scholarly journals Common host variation drives malaria parasite fitness in healthy human red cells

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Emily R Ebel ◽  
Frans A Kuypers ◽  
Carrie Lin ◽  
Dmitri A Petrov ◽  
Elizabeth S Egan
Keyword(s):  
Growth Rate ◽  
African Ancestry ◽  
Severe Disease ◽  
Negative Evidence ◽  
Fresh Blood ◽  
Healthy Human ◽  
Parasite Fitness ◽  
Deleterious Alleles ◽  
Healthy Donors ◽  
Common Genetic Variants

The replication of Plasmodium falciparum parasites within red blood cells (RBCs) causes severe disease in humans, especially in Africa. Deleterious alleles like hemoglobin S are well-known to confer strong resistance to malaria, but the effects of common RBC variation are largely undetermined. Here we collected fresh blood samples from 121 healthy donors, most with African ancestry, and performed exome sequencing, detailed RBC phenotyping, and parasite fitness assays. Over one third of healthy donors unknowingly carried alleles for G6PD deficiency or hemoglobinopathies, which were associated with characteristic RBC phenotypes. Among non-carriers alone, variation in RBC hydration, membrane deformability, and volume was strongly associated with P. falciparum growth rate. Common genetic variants in PIEZO1, SPTA1/SPTB, and several P. falciparum invasion receptors were also associated with parasite growth rate. Interestingly, we observed little or negative evidence for divergent selection on non-pathogenic RBC variation between Africans and Europeans. These findings suggest a model in which globally widespread variation in a moderate number of genes and phenotypes modulates P. falciparum fitness in RBCs.

scholarly journals Common host variation drives malaria parasite fitness in healthy human red cells

2020 ◽  
Author(s):  
Emily R Ebel ◽  
Frans A Kuypers ◽  
Carrie Lin ◽  
Dmitri A Petrov ◽  
Elizabeth S Egan
Keyword(s):  
Growth Rate ◽  
African Ancestry ◽  
Severe Disease ◽  
Parasite Growth ◽  
Hydration Status ◽  
Healthy Human ◽  
Parasite Fitness ◽  
Deleterious Alleles ◽  
Pathogenic Variation ◽  
Parasite Replication

SUMMARYThe replication of Plasmodium falciparum parasites within red blood cells (RBCs) causes severe disease in humans, especially in Africa. The influence of host RBC variation on parasite replication is largely uncharted, aside from a handful of deleterious alleles like sickle cell. Here, we integrated analyses of exome sequencing, RBC phenotyping, and parasite fitness assays on blood from 122 individuals, most with African ancestry. In donors lacking alleles for hemoglobinopathies or G6PD deficiency, RBC phenotypes including size, deformability, and hydration status explained 21-38% of the variation in parasite growth rate. With the addition of non-pathogenic polymorphisms in 14 RBC proteins including SPTA1, PIEZO1, and ATP2B4, our model explained 73-82% of the variation in parasite growth rate. Interestingly, we observed little evidence for divergent selection on this variation between Africans and Europeans. These findings suggest a model in which widespread, non-pathogenic variation in a moderate number of genes strongly modulates P. falciparum fitness in RBCs.

scholarly journals The SARS-CoV-2 Alpha variant is associated with increased clinical severity of disease

2021 ◽  
Author(s):  
David J Pascall ◽  
Guy Mollett ◽  
Rachel Blacow ◽  
Naomi Bulteel ◽  
Robyn Campbell ◽  
...  
Keyword(s):  
Growth Rate ◽  
Cohort Study ◽  
Mixed Model ◽  
Linear Mixed Model ◽  
Transmission Rate ◽  
Severe Disease ◽  
Positive Association ◽  
Clinical Severity ◽  
Generalised Linear Mixed Model ◽  
The Impact

