Mining Genomic Variants And Causal Pathways Linking Hdl And Triglycerides To Coronary Disease

Blood lipids are important biomarkers of risk of coronary heart disease (CHD), the leading cause of death in the world. Myriad data support a causal role of low-density lipoprotein cholesterol (LDL-C) in increasing risk of CHD. Long-standing epidemiology suggests that high-density lipoprotein cholesterol (HDL-C) may protect from disease while high triglycerides (TGs) increase CHD risk. However, the causality of HDL-C and TG to CHD remains controversial. New genetic methodologies have allowed a better look into causal pathways underlying relationships between these traits and disease. Using a combination of approaches for interrogating rare genetic variation in humans, we investigated how HDL and TG may relate to CHD. First, through sequencing and exome-wide genotyping of subjects with extremely high HDL-C, we identified the first homozygote for a loss-of-function (LOF) variant in SCARB1, which encodes scavenger receptor class BI (SR-BI), a hepatic receptor for HDL-C. Despite markedly elevated HDL-C, carriers of this variant had an increased risk of CHD. These findings suggest that HDL functionality in driving cholesterol removal through SR-BI (the reverse cholesterol transport hypothesis) is protective from CHD in humans. Next, we functionally examined one of the first novel loci from genome-wide association studies (GWAS) for HDL-C, GALNT2. Through discovery of humans with genetic GALNT2 LOF and additional studies in rodents and nonhuman primates, we showed that GALNT2 LOF lowers HDL-C across mammals. We also identify one physiological mechanism linking GALNT2 to HDL-C through its enzymatic function. Thirdly, we studied the mechanism of protection of the APOC3 A43T variant recently reported to lower TGs and CHD risk from exome sequencing. Studies in human carriers and animal models suggest that A43T accelerates renal clearance of circulating ApoC-III, thus hindering its function in delaying TG-rich lipoprotein turnover. These data establish ApoC-III clearance mechanisms as potential therapeutic targets for TG lowering. Finally, we adapted a targeted sequencing approach to increase discovery of causal rare coding and noncoding variants at candidate loci influencing HDL-C and TGs. Collectively, this work provides a sampling of approaches for leveraging the spectrum of genomic methods to identify clinically relevant variants impacting HDL, TG and CHD risk

Near-Threshold Neutral Pion Electroproduction at High Momentum Transfers and Generalized Form Factors

We report the measurement of near-threshold neutral pion electroproduction cross sections and the extraction of the associated structure functions on the proton in the kinematic range Q2 from 2 to 4.5 GeV2 and W from 1.08 to 1.16 GeV. These measurements allow us to access the dominant pion-nucleon s-wave multipoles E0+ and S0+ in the near-threshold region. In the light-cone sum-rule framework (LCSR), these multipoles are related to the generalized form factors Gπ0p1(Q2) and Gπ0p2(Q2). The data are compared to these generalized form factors and the results for Gπ0p1(Q2) are found to be in good agreement with the LCSR predictions, but the level of agreement with Gπ0p2(Q2) is poor

Stroke secondary to calcific bicuspid aortic valve: Case report and literature review

SummaryBackgroundAortic valve calcification is common in rheumatic endocarditis, elderly patients, and congenital bicuspid aortic valve. It is not a recognized risk factor for stroke. We report a case of non-calcific embolization from calcified bicuspid aortic valve.MethodsA 52-year-old male with bicuspid aortic valve presented with aphasia and right arm weakness of less than 3h duration. CT head revealed hypodensity in the left middle cerebral artery (MCA) distribution and laboratory testing showed factor V leiden heterozygosity. The patient improved after intra-arterial tissue plasminogen activator (t-PA), but developed recurrence of right sided hemiparesis and silent myocardial infarction (MI). Cerebral angiography revealed clot in the left MCA. The patient received t-PA followed by transcatheter clot retrieval and was started on anticoagulation.ConclusionsEmbolization from calcific bicuspid aortic valves can lead to stroke and MI. Conservative management with anticoagulation for treatment of associated poststagnation thrombosis or aortic valve replacement as treatment is debatable. This patient was successfully managed with anticoagulation

Near-threshold Neutral Pion Electroproduction at High Momentum Transfers and Generalized Form Factors

We report the measurement of near-threshold neutral pion electroproduction cross sections and the extraction of the associated structure functions on the proton in the kinematic range Q2 from 2 to 4.5 GeV2 and W from 1.08 to 1.16 GeV. These measurements allow us to access the dominant pion-nucleon s-wave multipoles E0+ and S0+ in the near-threshold region. In the light-cone sum-rule framework (LCSR), these multipoles are related to the generalized form factors G1π0p (Q2) and G2π0p (Q2). The data are compared to these generalized form factors and the results for G1π0p (Q2) are found to be in good agreement with the LCSR predictions, but the level of agreement with G2π0p (Q2) is poor