ABO Histo-blood Group Research Articles

Integrating plasma protein-centric multi-omics to identify potential therapeutic targets for pancreatic cancer

BackgroundDeciphering the role of plasma proteins in pancreatic cancer (PC) susceptibility can aid in identifying novel targets for diagnosis and treatment.MethodsWe examined the relationship between genetically determined levels of plasma proteins and PC through a systemic proteome-wide Mendelian randomization (MR) analysis utilizing cis-pQTLs from multiple centers. Rigorous sensitivity analyses, colocalization, reverse MR, replications with varying instrumental variable selections and additional datasets, as well as subsequent meta-analysis, were utilized to confirm the robustness of significant findings. The causative effect of corresponding protein-coding genes’ expression and their expression pattern in single-cell types were then investigated. Enrichment analysis, between-protein interaction and causation, knock-out mice models, and mediation analysis with established PC risk factors were applied to indicate the pathogenetic pathways. These candidate targets were ultimately prioritized upon druggability and potential side effects predicted by a phenome-wide MR.ResultsTwenty-one PC-related circulating proteins were identified in the exploratory phase with no evidence for horizontal pleiotropy or reverse causation. Of these, 11 were confirmed in a meta-analysis integrating external validations. The causality at a transcription level was repeated for neutrophil elastase, hydroxyacylglutathione hydrolase, lipase member N, protein disulfide-isomerase A5, xyloside xylosyltransferase 1. The carbohydrate sulfotransferase 11 and histo-blood group ABO system transferase exhibited high-support genetic colocalization evidence and were found to affect PC carcinogenesis partially through modulating body mass index and type 2 diabetes, respectively. Approved drugs have been established for eight candidate targets, which could potentially be repurposed for PC therapies. The phenome-wide investigation revealed 12 proteins associated with 51 non-PC traits, and interference on protein disulfide-isomerase A5 and cystatin-D would increase the risk of other malignancies.ConclusionsBy employing comprehensive methodologies, this study demonstrated a genetic predisposition linking 21 circulating proteins to PC risk. Our findings shed new light on the PC etiology and highlighted potential targets as priorities for future efforts in early diagnosis and therapeutic strategies of PC.

Association between plasma proteome and pulmonary heart disease: A two-stage Mendelian randomization analysis.

Pulmonary heart disease (PHD) involves altered structure and function of the right ventricle caused by an abnormal respiratory system that causes pulmonary hypertension. However, the association between changes in plasma proteomics and PHD remains unclear. Hence, we aimed to identify causal associations between genetically predicted plasma protein levels and PHD. Mendelian randomization was performed to test the target proteins associated with PHD. Summary statistics for the human plasma proteome and pulmonary heart disease were acquired from the UK Biobank (6038 cases and 426 977 controls) and the FinnGen study (6753 cases and 302 401 controls). Publicly available pQTLs datasets for human plasma proteins were obtained from a largescale genome-wide association study in the INTERVAL study. The results were validated using a case-control cohort. We first enrolled 3622 plasma proteins with conditionally independent genetic variants; three proteins (histo-blood group ABO system transferase, activating signal cointegration 1 complex subunit 1, and calcium/calmodulin-dependent protein kinase I [CAMK1]) were significantly associated with the risk of pulmonary heart disease in the UK Biobank cohort. Only CAMK1 was successfully replicated (odds ratio: 1.1056, 95% confidence interval: 1.019-1.095, p = 0.0029) in the FinnGen population. In addition, the level of CAMK1 in 40 patients with PHD was significantly higher (p = 0.023) than that in the control group. This work proposes that CAMK1 is associated with PHD, underscoring the importance of the calcium signaling pathway in the pathophysiology to improve therapies for PHD.