Background The Alpha (B.1.1.7) SARS-CoV-2 variant of concern has been associated with increased transmission and increased 28-day mortality. We aimed to investigate the impact of infection on clinical severity of illness, including the need for oxygen or ventilation in a national cohort study. Methods In this prospective clinical cohort study, 1475 SARS-CoV-2 sequences were obtained from patients infected in Scotland, UK between the 1st November 2020 and 30th January 2021 and matched to clinical outcomes as the lineage became dominant in Scotland. We modelled the association between B.1.1.7 infection and severe disease using a cumulative generalised linear mixed model employing a 4-point scale of maximum severity based on requirement of respiratory support at 28 days. We also estimated the growth rate of B.1.1.7-associated infections as it emerged in Scotland using a phylogenetic exponential growth rate population model. Results The B.1.1.7 lineage was responsible for a third wave of SARS-CoV-2 infection in Scotland in association with a transmission rate 5-fold higher than the preceding second wave B.1.177 lineage. Of 1475 patients, 364 were infected with B.1.1.7, 1030 with B.1.177 and 81 with other lineages. Our analysis found a positive association between increased clinical severity and lineage (B.1.1.7 versus non-B.1.1.7; cumulative odds ratio: 1.40, 95% CI: 1.02, 1.93). Viral load was higher in B.1.1.7 samples than in non-B.1.1.7 samples, as measured by cycle threshold (Ct) value (mean Ct change: -2.46, 95% CI: -4.22, -0.70). Conclusions The B.1.1.7 lineage was associated with more severe clinical disease in Scottish patients than co-circulating lineages.

scholarly journals Contributions of common genetic variants to risk of schizophrenia among individuals of African and Latino ancestry

2019 ◽  
Vol 25 (10) ◽  
pp. 2455-2467 ◽  
Author(s):  
Tim B. Bigdeli ◽  
◽  
Giulio Genovese ◽  
Penelope Georgakopoulos ◽  
Jacquelyn L. Meyers ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Association Studies ◽  
Large Fraction ◽  
African Ancestry ◽  
Common Variant ◽  
Human Populations ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Common Genetic Variants

Abstract Schizophrenia is a common, chronic and debilitating neuropsychiatric syndrome affecting tens of millions of individuals worldwide. While rare genetic variants play a role in the etiology of schizophrenia, most of the currently explained liability is within common variation, suggesting that variation predating the human diaspora out of Africa harbors a large fraction of the common variant attributable heritability. However, common variant association studies in schizophrenia have concentrated mainly on cohorts of European descent. We describe genome-wide association studies of 6152 cases and 3918 controls of admixed African ancestry, and of 1234 cases and 3090 controls of Latino ancestry, representing the largest such study in these populations to date. Combining results from the samples with African ancestry with summary statistics from the Psychiatric Genomics Consortium (PGC) study of schizophrenia yielded seven newly genome-wide significant loci, and we identified an additional eight loci by incorporating the results from samples with Latino ancestry. Leveraging population differences in patterns of linkage disequilibrium, we achieve improved fine-mapping resolution at 22 previously reported and 4 newly significant loci. Polygenic risk score profiling revealed improved prediction based on trans-ancestry meta-analysis results for admixed African (Nagelkerke’s R2 = 0.032; liability R2 = 0.017; P < 10−52), Latino (Nagelkerke’s R2 = 0.089; liability R2 = 0.021; P < 10−58), and European individuals (Nagelkerke’s R2 = 0.089; liability R2 = 0.037; P < 10−113), further highlighting the advantages of incorporating data from diverse human populations.

