFD, IPO9 and CETP). A network analysis of causal candidate genes was enriched in TGF beta and MAPK pathways. The pharmacologic inhibition of causal candidate gene MAP3K11 in vascular SMC reduced the expression of athero-relevant genes and lowered cell migration, a cardinal process in CAD. Genes connected to enhancers are enriched in vascular eQTL and druggable genes causally associated with CAD.

Alterations of the gut microbiota, often referred to as gut dysbiosis, have been associated with several chronic diseases and longevity in pre-clinical models as well as in observational studies. Whether these relationships underlie causal associations in humans remains to be established. We aimed to determine whether gut dysbiosis influences the risk of chronic diseases and longevity using a comprehensive 2-Sample Mendelian randomization (2SMR) approach. We included as exposures inflammatory bowel disease (IBD) as a human model of gut dysbiosis, 11 gut-associated metabolites and pathways and 48 microbial taxa. Study outcomes included eight chronic diseases previously linked with gut dysbiosis using observational studies (Alzheimer’s disease, depression, type 2 diabetes, non-alcoholic fatty liver disease, coronary artery disease (CAD), stroke, osteoporosis and chronic kidney disease) as well as parental longevity and life expectancy. Neither IBD, nor gut-associated metabolites were causally associated with chronic disease or lifespan. After multiple testing correction for 582 tests, no microbial taxa-chronic disease associations remained significant. After robustness analyses and multivariate MR to correct for body mass index and alcohol intake on all 42 nominally significant causal relationships, four associations remained. Altogether, results of this multidimensional Mendelian randomization study suggest that gut dysbiosis has little impact on chronic diseases and human longevity and that previous documented associations may not underly causal relationships. Studies with larger sample sizes and more optimal taxonomic discrimination may ultimately be required to determine whether the human gut microbiota plays a causal role in the etiology of chronic diseases and longevity.

Background: Elevated Lp(a) (Lipoprotein(a)) levels are associated with coronary artery disease (CAD), ischemic stroke (IS), and calcific aortic valve stenosis (CAVS). Studies investigating the association between Lp(a) levels and these diseases in women have yielded inconsistent results. Methods: To investigate the association of Lp(a) with sex-specific cardiovascular outcomes, we determined the association between genetically predicted Lp(a) levels (using 27 single nucleotide polymorphisms at the LPA locus) and hepatic LPA expression (using 80 single nucleotide polymorphisms at the LPA locus associated with LPA mRNA expression in liver samples from the Genotype-Tissue Expression dataset) on CAD, IS, and CAVS using individual participant data from the UK Biobank: 408 403 participants of European ancestry (37 102, 4283, and 2574 with prevalent CAD, IS, and CAVS, respectively). The long-term association between Lp(a) levels and incident CAD, IS, and CAVS was also investigated in European Prospective Investigation into Cancer and Nutrition-Norfolk: 18 721 participants (3964, 846, and 424 with incident CAD, IS, and CAVS, respectively). Results: Genetically predicted plasma Lp(a) levels were positively and similarly associated with prevalent and incident CAD and CAVS in men and women. Genetically predicted plasma Lp(a) levels were associated with prevalent and incident IS when we studied men and women pooled together, and in men only. Genetically predicted LPA expression levels were associated with prevalent CAD and CAVS in men and women but not with IS. Conclusions: Genetically predicted blood Lp(a) and hepatic LPA gene expression as well as serum Lp(a) levels predict the risk of CAD and CAVS in men and in women. Whether RNA interference therapies aiming at lowering Lp(a) levels could be useful in reducing cardiovascular disease risk in both men and women with high Lp(a) levels needs to be determined in large-scale cardiovascular outcomes trials.

