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Abstract Background The bleeding risks for nonsyndromic platelet function disorders (PFDs) that impair aggregation responses and/or cause dense granule deficiency (DGD) are uncertain. Objectives Our goal was to quantify bleeding risks for a cohort of consecutive cases with uncharacterized PFD. Methods Sequential cases with uncharacterized PFDs that had reduced maximal aggregation (MA) with multiple agonists and/or nonsyndromic DGD were invited to participate along with additional family members to reduce bias. Index cases were further evaluated by exome sequencing, with analysis of RUNX1‐dependent genes for cases with RUNX1 sequence variants. Bleeding assessment tools were used to estimate bleeding scores, with bleeding risks estimated as odds ratios (ORs) relative to general population controls. Relationships between symptoms and laboratory findings were also explored. Results Participants with uncharacterized PFD (n = 37; 23 index cases) had impaired aggregation function (70%), nonsyndromic DGD (19%) or both (11%), unlike unaffected relatives. Probable pathogenic RUNX1 variants were found in 2 (9%) index cases/families, whereas others had PFD of unknown cause. Participants with PFD had increased bleeding scores compared to unaffected family members and general population controls, and increased risks for mucocutaneous (OR, 4‐207) and challenge‐related bleeding (OR, 12‐43), and for receiving transfusions for bleeding (OR, 100). Reduced MA with collagen was associated with wound healing problems and bruising, and more severe DGD was associated with surgical bleeding (P

South Asians (SAs), originating from the Indian subcontinent (India, Pakistan, Sri Lanka, Bangladesh, Nepal, and Bhutan), represent one quarter of the global population and are the largest visible minority in Canada. SAs experience the highest rates of coronary artery disease in Canada. Although conventional cardiovascular risk factors remain predictive in SA, the excess risk is not fully explained by these risk factors alone. Abdominal obesity, metabolic syndrome, and insulin resistance likely contribute a greater risk in SAs than in other populations. The South Asian Heart Alliance has been recently formed to investigate and recommend the best strategies for the prevention of cardiometabolic disease in SAs in Canada. This topic review represents a comprehensive overview of the magnitude of cardiovascular disease in SAs in Canada, with a review of conventional and novel risk markers in the SA population. Both primary and secondary prevention strategies are suggested and when possible, adapted specifically for the SA population. The need for SAs and their healthcare professionals to be more aware of the problem and potential solutions, along with the need for population-specific research, is highlighted. Résumé: Les Asiatiques du sud originaires du sous-continent indien (Inde, Pakistan, Sri Lanka, Bangladesh, Népal et Bhoutan) représentent le quart de la population mondiale et constituent la plus importante minorité visible au Canada. C’est aussi au sein de cette population qu’on observe les taux de coronaropathie les plus élevés au Canada. Bien que les facteurs de risque cardiovasculaire classiques conservent leur valeur prédictive chez les Asiatiques du sud, ils n’expliquent pas à eux seuls le risque excédentaire observé. L’obésité abdominale, le syndrome métabolique et l’insulinorésistance constituent vraisemblablement des facteurs de risque plus importants chez les Asiatiques du sud que dans les autres populations. La South Asian Heart Alliance a récemment été mise sur pied afin d’explorer les stratégies exemplaires pour la prévention des maladies cardiométaboliques chez les Asiatiques du sud au Canada et de formuler des recommandations à cet égard. Cette revue thématique présente un aperçu de l’importance des maladies cardiovasculaires au sein de la population des Asiatiques du sud du Canada, ainsi qu’un résumé des marqueurs de risque classiques et nouveaux dans cette population. Les auteurs proposent des stratégies de prévention primaire et secondaire adaptées, dans la mesure du possible, à la population des Asiatiques du sud. Ils font également ressortir l’importance de sensibiliser davantage les Asiatiques du sud et les professionnels de la santé aux risques et aux solutions possibles, ainsi que la nécessité de mener des recherches axées sur cette population particulière.