The effect of histo-blood group ABO system transferase (BGAT) on pregnancy related outcomes：A Mendelian randomization study

Protein level of Histo-Blood Group ABO System Transferase (BGAT) has been reported to be associated with cardiometabolic diseases. But its effect on pregnancy related outcomes still remains unclear. Here we conducted a two-sample Mendelian randomization (MR) study to ascertain the putative causal roles of protein levels of BGAT in pregnancy related outcomes. Cis-acting protein quantitative trait loci (pQTLs) robustly associated with protein level of BGAT (P < 5 ×10−8) were used as instruments to proxy the BGAT protein level (N = 35,559, data from deCODE), with two additional pQTL datasets from Fenland (N = 10,708) and INTERVAL (N = 3301) used as validation exposures. Ten pregnancy related diseases and complications were selected as outcomes. We observed that a higher protein level of BGAT showed a putative causal effect on venous complications and haemorrhoids in pregnancy (VH) (odds ratio [OR]=1.19, 95% confidence interval [95% CI]=1.12–1.27, colocalization probability=91%), which was validated by using pQTLs from Fenland and INTERVAL. The Mendelian randomization results further showed effects of the BGAT protein on gestational hypertension (GH) (OR=0.97, 95% CI=0.96–0.99), despite little colocalization evidence to support it. Sensitivity analyses, including proteome-wide Mendelian randomization of the cis-acting BGAT pQTLs, showed little evidence of horizontal pleiotropy. Correctively, our study prioritised BGAT as a putative causal protein for venous complications and haemorrhoids in pregnancy. Future epidemiology and clinical studies are needed to investigate whether BGAT can be considered as a drug target to prevent adverse pregnancy outcomes.

ABO Histo-Blood Group and the von Willebrand Factor Axis in Severe COVID-19

ABO Histo-Blood Group and the von Willebrand Factor Axis in Severe COVID-19

ABO blood groups and expression of blood group antigens of epithelial ovarian cancer in Chinese women.

ABO blood groups has been associated with risk of several cancers; however, the results for an association with ovarian cancer are inconsistent and little is known about the expression of histo-blood group (ABH) antigens and ABO gene in ovarian tumor tissues. To assess the impact of genotype-derived ABO blood types on the risk of EOC, we conducted a case-control study in 1,870 EOC and 4,829 controls. Expression of A and B antigen in 70 pairs of ovarian tumor tissues and adjacent normal tissues were detected by immunohistochemistry. Gene expression and DNA methylation profiling was conducted in ovarian tumor tissues. We identified that blood group A was associated with increased risk for EOC compared to blood group O (OR=1.18, 95% CI=1.03-1.36, p=0.019). Increased frequency of aberrant expression of histo-blood group antigens was observed in patients with blood group A (76.5%) compared to patients with blood group O (21.1%) and B (5.0%) by immunohistochemistry (p < 0.001). ABO gene expression was down-regulated in ovarian tumor tissues compared with paired adjacent normal tissues (p=0.027). In addition, ABO gene expression was positively correlated with NFYB (r=0.38, p < 0.001) and inversely correlated with DNA methylation level of four CpG sites on ABO gene (cg11879188, r=- 0.3, p=0.002; cg22535403, r=- 0.30, p=0.002; cg13506600, r=- 0.22, p=0.025; cg07241568, r=- 0.21, p=0.049) in ovarian tumor tissues. We identified blood group A was associated with increased EOC risk in Chinese women and provided the clues of the possible molecular mechanisms of blood group A related to ovarian cancer risk.

Intestinal Norovirus Binding Patterns in Nonsecretor Individuals.

