👤 Jennifer W Bea

Physical activity (PA) and sedentary behavior (SB) are associated with many diseases, including Alzheimer's disease and all-cause dementia. However, the specific biological mechanisms through which PA protects against disease are not entirely understood. This study aims to address this gap, with a specific focus on all-cause dementia. We first assessed the conventional observational associations of three self-reported and three device-based PA/SB measures with circulating levels of 2,911 plasma proteins measured in the UK Biobank (n max =39,160) and assessed functional enrichment of identified proteins. We then used bi-directional Mendelian randomization (MR) to further evaluate the evidence for causal relationships of PA/SB with protein levels. Finally, we performed mediation analyses to identify proteins that may mediate the relationship of PA with incident all-cause dementia. Our findings revealed 41 proteins consistently associated with all PA measures and 1,027 proteins associated with at least one PA measure. Both conventional observational and MR study designs converged on proteins that appear to increase as a result of PA, including integrins such as ITGAV and ITGAM, as well as MXRA8, CLEC4A, CLEC4M, LPL, and ADGRG2; on proteins that appear to decrease as a result of PA such as LEP, INHBC, CLMP, PTGDS, ADM, OGN, and PI3; and on proteins that are more responsive to high-intensity PA, such as CA14, CA6, CA4, KIT, and ANGPT2. Functional enrichment analyses revealed processes such as cell-matrix adhesion, integrin-mediated signaling, and collagen binding. Finally, GDF15, ITGAV, ITGAM, ITGA11, HPGDS, GFAP, ADM, AHNAK, and DPP4 were among 21 unique proteins found to mediate the relationship of PA with all-cause dementia, implicating processes such as synaptic plasticity, neurogenesis, and inflammation. Our results provide insights into how PA affects biological processes and protects against dementia, and provide avenues for future research into the health-promoting effects of PA. Show less

The APOE p.(Leu167del) variant has been identified as a rare cause of autosomal dominant hypercholesterolemia. A comprehensive phenotypic profile of carriers remains undefined, and its frequency has not been systematically studied. To characterize the phenotypic differences between p.(Leu167del) carriers among individuals with primary hypercholesterolemia and those with familial hypercholesterolemia (FH), and to estimate the variant's frequency in different populations. Phenotypic differences were assessed from the Lipid Unit cohort of the Hospital Universitario Miguel Servet (HUMS, n = 6489). The allele frequency of the p.(Leu167del) variant was estimated using data from the HUMS and Aragon Workers Health Study (AWHS, n = 5678), a cohort of working adults, and international cohorts: GnomAD (n ≈ 807,162), TOPMed (n ≈ 180,000), 100 K Genomes Project (n ≈ 85,000). To characterize the profile of carriers, data from the HUMS cohort and a systematic review of the published literature were also used. Carriers showed significantly higher high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and non-HDL cholesterol and lower lipoprotein(a) [Lp(a)] concentrations compared to noncarriers with primary hypercholesterolemia. In comparison with FH patients carrying LDL receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/kexin type 9 (PCSK9) variants, carriers displayed higher triglycerides and HDL cholesterol but lower LDL cholesterol and Lp(a). The APOE p.(Leu167del) frequency is approximately 1 in 12,000 individuals in the general population and about 2.5% of FH. The study confirmed the association of APOE p.(Leu167del) with hypercholesterolemia but with lower LDL cholesterol than subjects with FH. These findings support p.(Leu167del) as a cause of FH and its inclusion in the genetic screening for FH, particularly in Caucasian populations. Show less

Physical activity (PA), including sedentary behavior, is associated with many diseases, including Alzheimer's disease and all-cause dementia. However, the specific biological mechanisms through which PA protects against disease are not entirely understood. To address this knowledge gap, we first assessed the conventional observational associations of three self-reported and three device-based PA measures with circulating levels of 2,911 plasma proteins measured in the UK Biobank (n Show less

Hypertriglyceridemia (HTG) is a common complex metabolic trait that results of the accumulation of relatively common genetic variants in combination with other modifier genes and environmental factors resulting in increased plasma triglyceride (TG) levels. The majority of severe primary hypertriglyceridemias is diagnosed in adulthood and their molecular bases have not been fully defined yet. The prevalence of HTG is highly variable among populations, possibly caused by differences in environmental factors and genetic background. However, the prevalence of very high TG and the frequency of rare mutations causing HTG in a whole non-selected population have not been previously studied. The total of 23,310 subjects over 18 years from a primary care-district in a middle-class area of Zaragoza (Spain) with TG >500 mg/dL were selected to establish HTG prevalence. Those affected of primary HTG were considered for further genetic analysis. The promoters, coding regions and exon-intron boundaries of LPL, LMF1, APOC2, APOA5, APOE and GPIHBP1 genes were sequenced. The frequency of rare variants identified was studied in 90 controls. One hundred ninety-four subjects (1.04%) had HTG and 90 subjects (46.4%) met the inclusion criteria for primary HTG. In this subgroup, nine patients (12.3%) were carriers of 7 rare variants in LPL, LMF1, APOA5, GPIHBP1 or APOE genes. Three of these mutations are described for the first time in this work. The presence of a rare pathogenic mutation did not confer a differential phenotype or a higher family history of HTG. The prevalence of rare mutations in candidate genes in subjects with primary HTG is low. The low frequency of rare mutations, the absence of a more severe phenotype or the dominant transmission of the HTG would not suggest the use of genetic analysis in the clinical practice in this population. Show less