Erythropoiesis in Polycythemia Vera Is Hyper-Proliferative and Has Accelerated Differentiation during In Vitro Erythroid Expansion and Is Associated with Higher Expressions of cMYB and EPOR at Early Erythroid Progenitors

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1549-1549
Author(s):  
Hana Bruchova ◽  
Donghoon Yoon ◽  
Archana Agarwal ◽  
Eva Otahalova ◽  
Hyojin Kim ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Mononuclear Cells ◽  
Early Stage ◽  
Severe Disease ◽  
Erythroid Differentiation ◽  
Erythroid Progenitors ◽  
Peripheral Blood Mononuclear ◽  
Healthy Donors ◽  
Differentiation Stage

Abstract Erythroid differentiation is a dynamic process leading to the production of mature red blood cells. Even small variations in this process may result in severe disease phenotype. To study this process, we used a three-phase erythroid expansion system to expand homogeneous erythroid progenitors (EPs) from peripheral blood mononuclear cells (PB-MNCs) (Bruchova H. et al, 2007, Exp. Hematology, in press). We then characterized the expanded EPs from polycythemia vera (PV) patients and healthy donors at various points of maturation comparing cell proliferation and differentiation stage. EPs from PV patients outgrew controls up to day 14 (∼12 fold for PV and ∼4 fold for control compared to day 1). Differentiation was analyzed using both FACS analysis (with CD71/CD235a staining) and morphological evaluation (Wright-Giemsa staining), and demonstrated a more rapid differentiation of PV EPs when compared to controls up to day 14. We then evaluated apoptosis/cell cycle analysis by propidium iodide staining. Although PV EPs contained larger S phase population (45%) than controls (34%) at day 11, the apoptosis proportion of PV EPs was increased ∼2 fold to control from day 14. To understand the molecular mechanism of these differences between PV and controls, we analyzed the gene expression of several known regulators in erythropoiesis - BCL2, EPOR, cMYB, p27. Two transcripts (EPOR and cMYB) showed unique profiles on PV EPs. The EPOR transcript increased earlier in PV; i.e. from day 7 until day 21 and reached a plateau at day 11, compared to day 9 until day 19 and plateau at day 14 in controls. In addition, PV EPs contained higher levels of EPOR transcripts than control on most of timepoints. Interestingly, cMYB, which is known to augment early progenitor proliferation, was highly expressed from day 7 in PV, through day 11. Control EPs also expressed cMYB from day 9 through day 11; however, cMYB levels from any stages of control EPs were markedly lower than PV EPs at day 7. In this study, we demonstrate that PV erythropoiesis has unique features of hyperproliferation and an accelerated differentiation. These features are associated with earlier and higher expressions of cMYB and EPOR at the early stage of erythropoiesis.

scholarly journals Immunological Biomarkers of Fatal COVID-19: A Study of 868 Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Esperanza Martín-Sánchez ◽  
Juan José Garcés ◽  
Catarina Maia ◽  
Susana Inogés ◽  
Ascensión López-Díaz de Cerio ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
Large Scale ◽  
Immune Cell ◽  
Severe Disease ◽  
Fatal Outcome ◽  
Cell Types ◽  
Risk Of Death ◽  
Immune Biomarkers ◽  
Healthy Donors

Information on the immunopathobiology of coronavirus disease 2019 (COVID-19) is rapidly increasing; however, there remains a need to identify immune features predictive of fatal outcome. This large-scale study characterized immune responses to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection using multidimensional flow cytometry, with the aim of identifying high-risk immune biomarkers. Holistic and unbiased analyses of 17 immune cell-types were conducted on 1,075 peripheral blood samples obtained from 868 COVID-19 patients and on samples from 24 patients presenting with non-SARS-CoV-2 infections and 36 healthy donors. Immune profiles of COVID-19 patients were significantly different from those of age-matched healthy donors but generally similar to those of patients with non-SARS-CoV-2 infections. Unsupervised clustering analysis revealed three immunotypes during SARS-CoV-2 infection; immunotype 1 (14% of patients) was characterized by significantly lower percentages of all immune cell-types except neutrophils and circulating plasma cells, and was significantly associated with severe disease. Reduced B-cell percentage was most strongly associated with risk of death. On multivariate analysis incorporating age and comorbidities, B-cell and non-classical monocyte percentages were independent prognostic factors for survival in training (n=513) and validation (n=355) cohorts. Therefore, reduced percentages of B-cells and non-classical monocytes are high-risk immune biomarkers for risk-stratification of COVID-19 patients.