Human norovirus (HuNoV) infection is associated with an active FUT2 gene, which characterizes the secretor phenotype. However, nonsecretor individuals are also affected by HuNoV infection although in a lesser proportion. Here, we studied GII.3, GII.4, and GII.17 HuNoV interactions in nonsecretor individuals using virus-like particles (VLPs). Only GII.4 HuNoV specifically interacted with nonsecretor saliva. Competition experiments using histo-blood group antigen (HBGA)-specific monoclonal antibodies (MAbs) demonstrate that GII.4 VLPs recognized the Lewis a (Lea) antigen. We also analyzed HuNoV VLP interactions on duodenum tissue blocks from healthy nonsecretor individuals. VLP binding was observed for the three HuNoV genotypes in 10 of the 13 individuals, and competition experiments demonstrated that VLP recognition was driven by an interaction with the Lea antigen. In 3 individuals, binding was restricted to either GII.4 alone or GII.3 and GII.17. Finally, we performed a VLP binding assay on proximal and distal colon tissue blocks from a nonsecretor patient with Crohn's disease. VLP binding to inflammatory tissues was genotype specific since GII.4 and GII.17 VLPs were able to interact with regenerative mucosa, whereas GII.3 VLP was not. The binding of GII.4 and GII.17 HuNoV VLPs was linked to Lea in regenerative mucosae from the proximal and distal colon. Overall, our data clearly showed that Lea has a pivotal role in the recognition of HuNoV in nonsecretors. We also showed that Lea is expressed in inflammatory/regenerative tissues and interacts with HuNoV in a nonsecretor individual. The physiological and immunological consequences of such interactions in nonsecretors have yet to be elucidated. IMPORTANCE Human norovirus (HuNoV) is the main etiological agent of viral gastroenteritis in all age classes. HuNoV infection affects mainly secretor individuals where ABO(H) and Lewis histo-blood group antigens (HBGAs) are present in the small intestine. Nonsecretor individuals, who only express Lewis (Le) antigens, are less susceptible to HuNoV infection. Here, we studied the interaction of common HuNoV genotypes (GII.3, GII.4, and GII.17) in nonsecretor individuals using synthetic viral particles. Saliva binding assays showed that only GII.4 interacted with nonsecretor saliva via the Lewis a (Lea) antigen Surprisingly, the three genotypes interacted with nonsecretor enterocytes via the Lea antigen on duodenal tissue blocks, which were more relevant for HuNoV/HBGA studies. The Lea antigen also played a pivotal role in the recognition of GII.4 and GII.17 particles by inflammatory colon tissue from a nonsecretor Crohn's disease patient. The implications of HuNoV binding in nonsecretors remain to be elucidated in physiological and pathological conditions encountered in other intestinal diseases.

Identifying factors contributing to increased susceptibility to COVID-19 risk: a systematic review of Mendelian randomization studies.

BackgroundTo summarize modifiable factors for coronavirus disease 2019 (COVID-19) suggested by Mendelian randomization studies.MethodsIn this systematic review, we searched PubMed, EMBASE and MEDLINE, from inception to 15 November 2021, for Mendelian randomization studies in English. We selected studies that assessed associations of genetically predicted exposures with COVID-19-related outcomes (severity, hospitalization and susceptibility). Risk of bias of the included studies was evaluated based on the consideration of the three main assumptions for instrumental variable analyses.ResultsWe identified 700 studies through systematic search, of which 50 Mendelian randomization studies were included. Included studies have explored a wide range of socio-demographic factors, lifestyle attributes, anthropometrics and biomarkers, predisposition to diseases and druggable targets in COVID-19 risk. Mendelian randomization studies suggested that increases in smoking, obesity and inflammatory factors were associated with higher risk of COVID-19. Predisposition to ischaemic stroke, combined bipolar disorder and schizophrenia, attention-deficit and hyperactivity disorder, chronic kidney disease and idiopathic pulmonary fibrosis was potentially associated with higher COVID-19 risk. Druggable targets, such as higher protein expression of histo-blood group ABO system transferase (ABO), interleukin (IL)-6 and lower protein expression of 2′-5′ oligoadenylate synthetase 1 (OAS1) were associated with higher risk of COVID-19. There was no strong genetic evidence supporting the role of vitamin D, glycaemic traits and predisposition to cardiometabolic diseases in COVID-19 risk.ConclusionThis review summarizes modifiable factors for intervention (e.g. smoking, obesity and inflammatory factors) and proteomic signatures (e.g. OAS1 and IL-6) that could help identify drugs for treating COVID-19.

