Genetic Testing and Risk Scores: Impact on Familial Hypercholesterolemia

Familial Hypercholesterolemia (FH) is an inherited lipid disorder affecting 1 in 220 individuals resulting in highly elevated low-density lipoprotein levels and risk of premature coronary disease. Pathogenic variants causing FH typically involve the LDL receptor (LDLR), apolipoprotein B-100 (APOB), and proprotein convertase subtulisin/kexin type 9 genes (PCSK9) and if identified convey a risk of early onset coronary artery disease (ASCVD) of 3- to 10-fold vs. the general population depending on the severity of the mutation. Identification of monogenic FH within a family has implications for family-based testing (cascade screening), risk stratification, and potentially management, and it has now been recommended that such testing be offered to all potential FH patients. Recently, robust genome wide association studies (GWAS) have led to the recognition that the accumulation of common, small effect alleles affecting many LDL-c raising genes can result in a clinical phenotype largely indistinguishable from monogenic FH (i.e., a risk of early onset ASCVD of ~3-fold) in those at the extreme tail of the distribution for these alleles (i.e., the top 8% of the population for a polygenic risk score). The incorporation of these genetic risk scores into clinical practice for non-FH patients may improve risk stratification but is not yet widely performed due to a less robust evidence base for utility. Here, we review the current status of FH genetic testing, potential future applications as well as challenges and pitfalls

Lectin-Dependent Enhancement of Ebola Virus Infection via Soluble and Transmembrane C-type Lectin Receptors

Mannose-binding lectin (MBL) is a key soluble effector of the innate immune system that recognizes pathogen-specific surface glycans. Surprisingly, low-producing MBL genetic variants that may predispose children and immunocompromised individuals to infectious diseases are more common than would be expected in human populations. Since certain immune defense molecules, such as immunoglobulins, can be exploited by invasive pathogens, we hypothesized that MBL might also enhance infections in some circumstances. Consequently, the low and intermediate MBL levels commonly found in human populations might be the result of balancing selection. Using model infection systems with pseudotyped and authentic glycosylated viruses, we demonstrated that MBL indeed enhances infection of Ebola, Hendra, Nipah and West Nile viruses in low complement conditions. Mechanistic studies with Ebola virus (EBOV) glycoprotein pseudotyped lentiviruses confirmed that MBL binds to N-linked glycan epitopes on viral surfaces in a specific manner via the MBL carbohydrate recognition domain, which is necessary for enhanced infection. MBL mediates lipid-raft-dependent macropinocytosis of EBOV via a pathway that appears to require less actin or early endosomal processing compared with the filovirus canonical endocytic pathway. Using a validated RNA interference screen, we identified C1QBP (gC1qR) as a candidate surface receptor that mediates MBL-dependent enhancement of EBOV infection. We also identified dectin-2 (CLEC6A) as a potentially novel candidate attachment factor for EBOV. Our findings support the concept of an innate immune haplotype that represents critical interactions between MBL and complement component C4 genes and that may modify susceptibility or resistance to certain glycosylated pathogens. Therefore, higher levels of native or exogenous MBL could be deleterious in the setting of relative hypocomplementemia which can occur genetically or because of immunodepletion during active infections. Our findings confirm our hypothesis that the pressure of infectious diseases may have contributed in part to evolutionary selection of MBL mutant haplotypes

Stable Ischemic Heart Disease: Medical Therapy With or Without Revascularization

Coronary artery disease (CAD) poses a significant global public health burden. Patients with CAD who do not present with acute coronary syndromes are considered to have stable ischemic heart disease (SIHD). Options for the management of SIHD are medical therapy including pharmacologic therapy and lifestyle modification and revascularization with either percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). Guideline-directed medical therapy is recommended for all patients with SIHD. Aside from severe stenosis in an unprotected left main coronary artery, the role of routine revascularization in the management of SIHD is unclear. Early CABG trials from the 1970s and 1980s demonstrated prognostic benefit with CABG versus medical therapy, but these results have limited applicability in the setting of modern medical therapy, including the widespread use of statins and aspirin and intensive lifestyle interventions. Contemporary strategy trials examining PCI plus medical therapy versus medical therapy alone have not demonstrated prognostic benefit with the addition of PCI. The addition of revascularization offers consistent symptom and quality-of-life benefit compared with medical therapy alone based on trial data, though this benefit may be time limited with PCI. Thus, there is a state of equipoise regarding the addition of revascularization to guideline-directed medical therapy in the management of SIHD. Therefore, shared decision-making is key when determining the best management strategy for a patient with SIHD and should include discussion of expected risks and benefits based on high-quality evidence, costs, and patient preferences. This review contains 6 figures, 8 tables, and 55 references.  Key Words: angina, antianginal therapy, coronary artery disease, coronary artery bypass grafting, guideline-directed medical therapy, ischemia, optimal medical therapy, percutaneous coronary intervention, revascularization</jats:p

The leaky pipeline of diverse race and ethnicity representation in academic science and technology training in the United States, 2003-2019.

IntroductionDiverse race and ethnicity representation remains lacking in science and technology (S&T) careers in the United States (US). Due to systematic barriers across S&T training stages, there may be sequential loss of diverse representation leading to low representation, often conceptualized as a leaky pipeline. We aimed to quantify the contemporary leaky pipeline of S&T training in the US.MethodsWe analyzed US S&T degree data, stratified by sex and then by race or ethnicity, obtained from survey data the National Science Foundation and the National Center for Science and Engineering Statistics. We assessed changes in race and ethnicity representation in 2019 at two major S&T transition points: bachelor to doctorate degrees (2003-2019) and doctorate degrees to postdoctoral positions (2010-2019). We quantified representation changes at each point as the ratio of representation in the later stage to earlier stage (representation ratio [RR]). We assessed secular trends in the representation ratio through univariate linear regression.ResultsFor 2019, the survey data included for bachelor degrees, 12,714,921 men and 10.612,879 women; for doctorate degrees 14,259 men and 12,860 women; and for postdoctoral data, 11,361 men and 8.672 women. In 2019, we observed that Black, Asian, and Hispanic women had comparable loss of representation among women in the bachelor to doctorate transition (RR 0.86, 95% confidence interval [CI] 0.81-0.92; RR 0.85, 95% CI 0.81-0.89; and RR 0.82, 95% CI 0.77-0.87, respectively), while among men, Black and Asian men had the greatest loss of representation (Black men RR 0.72, 95% CI 0.66-0.78; Asian men RR 0.73, 95% CI 0.70-0.77)]. We observed that Black men (RR 0.60, 95% CI 0.51-0.69) and Black women (RR 0.56, 95% CI 0.49-0.63) experienced the greatest loss of representation among men and women, respectively, in the doctorate to postdoctoral transition. Black women had a statistically significant decrease in their representation ratio in the doctorate to postdoctoral transition from 2010 to 2019 (p-trend = 0.02).ConclusionWe quantified diverse race and ethnicity representation in contemporary US S&T training and found that Black men and women experienced the most consistent loss in representation across the S&T training pipeline. Findings should spur efforts to mitigate the structural racism and systemic barriers underpinning such disparities