👤 Giorgio E M Melloni

Cerebral small vessel disease (CSVD) contributes to the development of Alzheimer's disease (AD) dementia and co-occurs with AD-associated proteinopathies. However, how sex modulates the interaction between CSVD and AD-associated proteinopathies in the medial temporal lobe (MTL) remains unclear. One hundred fifty-two autopsy cases from the Massachusetts Alzheimer's Disease Research Center were included. Deep-learning and semiquantitative scores were applied to MTL histological sections to obtain quantitative measures of proteinopathies and CSVD (cerebral amyloid angiopathy [CAA] and arteriolosclerosis). The effect of sex on AD-associated proteinopathies and the interaction between sex, CSVD, and apolipoprotein E (APOE) genotype were analyzed using linear mixed-effect models. In women, higher CAA burden was associated with lower amyloid beta (Aβ) plaques but higher tau tangles density. No interaction effect was found for arteriolosclerosis. Women <75 years of age carrying the APOE ε4 allele had higher Aβ plaque burden than ε4 non-carriers. Our results highlight the complex effect of sex on microvascular and AD-associated pathologies in the MTL. Show less

Apolipoprotein B concentration reflects the number of atherogenic lipoproteins and is recognized as a key lipid risk marker. Whether the type or size of apoB particle (apoB-P) adds predictive value for coronary artery disease (CAD) remains unclear. A prospective analysis of 207 368 UK Biobank participants with comprehensive lipoprotein profiling and no prior history of atherosclerotic disease, diabetes, or active lipid-lowering therapy was conducted. Multivariable-adjusted Cox regression models were used to examine the association between each of the following lipid parameters with incident CAD: (i) nuclear magnetic resonance-measured apoB-P, (ii) concentrations of individual lipoprotein classes [very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL)], (iii) size subclasses, (iv) average particle diameter, and (v) immunoassay-measured lipoprotein(a) [Lp(a)]. A one standard deviation (SD) increase in apoB-P was associated with a 33% higher CAD risk [hazard ratio (HR): 1.33, 95% CI: 1.30-1.36]. Although VLDL particles were observed to carry a higher per-particle risk (HR per 100 nmol/L: 1.22, 1.11-1.34) compared with LDL (HR per 100 nmol/L: 1.07, 1.05-1.08), this difference was counterbalanced after considering relative particle abundance (LDL 91% vs VLDL 9% of total apoB-P). Thus the respective HR per 1-SD were 1.09 (1.05-1.14) and 1.24 (1.19-1.30). Particle diameter or size subclasses were not associated with CAD after apoB-P adjustment. The association of Lp(a) was robust even after apoB-P adjustment (HR:1.18, 1.16-1.20) and added independent prognostic value for CAD (area under curve: 0.769 vs 0.774, P < .001). Lipid-related atherosclerotic risk is most accurately reflected by the total count of apoB-P and is largely unaffected by the major particle type (VLDL, LDL) or size. Elevated count of Lp(a) adds additional risk, and thus adequate assessment of atherogenic risk from dyslipidemia is best accomplished by consideration of both apoB-P and Lp(a) concentrations. Show less

The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 × 10 HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction. Show less

The role of rare variants in complex traits remains uncharted. Here, we conduct deep whole genome sequencing of 1457 individuals from an isolated population, and test for rare variant burdens across six cardiometabolic traits. We identify a role for rare regulatory variation, which has hitherto been missed. We find evidence of rare variant burdens that are independent of established common variant signals (ADIPOQ and adiponectin, P = 4.2 × 10 Show less