Abstract WMP99: Proteomics Study Of Stroke In Young Adults

Introduction: A prior systematic Mendelian randomization screen of 653 circulating proteins in a predominantly older ischemic stroke (IS) population identified a causal role for several established and novel biomarkers for IS and IS subtypes. We contrasted the magnitude of genetically determined levels of 6 of these biomarkers between early- and late-onset IS. Methods: We constructed genetic risk scores (GRS) for these 6 protein biomarkers from previously published GWAS analyses carried out in European populations. Using regression analysis, we evaluated associations of these GRS with IS and IS subtypes in 10,549 early onset (ages 18-59) and 9,272 late onset (ages 60 and older) IS cases and associated controls. The Wald test was used to test for heterogeneity in the odds ratios between the two groups. Results: Of the 6 biomarkers, only genetically determined protein levels of histo-blood group ABO system transferase were more strongly associated with early compared to late onset stroke (p &lt; 0.002). Higher genetically determined levels of F11 and LPA and lower genetically determined levels of MMP12 were associated with both early and late onset IS with no evidence for differential effect sizes, while genetically determined levels of CD40 and SCARA5 showed no association with either early or late onset stroke. In subtype-specific analyses, increasing levels of genetically determined F11 were correlated with increased risk of all strokes in both groups. Higher genetically determined LPA levels were associated with large artery atherosclerotic (LAA) strokes in both groups, while lower genetically determined MMP12 levels were associated with LAA strokes in both groups. Conclusions: Genetically determined histo-blood group ABO system transferase levels are more strongly associated with all strokes in early than in late onset stroke. Genetically determined blood protein levels of F11, LPA, and MMP12 were associated with both early and late onset stroke. Lack of association for CD40 and SCARA5 may be due to a smaller sample size than the initial discovery study.

Red blood cell blood group A antigen level affects the ability of heparin and PfEMP1 antibodies to disrupt Plasmodium falciparum rosettes

BackgroundThe histo-blood group ABO system has been associated with adverse outcomes in COVID-19, thromboembolic diseases and Plasmodium falciparum malaria. An integral part of the severe malaria pathogenesis is rosetting, the adherence of parasite infected red blood cells (RBCs) to uninfected RBCs. Rosetting is influenced by the host’s ABO blood group (Bg) and rosettes formed in BgA have previously been shown to be more resilient to disruption by heparin and shield the parasite derived surface antigens from antibodies. However, data on rosetting in weak BgA subgroups is scarce and based on investigations of relatively few donors.MethodsAn improved high-throughput flow cytometric assay was employed to investigate rosetting characteristics in an extensive panel of RBC donor samples of all four major ABO Bgs, as well as low BgA expressing samples.ResultsAll non-O Bgs shield the parasite surface antigens from strain-specific antibodies towards P. falciparum erythrocyte membrane protein 1 (PfEMP1). A positive correlation between A-antigen levels on RBCs and rosette tightness was observed, protecting the rosettes from heparin- and antibody-mediated disruption.ConclusionsThese results provide new insights into how the ABO Bg system affects the disease outcome and cautions against interpreting the results from the heterogeneous BgA phenotype as a single group in epidemiological and experimental studies.Graphical

Abstract 882: Associations of genetically predicted blood protein biomarkers with pancreatic ductal adenocarcinoma risk: A study using comprehensive protein genetic prediction models