Malignant coronary artery disease (CAD) refers to a severe and extensive atherosclerotic process involving multiple coronary arteries in young individuals (aged

Lipoprotein(a) [Lp(a)] is a circulating lipoprotein, and its level is largely determined by variation in the Lp(a) gene (LPA) locus encoding apo(a). Genetic variation in the LPA gene that increases Lp(a) level also increases coronary artery disease (CAD) risk, suggesting that Lp(a) is a causal factor for CAD risk. Lp(a) is the preferential lipoprotein carrier for oxidized phospholipids (OxPL), a proatherogenic and proinflammatory biomarker. Lp(a) adversely affects endothelial function, inflammation, oxidative stress, fibrinolysis, and plaque stability, leading to accelerated atherothrombosis and premature CAD. The INTER-HEART Study has established the usefulness of Lp(a) in assessing the risk of acute myocardial infarction in ethnically diverse populations with South Asians having the highest risk and population attributable risk. The 2018 Cholesterol Clinical Practice Guideline have recognized elevated Lp(a) as an atherosclerotic cardiovascular disease risk enhancer for initiating or intensifying statin therapy. Keywords: Lipoprotein(a), Oxidized phospholipids, Genetic risk factor, Indians, Acute myocardial infarction, Premature coronary artery disease, Cardiovascular disease, Kringles, Isoforms, Mendelian randomization, Single nucleotide polymorphism, Genome-wide association studies, meta-analysis

Background: Genetic risk factors for dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) and dengue fever (DF) are limited, in particular there are sparse data on genetic risk across diverse populations. Methods: We conducted a genome-wide association study (GWAS) in a derivation and validation sample of 7, 460 participants of Latin American, South Asian, and South East Asian ancestries. We then developed a weighted polygenic risk score (PRS) for each participant in each of the validation cohorts of the three ancestries to predict the risk of DHF/DSS compared to DF, DHF/DSS compared to controls, and, DF compared to controls. Findings: The risk of DHF/DSS was significantly increased, odds ratio [OR] 1.84 (95%CI 1.47 to 2.31) (195 SNPs), compared to DF, fourth PRS quartile versus first quartile, in the validation cohort. The risk of DHF/DSS compared to controls was increased (OR=3.94; 95% CI 2.84 to 5.45) (278 SNPs), as was the risk of DF compared to controls (OR=1.97; 95%CI 1.63 to 2.39) (251 SNPs). Risk increased in a dose-dependent manner with increase in quartiles of PRS across comparisons. Significant associations persisted for PRS built within ancestries and applied to the same or different ancestries as well as for PRS built for one outcome (DHF/DSS or DF) and applied to the other. Interpretation: There is a strong genetic effect that predisposes to risk of DHF/DSS and DF. The genetic risk for DHF/DSS is higher than that for DF when compared to controls, and this effect persists across multiple ancestries. Keywords: Dengue, Genetics, Risk, GWAS, Ancestry

Summary: Chronic kidney disease is a leading cause of death and disability globally and impacts individuals of African ancestry (AFR) or with ancestry in the Americas (AMS) who are under-represented in genome-wide association studies (GWASs) of kidney function. To address this bias, we conducted a large meta-analysis of GWASs of estimated glomerular filtration rate (eGFR) in 145,732 AFR and AMS individuals. We identified 41 loci at genome-wide significance (p

The proprotein convertase subtilisin kexin-9 (PCSK9) circulates in plasma as mature and furin-cleaved forms. A polyclonal antibody against human PCSK9 was used to develop an ELISA that measures total plasma PCSK9 rather than only the mature form. A cross-sectional study evaluated plasma levels in normal (n = 254) and hypercholesterolemic (n = 200) subjects treated or untreated with statins or statin plus ezetimibe. In controls, mean plasma PCSK9 (89.5 ± 31.9 ng/ml) correlated positively with age, total cholesterol, LDL-cholesterol (LDL-C), triglycerides, and fasting glucose. Sequencing PCSK9 from individuals at the extremes of the normal PCSK9 distribution identified a new loss-of-function R434W variant associated with lower levels of circulating PCSK9 and LDL-C. In hypercholesterolemic subjects, PCSK9 levels were higher than in controls (99.3 ± 31.7 ng/ml, P < 0.04) and increased in proportion to the statin dose, combined or not with ezetimibe. In treated patients (n = 139), those with familial hypercholesterolemia (FH; due to LDL receptor gene mutations) had higher PCSK9 values than non-FH (147.01 ± 42.5 vs. 127.2 ± 40.8 ng/ml, P < 0.005), but LDL-C reduction correlated positively with achieved plasma PCSK9 levels to a similar extent in both subsets (r = 0.316, P < 0.02 in FH and r = 0.275, P < 0.009 in non-FH). The detection of circulating PCSK9 in both FH and non-FH subjects means that this assay could be used to monitor response to therapy in a wide range of patients.