scholarly journals Impact of rare and common genetic variants on diabetes diagnosis by hemoglobin A1c in multi-ancestry cohorts: The Trans-Omics for Precision Medicine Program

2019 ◽  
Author(s):  
Chloé Sarnowski ◽  
Aaron Leong ◽  
Laura M Raffield ◽  
Peitao Wu ◽  
Paul S de Vries ◽  
...  
Keyword(s):  
African Americans ◽  
Precision Medicine ◽  
Hemoglobin A1c ◽  
Sequence Data ◽  
African Ancestry ◽  
Low Frequency ◽  
Diabetes Diagnosis ◽  
Common Genetic Variants ◽  
Patients With Diabetes ◽  
The Uk

AbstractHemoglobin A1c (HbA1c) is widely used to diagnose diabetes and assess glycemic control in patients with diabetes. However, nonglycemic determinants, including genetic variation, may influence how accurately HbA1c reflects underlying glycemia. Analyzing the NHLBI Trans-Omics for Precision Medicine (TOPMed) sequence data in 10,338 individuals from five studies and four ancestries (6,158 Europeans, 3,123 African-Americans, 650 Hispanics and 407 East Asians), we confirmed five regions associated with HbA1c (GCK in Europeans and African-Americans, HK1 in Europeans and Hispanics, FN3K/FN3KRP in Europeans and G6PD in African-Americans and Hispanics) and discovered a new African-ancestry specific low-frequency variant (rs1039215 in HBG2/HBE1, minor allele frequency (MAF)=0.03). The most associated G6PD variant (p.Val98Met, rs1050828-T, MAF=12% in African-Americans, MAF=2% in Hispanics) lowered HbA1c (−0.88% in hemizygous males, −0.34% in heterozygous females) and explained 23% of HbA1c variance in African-Americans and 4% in Hispanics. Additionally, we identified a rare distinct G6PD coding variant (rs76723693 - p.Leu353Pro, MAF=0.5%; −0.98% in hemizygous males, −0.46% in heterozygous females) and detected significant association with HbA1c when aggregating rare missense variants in G6PD. We observed similar magnitude and direction of effects for rs1039215 (HBG2) and rs76723693 (G6PD) in the two largest TOPMed African-American cohorts and replicated the rs76723693 association in the UK Biobank African-ancestry participants. These variants in G6PD and HBG2 were monomorphic in the European and Asian samples. African or Hispanic ancestry individuals carrying G6PD variants may be underdiagnosed for diabetes when screened with HbA1c. Thus, assessment of these variants should be considered for incorporation into precision medicine approaches for diabetes diagnosis.

scholarly journals Genetic underpinnings of regional adiposity distribution in African Americans: Assessments from the Jackson Heart Study

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0255609
Author(s):  
Mohammad Y. Anwar ◽  
Laura M. Raffield ◽  
Leslie A. Lange ◽  
Adolfo Correa ◽  
Kira C. Taylor
Keyword(s):  
Waist Circumference ◽  
Genetic Variants ◽  
African Ancestry ◽  
Visceral Adiposity ◽  
European Ancestry ◽  
Risk Scores ◽  
Jackson Heart Study ◽  
Anthropometric Measures ◽  
Heart Study ◽  
Common Genetic Variants

