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Aging (Albany NY) ; 14(15): 5964-5965, 2022 08 13.
Article in English | MEDLINE | ID: covidwho-2025976
J Clin Endocrinol Metab ; 106(11): e4471-e4486, 2021 10 21.
Article in English | MEDLINE | ID: covidwho-1854902


CONTEXT: Estradiol is the primary female sex hormone and plays an important role for skeletal health in both sexes. Several enzymes are involved in estradiol metabolism, but few genome-wide association studies (GWAS) have been performed to characterize the genetic contribution to variation in estrogen levels. OBJECTIVE: Identify genetic loci affecting estradiol levels and estimate causal effect of estradiol on bone mineral density (BMD). DESIGN: We performed GWAS for estradiol in males (n = 147 690) and females (n = 163 985) from UK Biobank. Estradiol was analyzed as a binary phenotype above/below detection limit (175 pmol/L). We further estimated the causal effect of estradiol on BMD using Mendelian randomization. RESULTS: We identified 14 independent loci associated (P < 5 × 10-8) with estradiol levels in males, of which 1 (CYP3A7) was genome-wide and 7 nominally (P < 0.05) significant in females. In addition, 1 female-specific locus was identified. Most loci contain functionally relevant genes that have not been discussed in relation to estradiol levels in previous GWAS (eg, SRD5A2, which encodes a steroid 5-alpha reductase that is involved in processing androgens, and UGT3A1 and UGT2B7, which encode enzymes likely to be involved in estradiol elimination). The allele that tags the O blood group at the ABO locus was associated with higher estradiol levels. We identified a causal effect of high estradiol levels on increased BMD in both males (P = 1.58 × 10-11) and females (P = 7.48 × 10-6). CONCLUSION: Our findings further support the importance of the body's own estrogen to maintain skeletal health in males and in females.

Bone Density/genetics , Estradiol/blood , Estradiol/genetics , Genome-Wide Association Study , 3-Oxo-5-alpha-Steroid 4-Dehydrogenase/genetics , ABO Blood-Group System/genetics , Bone Density/physiology , Cohort Studies , Cross-Sectional Studies , Cytochrome P-450 CYP3A/genetics , Estrogens/genetics , Estrogens/physiology , Female , Genotype , Glucuronosyltransferase/genetics , Humans , Male , Membrane Proteins/genetics , Mendelian Randomization Analysis , Middle Aged , N-Acetylglucosaminyltransferases/genetics , Polymorphism, Single Nucleotide/genetics , United Kingdom
Viruses ; 13(8)2021 08 13.
Article in English | MEDLINE | ID: covidwho-1376992


While investigating a signal of adaptive evolution in humans at the gene LARGE, we encountered an intriguing finding by Dr. Stefan Kunz that the gene plays a critical role in Lassa virus binding and entry. This led us to pursue field work to test our hypothesis that natural selection acting on LARGE-detected in the Yoruba population of Nigeria-conferred resistance to Lassa Fever in some West African populations. As we delved further, we conjectured that the "emerging" nature of recently discovered diseases like Lassa fever is related to a newfound capacity for detection, rather than a novel viral presence, and that humans have in fact been exposed to the viruses that cause such diseases for much longer than previously suspected. Dr. Stefan Kunz's critical efforts not only laid the groundwork for this discovery, but also inspired and catalyzed a series of events that birthed Sentinel, an ambitious and large-scale pandemic prevention effort in West Africa. Sentinel aims to detect and characterize deadly pathogens before they spread across the globe, through implementation of its three fundamental pillars: Detect, Connect, and Empower. More specifically, Sentinel is designed to detect known and novel infections rapidly, connect and share information in real time to identify emerging threats, and empower the public health community to improve pandemic preparedness and response anywhere in the world. We are proud to dedicate this work to Stefan Kunz, and eagerly invite new collaborators, experts, and others to join us in our efforts.

Disaster Planning , Lassa Fever/epidemiology , Lassa virus/physiology , Africa, Western/epidemiology , Disaster Planning/methods , Humans , Lassa Fever/genetics , Lassa Fever/prevention & control , Lassa Fever/virology , Lassa virus/genetics , N-Acetylglucosaminyltransferases/genetics , N-Acetylglucosaminyltransferases/immunology , Nigeria/epidemiology , Pandemics , Polymorphism, Genetic , Receptors, Virus/genetics , Receptors, Virus/immunology
PLoS Pathog ; 17(2): e1009282, 2021 02.
Article in English | MEDLINE | ID: covidwho-1069635


Receptor binding studies on sarbecoviruses would benefit from an available toolkit of recombinant spike proteins, or domains thereof, that recapitulate receptor binding properties of native viruses. We hypothesized that trimeric Receptor Binding Domain (RBD) proteins would be suitable candidates to study receptor binding properties of SARS-CoV-1 and -2. Here we created monomeric and trimeric fluorescent RBD proteins, derived from adherent HEK293T, as well as in GnTI-/- mutant cells, to analyze the effect of complex vs high mannose glycosylation on receptor binding. The results demonstrate that trimeric, complex glycosylated proteins are superior in receptor binding compared to monomeric and immaturely glycosylated variants. Although differences in binding to commonly used cell lines were minimal between the different RBD preparations, substantial differences were observed when respiratory tissues of experimental animals were stained. The RBD trimers demonstrated distinct ACE2 expression profiles in bronchiolar ducts and confirmed the higher binding affinity of SARS-CoV-2 over SARS-CoV-1. Our results show that complex glycosylated trimeric RBD proteins are attractive to analyze sarbecovirus receptor binding and explore ACE2 expression profiles in tissues.

Angiotensin-Converting Enzyme 2/metabolism , Protein Multimerization , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , A549 Cells , Angiotensin-Converting Enzyme 2/genetics , Animals , Chlorocebus aethiops , Dogs , Glycosylation , HEK293 Cells , Humans , Madin Darby Canine Kidney Cells , Mesocricetus , Mice , N-Acetylglucosaminyltransferases/genetics , N-Acetylglucosaminyltransferases/metabolism , Protein Binding , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Vero Cells