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Understanding the genetic architecture of host proteins interacting with SARS-CoV-2 or mediating the maladaptive host response to COVID-19 can help to identify new or repurpose existing drugs targeting those proteins. We present a genetic discovery study of 179 such host proteins among 10,708 individuals using an aptamer-based technique. We identify 220 host DNA sequence variants acting in cis (MAF 0.01-49.9%) and explaining 0.3-70.9% of the variance of 97 of these proteins, including 45 with no previously known protein quantitative trait loci (pQTL) and 38 encoding current drug targets. Systematic characterization of pQTLs across the phenome identified protein-drug-disease links and evidence that putative viral interaction partners such as MARK3 affect immune response. Our results accelerate the evaluation and prioritization of new drug development programmes and repurposing of trials to prevent, treat or reduce adverse outcomes. Rapid sharing and detailed interrogation of results is facilitated through an interactive webserver ( https://omicscience.org/apps/covidpgwas/ ).
BACKGROUND AND OBJECTIVES - Obtaining IgM and IgG titres is important in numerous clinical situations, including solid-organ transplant, obstetrics, and for testing of out-of-group plasma-containing components. Tube method is the most prevalent testing modality, though it is both labour-intensive and known for intra- and inter-laboratory variability. The utility of automated gel testing as a method to improve both inter- and intra-laboratory reproducibility is unknown.
MATERIALS AND METHODS - Two academic centres participated in a study evaluating automated gel titreing. Group O plasma samples were used to measure titres of antibodies against ABO (IgM) with buffered gel cards and 4 minor and minor red-blood-cell antigens (IgG) anti-IgG gel cards. Multiple ORTHO VISION automated analyzers were used to assess inter-instrument variation. A subset of ABO (IgM) samples were compared between laboratories to evaluate inter-laboratory variability. Multiple samples were titred by tube and by automated gel technology to determine similarity of results.
RESULTS - Testing demonstrated no significant difference between analysers or between sites when performing automated titrations (P ≥ 0·99). Non-ABO IgG titres were evaluated and demonstrated little inter-instrument variability. The IgM anti-A and -B titres obtained by automated gel testing were neither consistently higher nor lower than tube titres. Greater than 90% of titre values were within one dilution.
CONCLUSION - Based on this study, our data suggest that titreing by automated gel testing is both highly reproducible (IgM and IgG) and does not differ significantly from manual tube testing results of direct agglutination (IgM).
© 2020 International Society of Blood Transfusion.
OBJECTIVE - Blood type A and the A1 allele have been associated with increased ovarian cancer risk. With only two small studies published to date, evidence for an association between ABO blood type and ovarian cancer survival is limited.
METHODS - We conducted a retrospective cohort study of Tumor Registry confirmed ovarian cancer cases from the Vanderbilt University Medical Center with blood type from linked laboratory reports and ABO variants from linked Illumina Exome BeadChip data. Associations with overall survival (OS) were quantified by hazard ratios (HR) and confidence intervals (CI) from proportional hazards regression models; covariates included age, race, stage, grade, histologic subtype, and year of diagnosis.
RESULTS - ABO phenotype (N = 694) and/or genotype (N = 154) data were available for 713 predominantly Caucasian (89.3%) cases. In multivariable models, blood type A had significantly better OS compared to either O (HR: 0.75, 95% CI: 0.60-0.93) or all non-A (HR: 0.77, 95% CI: 0.63-0.94) cases. Similarly, missense rs1053878 minor allele carriers (A2) had better OS (HR: 0.50, 95% CI: 0.25-0.99). Among Caucasians, this phenotype association was strengthened, but the genotype association was attenuated; instead, four variants sharing moderate linkage disequilibrium with the O variant were associated with better OS (HR: 0.62, 95% CI: 0.39-0.99) in unadjusted models.
CONCLUSIONS - Blood type A was significantly associated with longer ovarian cancer survival in the largest such study to date. This finding was supported by genetic analysis, which implicated the A2 allele, although O related variants also had suggestive associations. Further research on ABO and ovarian cancer survival is warranted.
BACKGROUND - Outcomes in cases of adult accidental ABO incompatible cardiac transplantation are highly variable, with some patients suffering nearly immediate catastrophic antibody-mediated rejection while others (~37%-45%) survive. We hypothesize that these disparate outcomes could be influenced by variations in blood group antigen expression on allograft endothelium.