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with few known risk factors and biomarkers. Identification of biomarkers is critical for understanding the pathogenesis of this deadly cancer and identifying high-risk individuals for close surveillance. Several blood protein biomarkers have been linked to PDAC in previous studies, but these studies have assessed only a limited number of protein biomarkers usually in small set(s) of samples. To identify novel circulating protein biomarkers of PDAC, we studied 8,275 cases and 6,723 controls of European descent from the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case-Control Consortium. Leveraging genome and plasma proteome data of 2,841 healthy European descendants included in the INTERVAL study, we established models using four methods (best linear unbiased predictor, elastic net, LASSO, and top1) to predict protein levels based on genetic variants. For each protein, of the four sets of models developed, the model showing the highest prediction performance (R2) was retained. We selected 2,164 built protein models with a prediction performance (R2) of &amp;gt;0.01 for association analyses with PDAC risk. We observed associations between predicted concentrations of 14 proteins and PDAC risk at a false discovery rate of &amp;lt; 0.05, including those of eight proteins that showed a significant association after Bonferroni correction (2.31 × 10-5). These include Histo-blood group ABO system transferase encoded by ABO, which has been previously implicated as a potential target gene of PDAC risk variant identified in GWAS. Besides eight proteins that were previously reported in our earlier study using protein quantitative trait loci as instruments, we identified six novel proteins which have not been identified in previous studies. Six of the identified proteins showed positive associations and eight showed inverse associations (P-values from 2.62 × 10-4 to 5.71 × 10-21). In conclusion, we identified 14 protein biomarker candidates for PDAC risk, which if validated in future studies, may contribute to the etiological understanding of PDAC development. Citation Format: Dalia Ghoneim, Jingjing Zhu, Jihwan Ha, Praveen Surendran, Qizhi Cathy Yao, Tao Liu, Sarah Fahle, Adam Butterworth, Chong Wu, Lang Wu. Associations of genetically predicted blood protein biomarkers with pancreatic ductal adenocarcinoma risk: A study using comprehensive protein genetic prediction models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 882.

The Potential Contribution of ABO, Lewis and Secretor Histo-Blood Group Carbohydrates in Infection by Toxoplasma gondii.

The glycosyltransferases encoded by genes from the human ABO, Lewis, and Secretor histo-blood group systems synthesize part of the carbohydrate antigens in hematopoietic and non-hematopoietic tissues. The combined action of these glycosyltransferases strongly influences cell, tissue, mucosa, and exocrine secretion carbohydrate phenotypes, including those serving as habitat for mutualistic and pathogenic microorganisms. A set of reports investigated associations between Toxoplasma gondii infection and the ABO histo-blood group system, but the results are contradictory. As T. gondii uses the gastrointestinal tract as a route for infection, and in this organ, the expression of ABO, Lewis, and Secretor histo-blood group carbohydrates occurs, it is reasonable to suppose some biological relationship between them. This text reviewed association studies published in recent decades focusing on the potential contribution of the ABO, Lewis, and Secretor histo-blood group carbohydrates and infection by T. gondii.

Associations between Genetically Predicted Circulating Protein Concentrations and Endometrial Cancer Risk.

