👤 Kurt R Auger

Familial dysbetalipoproteinemia (FDB) is a genetic lipoprotein disorder that can develop in patients homozygous for the APOE2 genotype (ε2/ε2). It is associated with decreased clearance of remnant lipoproteins and increased atherosclerotic cardiovascular disease (ASCVD) risk disproportionate to their level of LDL-C. A goal of this study was to develop a screening test for the ε2/ε2 genotype based on routinely available lipid tests and to determine those at most risk for ASCVD. After assembly of a primary prevention cohort from the UK Biobank (n= 269,895), gene array and exome data was utilized to classify patients as being ε2/ε2 genotype positive or negative. Lipid profiles and APOB levels were extracted and the number of ASCVD events was tabulated during a 15-year follow-up period. Using a newly developed equation for estimating APOB (eAPOB) with lipid panel test results, the ratio of measured APOB to eAPOB was better than any other individual lipid test or ratio for identifying patients with the ε2/ε2 genotype (AUC: APOB/eAPOB: 0.990 (0.986-0.994), nonHDL-C/APOB: 0.961 (0.952-0.970), APOB: 0.955 (0.949-0.961), VLDL/TG: 0.788 (0.771-0.804)). The majority of ε2/ε2 patients could be identified with the APOB/eAPOB ratio even before they expressed the FDB phenotype with elevated TG and nonHDL-C. The PCE or PREVENT risk equations were the most accurate method for identifying higher risk patients (AUC: PREVENT: 0.690 (0.637-0.742), PCE: 0.697 (0.645-0.749)). The APOB/eAPOB ratio can be used to accurately identify the ε2/ε2 genotype and conventional risk equations are the best method for determining those at risk for ASCVD. Show less

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

Phosphoinositide lipid kinases (PIKs) generate specific phosphorylated variants of phosatidylinositols (PtdIns) that are critical for second messenger signaling and cellular membrane remodeling. Mammals have 19 PIK isoforms spread across three major families: the PtIns 3-kinases (PI3Ks), PtdIns 4-kinases (PI4Ks), and PtdIns-P (PIP) kinases (PIPKs). Other eukaryotes have fewer yet varying PIK complements. PIKs are also an important, emerging class of drug targets for many therapeutic areas including cancer, inflammatory and metabolic diseases and host-pathogen interactions. Here, we report the genomic occurrences and evolutionary relationships or phylogenomics of all three PIK families across major eukaryotic groups and suggest potential ramifications for drug discovery. Our analyses reveal four core eukaryotic PIKs which are type III PIK4A and PIK4B, and at least one homolog each from PI3K (possibly PIK3C3 as the ancestor) and PIP5K families. We also applied evolutionary analyses to PIK disease ontology and drug discovery. Mutated PIK3CA are known to be oncogenic and several inhibitors are in anti-cancer clinical trials. We found conservation of activating mutations of PIK3CA in paralogous isoforms suggesting specific functional constraints on these residues. By mapping published compound inhibition data (IC50s) onto a phylogeny of PI3Ks, type II PI4Ks and distantly related, MTOR, ATM, ATR and PRKDC kinases, we also show that compound polypharmacology corresponds to kinase evolutionary relationships. Finally, we extended the rationale for drugs targeting PIKs of malarial Plasmodium falciparum, and the parasites, Leishmania sp. and Trypanosoma sp. by identifying those PIKs highly divergent from human homologs. Our phylogenomic analysis of PIKs provides new insights into the evolution of second messenger signaling. We postulate two waves of PIK diversification, the first in metazoans with a subsequent expansion in cold-blooded vertebrates that was post-emergence of Deutrostomia\Chordata but prior to the appearance of mammals. Reconstruction of the evolutionary relationships among these lipid kinases also adds to our understanding of their roles in various diseases and assists in their development as potential drug targets. Show less