Background African ancestry individuals with comparable overall anthropometric measures to Europeans have lower abdominal adiposity. To explore the genetic underpinning of different adiposity patterns, we investigated whether genetic risk scores for well-studied adiposity phenotypes like body mass index (BMI) and waist circumference (WC) also predict other, less commonly measured adiposity measures in 2420 African American individuals from the Jackson Heart Study. Methods Polygenic risk scores (PRS) were calculated using GWAS-significant variants extracted from published studies mostly representing European ancestry populations for BMI, waist-hip ratio (WHR) adjusted for BMI (WHRBMIadj), waist circumference adjusted for BMI (WCBMIadj), and body fat percentage (BF%). Associations between each PRS and adiposity measures including BF%, subcutaneous adiposity tissue (SAT), visceral adiposity tissue (VAT) and VAT:SAT ratio (VSR) were examined using multivariable linear regression, with or without BMI adjustment. Results In non-BMI adjusted models, all phenotype-PRS were found to be positive predictors of BF%, SAT and VAT. WHR-PRS was a positive predictor of VSR, but BF% and BMI-PRS were negative predictors of VSR. After adjusting for BMI, WHR-PRS remained a positive predictor of BF%, VAT and VSR but not SAT. WC-PRS was a positive predictor of SAT and VAT; BF%-PRS was a positive predictor of BF% and SAT only. Conclusion These analyses suggest that genetically driven increases in BF% strongly associate with subcutaneous rather than visceral adiposity and BF% is strongly associated with BMI but not central adiposity-associated genetic variants. How common genetic variants may contribute to observed differences in adiposity patterns between African and European ancestry individuals requires further study.

Abstract 355: Heart Failure Impairs Bone Marrow Mesenchymal Stem Cell Renewing Capacity and Migration

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Victoria Florea ◽  
Cristina Sanina ◽  
Darcy Difede ◽  
Krystalenia Valasaki ◽  
Aisha Khan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Stem Cells ◽  
Bone Marrow ◽  
Growth Rate ◽  
Clinical Trials ◽  
Stem Cell ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Healthy Donors

Background: Clinical trials have shown a sustained beneficial effect of bone marrow mesenchymal stem cells (MSCs) as a therapy for acute and chronic heart failure (HF). Clinical grade cell manufacturing of autologous and allogeneic MSCs is becoming a standard procedure. This study investigates the differences of bone marrow MSC isolation and expansion in favorable in vitro conditions. We compared MSC production from both healthy young donors and chronic HF patients. Methods: We analyzed MSC manufacturing records from five clinical trials: TAC-HFT (Ischemic cardiomyopathy (CMP), patient and donors), POSEIDON (Ischemic CMP, donors), POSEIDON DCM (Dilated CMP, donors), TRIDENT (Ischemic CMP, donors), and CRATUS (Frailty, donors). Results: All cells expressed CD105, CD90 and lacked hematopoietic marker CD45. The age of healthy donors (25.5 ± 0.7 y.o., N=24) and HF patients (56.1 ± 2.5, y.o., N=23), was significantly different (P<0.0001). Collectively, the number of mononuclear cells (MNCs) isolated from bone marrow (volume range 58-125ml) didn’t differ between the groups. However, plated MNCs from healthy adults generated more MSCs than MNCs from HF patients (p0: 5.9x10^6±0.5x10^6, N=23 vs 3.8x10^6±0.4x10^6, N=24, respectively, P=0.003 and p1: 15.4x10^6±2.5x10^6, N=23 vs 10.8x10^6±1.1x10^6, N=24, respectively, P=0.036). No correlation was found between stem cell growth and age (35 to 78y.o.). Left ventricular ejection fraction (LVEF) in patients with HF had a direct correlation with MSC growth rate (P=0.03), particularly, in patients with severely depressed LVEF (<30%), which had a tendency to generate less MSCs overall. Moreover, MSCs from HF patients demonstrated less migration compared to MSCs from healthy donors at 6, 10 and 24 hours (h) relative to baseline (6 h: 9.5±3.0% vs 30.7±2.1%; 10 h: 19.9±13.7% vs 53.1±2.5% and 24 h: 41.5±15.8% vs 88.9±1.6%, N=4, respectively. P=0.03). Conclusions: Despite equivalent numbers of MNCs, healthy young donors generate significantly more MSCs than HF patients, due to increased growth rate and higher number of resident stromal bone marrow stem cells. MSC migration was impaired in HF patients compared to healthy donors. HF appears to be an independent factor for MSC renewal capacity and culture phenotype.