METHODOLOGY - Immunohistochemical stains for blood Group A antigen were performed on cardiac tissue from 18 blood Type A cadavers. Staining was evaluated by two distinct modalities: semiquantitative light microscopy, which measured the intensity of antigen expression on endothelium, and quantitative digital analysis, which determined the percentage of the total tissue section area staining positive for blood Group A antigen. These data were used to compute a Comprehensive Expression Index (CEI) of blood Group A antigen expression for each specimen.
RESULTS - Semiquantitative light microscopic examination determined that endothelium was stained with low intensity in four (22%) myocardial samples, intermediate intensity in five (28%) samples, and high intensity in nine (50%) samples. Quantitative digital analysis revealed a range in the percentage of total cross sectional area composed of blood Group A-positive signal (median, 2.69%; interquartile range, 1.68%-2.94%). Increased percentage of total cross sectional area composed of blood Group A-positive signal was positively associated with patient age (P=.0037). The CEI showed a broad range, with a median of 5.27 and an interquartile range of 2.92-8.22.
CONCLUSIONS - There are little data available regarding interindividual differences in blood Group A antigen expression in cardiac endothelium. Here, we report interindividual variation in endothelial expression of blood Group A antigen in 18 specimens. These variations may help to explain disparate outcomes in cases of accidental ABO incompatible cardiac transplantation in adults.
Published by Elsevier Inc.
Familial amyloid polyneuropathy is a rare, progressively disabling, and ultimately fatal inherited disease. Liver transplant is currently the only available treatment proven to halt the progression of familial amyloid polyneuropathy. We report a 31-year-old woman with familial amyloid polyneuropathy who received a living-donor liver transplant from her husband who was hepatitis C virus antibody-positive but HCV-RNA negative and ABO incompatible. Six years after the transplant, both donor and recipient have normal liver biochemistry results; no hepatitis C viral load has been detectable in the recipient. This is the first report of a living ABO-incompatible liver transplant from an anti-hepatitis C virus antibody-positive but an HCV-RNA negative donor. This experience suggests that the use of an anti-hepatitis C virus antibody-positive hepatic graft is possible in select circumstances.
UNLABELLED - What's known on the subject? and What does the study add? Some evidence suggests that ABO blood type may be a risk factor for cancer incidence and prognosis. For example, a large study recently discovered an increased incidence of pancreatic cancer in patients with non-O blood type; however, it is not known whether blood group correlates with outcomes in patients with RCC. We found a significant and independent association between ABO blood group and overall survival in patients undergoing surgery for locoregional RCC. Specifically, we identified non-O blood type as a predictor of mortality.
OBJECTIVE - • To determine whether ABO blood group is associated with survival after nephrectomy or partial nephrectomy for renal cell carcinoma (RCC).
PATIENTS AND METHODS - • We conducted a retrospective cohort study of 900 patients who underwent surgery for locoregional RCC between 1997 and 2008 at a single institution. • Covariates included age, gender, race, American Society of Anesthesiology Physical Status, preoperative anaemia and hypoalbuminemia, tumour characteristics, lymph node status, procedure performed, transfusion status and ABO blood group. • Primary outcomes were overall (OS) and disease-specific survival (DSS). • Univariable survival analyses were performed using the Kaplan-Meier and log-rank methods. Multivariable analysis was performed using a Cox proportional hazards model.
RESULTS - • The 3-year OS estimate was 75% (95%CI 70-79%) for O blood group and 68% (95% CI 63-73%) for non-O blood group (P= 0.072). The 3-year DSS was 81% (95% CI 76-85%) for O blood group and 76% (95%CI 71-80%) for non-O blood group (P= 0.053). • In the multivariable analysis for OS, non-O blood type was significantly associated with decreased OS (HR 1.68, 95%CI 1.18-2.39; P= 0.004) but not DSS (HR 1.53, 95%CI 0.97-2.41; P= 0.065).
CONCLUSION - • These data suggest that ABO blood group is independently associated with OS in patients undergoing surgery for locoregional RCC. ABO blood group has not been previously recognized as a predictor of survival in RCC.
© 2012 BJU INTERNATIONAL.
BACKGROUND - We tested whether genetic factors distinctly contribute to either development of coronary atherosclerosis or, specifically, to myocardial infarction in existing coronary atherosclerosis.
METHODS - We did two genome-wide association studies (GWAS) with coronary angiographic phenotyping in participants of European ancestry. To identify loci that predispose to angiographic coronary artery disease (CAD), we compared individuals who had this disorder (n=12,393) with those who did not (controls, n=7383). To identify loci that predispose to myocardial infarction, we compared patients who had angiographic CAD and myocardial infarction (n=5783) with those who had angiographic CAD but no myocardial infarction (n=3644).