Lipoprotein(a) (Lp(a)) is one of the most important risk factors for the development of calcific aortic valve stenosis (CAVS). However, the mechanisms through which Lp(a) causes CAVS are currently unknown. Our objectives were to characterize the Lp(a) proteome and to identify proteins that may be differentially associated with Lp(a) in patients with versus without CAVS. Our second objective was to identify genes that may be differentially regulated by exposure to high versus low Lp(a) levels in explanted aortic valves from patients with CAVS. We isolated Lp(a) from the blood of 21 patients with CAVS and 22 volunteers and performed untargeted label-free analysis of the Lp(a) proteome. We also investigated the transcriptomic signature of calcified aortic valves from patients who underwent aortic valve replacement with high versus low Lp(a) levels (n = 118). Proteins involved in the protein activation cascade, platelet degranulation, leukocyte migration, and response to wounding may be associated with Lp(a) depending on CAVS status. The transcriptomic analysis identified genes involved in cardiac aging, chondrocyte development, and inflammation as potentially influenced by Lp(a). Our multi-omic analyses identified biological pathways through which Lp(a) may cause CAVS, as well as key molecular events that could be triggered by Lp(a) in CAVS development.

BackgroundSeveral risk factors for coronary artery disease (CAD) have been described, some of which are genetically determined. The use of a polygenic risk score (PRS) could improve CAD risk assessment, but predictive accuracy according to age and sex is not well established.MethodsA PRSCAD including the weighted effects of >1.14 million SNPs associated with CAD was calculated in UK Biobank (n=408,422), using LDPred. Cox regressions were performed, stratified by age quartiles and sex, for incident MI and mortality, with a median follow-up of 11.0 years. Improvement in risk prediction of MI was assessed by comparing PRSCAD to the pooled cohort equation with categorical net reclassification index using a 2% threshold (NRI0.02) and continuous NRI (NRI>0).ResultsFrom 7,746 incident MI cases and 393,725 controls, hazard ratio (HR) for MI reached 1.53 (95% CI [1.49-1.56], p=2.69e-296) per standard deviation (SD) increase of PRSCAD. PRSCAD was significantly associated with MI in both sexes, with a stronger association in men (interaction p=0.002), particularly in those aged between 40-51 years (HR=2.00, 95% CI [1.86-2.16], p=1.93e-72). This group showed the highest reclassification improvement, mainly driven by the up-classification of cases (NRI0.02=0.199, 95% CI [0.157-0.248] and NRI>0=0.602, 95% CI [0.525-0.683]). From 23,982 deaths, HR for mortality was 1.08 (95% CI [1.06-1.09], p=5.46e-30) per SD increase of PRSCAD, with a stronger association in men (interaction p=1.60e-6).ConclusionOur PRSCAD predicts MI incidence and all-cause mortality, especially in men aged between 40-51 years. PRS could optimize the identification and management of individuals at risk for CAD.

Background and objective Transcutaneous pulse oximetry saturation (SpO2) is widely used to diagnose severe hypoxaemia and to prescribe long-term oxygen therapy (LTOT) in COPD. This practice is not based on evidence. The primary objective of this study was to determine the accuracy (false positive and false negative rates) of oximetry for prescribing LTOT or for screening for severe hypoxaemia in patients with COPD. Methods In a cross-sectional study, we correlated arterial oxygen saturation (SaO2) and SpO2 in patients with COPD and moderate hypoxaemia (n=240) and calculated the false positive and false negative rates of SaO2 at the threshold of ≤88% to identify severe hypoxaemia (arterial oxygen tension (PaO2) ≤55 mmHg or PaO2 88% (i.e., false negative result). Conversely, LTOT would be prescribed on the basis of a SaO2 ≤88% in 2% of patients who would not qualify for LTOT (i.e., false positive result). Using a screening threshold of ≤92%, 5% of severely hypoxaemic patients would not be referred for further evaluation. Conclusions Several patients who qualify for LTOT would be denied treatment using a prescription threshold of saturation ≤88% or a screening threshold of ≤92%. Prescription of LTOT should be based on PaO2 measurement., Although transcutaneous pulse oximetry is widely used to diagnose severe hypoxaemia and prescribe long-term oxygen therapy in COPD, up to 40% of patients who qualify for this therapy would be denied treatment using the saturation threshold of ≤88% https://bit.ly/3jolWU5