Abstract 1: Human Monocyte Diversity in Cardiovascular Disease Revealed by Mass Cytometry

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Anouk A Hamers ◽  
Graham D Thomas ◽  
Cheryl Kim ◽  
Anh T Nguyen ◽  
Chantel McSkimming ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Suppressor Cells ◽  
Human Monocyte ◽  
Significant Heterogeneity ◽  
Monocyte Subsets ◽  
Mass Cytometry ◽  
Healthy Human ◽  
Healthy Humans ◽  
New Information ◽  
Healthy Donors

Background: Monocytes are critical to the initiation and development of atherosclerosis. To date, 3 distinct human monocyte subsets have been identified based primarily on their expression of the surface markers CD14 and CD16. With the emerging knowledge of myeloid-derived suppressor cells and other myeloid subsets, we hypothesized that monocytes are likely more heterogeneous in composition. Therefore, we set out to use the high dimensionality of mass cytometry to accurately identify and define monocyte subsets in blood of healthy humans and their changes in cardiovascular patients. Methods: Heparinized blood from 12 healthy donors and 15 patients with defined cardiovascular disease (CVD) based on angiography and gensini score was obtained and analyzed by CyTOF mass cytometry. We employed the Phenograph algorithm to cluster and identify all healthy monocyte subsets based on their phenotypes using a 40-marker mass cytometry panel. Results: Phenograph identified a total of 15 monocyte clusters in healthy human blood. By performing hierarchical clustering, we were able to group these clusters into 6 larger meta-clusters and found that most of these meta-clusters fall within the CD14 classical monocyte population, illustrating significant heterogeneity among this monocyte population. Cell numbers of one of these monocyte meta-clusters were significantly increased in blood from patients with CVD. We also identified two subsets of nonclassical monocytes in healthy donors. One of these subsets showed higher expression of the integrin CD61 and tetraspanin CD9, pointing to a possible role for this subset in patrolling and platelet activation. Conclusion: Monocytes are highly diverse with the conventional classical subset showing the most diversity. The numbers and frequencies of some of these monocyte subsets are changed in CVD. Studies to identify their functions in CVD should provide new information for the role of monocytes in CVD.

Variation in pathogenicity and virulence of Phytophthora clandestina on four cultivars of subterranean clover

1995 ◽  
Vol 35 (6) ◽  
pp. 717 ◽  
Author(s):  
A Purwantara ◽  
SP Flett ◽  
PJ Keane
Keyword(s):  
Growth Rate ◽  
Agar Medium ◽  
Sandy Loam ◽  
Severe Disease ◽  
Subterranean Clover ◽  
Race 1 ◽  
Pathogenicity Tests ◽  
Loam Soil ◽  
Race 2 ◽  
Cultivar Specificity

The pathogenicity of 6 isolates of Phytophthora clandestina on seedlings of 4 cultivars of subterranean clover was studied. There was a highly significant isolate x cultivar interaction in pathogenicity tests on axenic seedlings and seedlings grown in pasteurised potting mix or untreated sandy loam soil, indicating the existence of race-cultivar specificity. The isolates showed differences in virulence against the cultivars. Three isolates (race 0) caused severe disease only on Woogenellup; 2 isolates (race 1) caused severe disease on Larisa, Trikkala, and Woogenellup, but not on Meteora; one isolate (race 2) caused severe disease on Meteora and Woogenellup, but not on Larisa and Trikkala. As well as differing in virulence (the ability of a race to attack a range of cultivars), the races also differed in their aggressiveness on Woogenellup, with race 2 being the most, and race 0 the least, pathogenic. The isolates varied in their growth rate on agar medium, but this was not related to virulence or aggressiveness.

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