FINDINGS - In the comparison of patients with angiographic CAD versus controls, we identified a novel locus, ADAMTS7 (p=4·98×10(-13)). In the comparison of patients with angiographic CAD who had myocardial infarction versus those with angiographic CAD but no myocardial infarction, we identified a novel association at the ABO locus (p=7·62×10(-9)). The ABO association was attributable to the glycotransferase-deficient enzyme that encodes the ABO blood group O phenotype previously proposed to protect against myocardial infarction.
INTERPRETATION - Our findings indicate that specific genetic predispositions promote the development of coronary atherosclerosis whereas others lead to myocardial infarction in the presence of coronary atherosclerosis. The relation to specific CAD phenotypes might modify how novel loci are applied in personalised risk assessment and used in the development of novel therapies for CAD.
FUNDING - The PennCath and MedStar studies were supported by the Cardiovascular Institute of the University of Pennsylvania, by the MedStar Health Research Institute at Washington Hospital Center and by a research grant from GlaxoSmithKline. The funding and support for the other cohorts contributing to the paper are described in the webappendix.
Copyright © 2011 Elsevier Ltd. All rights reserved.
A recent genome-wide association study (PanScan) identified significant associations at the ABO gene locus with risk of pancreatic cancer, but the influence of specific ABO genotypes remains unknown. We determined ABO genotypes (OO, AO, AA, AB, BO, and BB) in 1,534 cases and 1,583 controls from 12 prospective cohorts in PanScan, grouping participants by genotype-derived serologic blood type (O, A, AB, and B). Adjusted odds ratios (ORs) for pancreatic cancer by ABO alleles were calculated using logistic regression. Compared with blood type O, the ORs for pancreatic cancer in subjects with types A, AB, and B were 1.38 [95% confidence interval (95% CI), 1.18-1.62], 1.47 (95% CI, 1.07-2.02), and 1.53 (95% CI, 1.21-1.92), respectively. The incidence rates for blood types O, A, AB, and B were 28.9, 39.9, 41.8, and 44.5 cases per 100,000 subjects per year. An increase in risk was noted with the addition of each non-O allele. Compared with OO genotype, subjects with AO and AA genotype had ORs of 1.33 (95% CI, 1.13-1.58) and 1.61 (95% CI, 1.22-2.18), whereas subjects with BO and BB genotypes had ORs of 1.45 (95% CI, 1.14-1.85) and 2.42 (1.28-4.57). The population attributable fraction for non-O blood type was 19.5%. In a joint model with smoking, current smokers with non-O blood type had an adjusted OR of 2.68 (95% CI, 2.03-3.54) compared with nonsmokers of blood type O. We concluded that ABO genotypes were significantly associated with pancreatic cancer risk.
Induction of immune tolerance on memory B cells specific to transplantation carbohydrate antigens was studied in the experimental animal model of alpha1,3galactosyltransferase knockout (KO) mice, which lack the alpha-gal epitope (Galalpha1-3Galbeta1-4GlcNAc-R) and can produce the anti-Gal antibody against it. Memory anti-Gal B cells were generated by immunization of KO mice with pig kidney membranes (ie, xenogeneic cell membranes expressing an abundance of alpha-gal epitopes). Lymphocytes including memory anti-Gal B cells were administered into lethally irradiated KO mice, together with syngeneic wild-type (WT) lymphocytes expressing alpha-gal epitopes. Memory anti-Gal B cells were completely tolerized after being in vivo for 14 days with WT lymphocytes. This was indicated by the lack of anti-Gal immunoglobulin G (IgG) response following immunization with pig kidney membranes vs the extensive anti-Gal response in mice that did not receive WT lymphocytes. Tolerance induction was prevented if T cells were activated by alloantigens. This tolerance was highly specific to anti-Gal B cells and did not affect memory B cells with closely related specificity, such as B cells with anti-blood group A specificity. Tolerance induction on anti-Gal B cells was found to be time dependent and required more than 10 days of in vivo exposure of these B cells to WT lymphocytes. These observations suggest a novel method for induction of tolerance to transplantation carbohydrate antigens in humans, by in vitro transduction of autologous blood lymphocytes with an adenovirus containing the corresponding glycosyltransferase gene and administration of the transduced cells into the circulation after removal of natural antibodies to the antigen.