Simple SummaryEndometrial cancer is the leading female reproductive tract cancer in developed countries. Discovering new biomarkers is critical for understanding the etiology this cancer and identifying women with a higher risk of this cancer from the general population. Several blood protein biomarkers have been linked to endometrial cancer in previous studies, but these studies have assessed only a limited number of biomarkers usually among a small number of participants. The current study aimed at identifying novel circulating protein biomarkers of endometrial cancer by using the largest available dataset to date. Our finding suggested nine proteins to be associated with endometrial cancer risk, and five of the identified associations showed suggestive associations with risk of non-endometrioid EC, a much more lethal subtype. If validated by additional studies, our findings may contribute to understanding the pathogenesis of endometrial tumor development and facilitating the risk assessment of endometrial cancer.Endometrial cancer (EC) is the leading female reproductive tract malignancy in developed countries. Currently, genome-wide association studies (GWAS) have identified 17 risk loci for EC. To identify novel EC-associated proteins, we used previously reported protein quantitative trait loci for 1434 plasma proteins as instruments to evaluate associations between genetically predicted circulating protein concentrations and EC risk. We studied 12,906 cases and 108,979 controls of European descent included in the Endometrial Cancer Association Consortium, the Epidemiology of Endometrial Cancer Consortium, and the UK Biobank. We observed associations between genetically predicted concentrations of nine proteins and EC risk at a false discovery rate of <0.05 (p-values range from 1.14 × 10−10 to 3.04 × 10−4). Except for vascular cell adhesion protein 1, all other identified proteins were independent from known EC risk variants identified in EC GWAS. The respective odds ratios (95% confidence intervals) per one standard deviation increase in genetically predicted circulating protein concentrations were 1.21 (1.13, 1.30) for DNA repair protein RAD51 homolog 4, 1.27 (1.14, 1.42) for desmoglein-2, 1.14 (1.07, 1.22) for MHC class I polypeptide-related sequence B, 1.05 (1.02, 1.08) for histo-blood group ABO system transferase, 0.77 (0.68, 0.89) for intestinal-type alkaline phosphatase, 0.82 (0.74, 0.91) for carbohydrate sulfotransferase 15, 1.07 (1.03, 1.11) for D-glucuronyl C5-epimerase, and 1.07 (1.03, 1.10) for CD209 antigen. In conclusion, we identified nine potential EC-associated proteins. If validated by additional studies, our findings may contribute to understanding the pathogenesis of endometrial tumor development and identifying women at high risk of EC along with other EC risk factors and biomarkers.

Convalescent blood plasma (CBP) donated by recovered COVID-19 patients – A comment

Convalescent blood plasma (CBP) donated by recovered COVID-19 patients – A comment

Genome-wide association study in 8,956 German individuals identifies influence of ABO histo-blood groups on gut microbiome.

The intestinal microbiome is implicated as an important modulating factor in multiple inflammatory1,2, neurologic3 and neoplastic diseases4. Recent genome-wide association studies yielded inconsistent, underpowered and rarely replicated results such that the role of human host genetics as a contributing factor to microbiome assembly and structure remains uncertain5-11. Nevertheless, twin studies clearly suggest host genetics as a driver of microbiome composition11. In a genome-wide association analysis of 8,956 German individuals, we identified 38 genetic loci to be associated with single bacteria and overall microbiome composition. Further analyses confirm the identified associations of ABO histo-blood groups and FUT2 secretor status with Bacteroides and Faecalibacterium spp. Mendelian randomization analysis suggests causative and protective effects of gut microbes, with clade-specific effects on inflammatory bowel disease. This holistic investigative approach of the host, its genetics and its associated microbial communities as a 'metaorganism' broaden our understanding of disease etiology, and emphasize the potential for implementing microbiota in disease treatment and management.

FEMALE COMPLEXITY: HIGH ‘NATURAL’ ABO ANTI-A ANTIBODIES AND IGG CLASS SWITCH IN FEMALE VS MALE MICE

Introduction: ABO histo-blood group incompatibility is a barrier in solid organ transplant due to the presence of ‘natural’ preformed ABO antibodies (Abs). However, ABO-incompatible (ABOi) heart transplantation is successful in infants as ABO Abs are low/absent. A better understanding of the specificity and the production of ABO Abs may allow for successful ABOi transplantation at older ages. Here, we sought to determine the isotype (IgM/IgG) and subtype (I-VI) specificity of ABO Abs produced naturally or induced by sensitization in mice as a function of age and sex. Methods: BALB/c mice were assessed for natural anti-A and anti-B Ab production over time (n=45/47, female/male; age 1-18 months), or challenged with human A erythrocytes (5 weekly ip injection) beginning at age 5 weeks to measure induced anti-A Abs (n=13/8, female/male; age 1-3 months). Plasma A/B Ab titre was determined by hemagglutination assay using human reagent erythrocytes; ABO Ab isotype and subtype-specificity were assessed by a novel ABH glycan microarray created in our lab. Results: Female mice produced markedly higher natural anti-A Abs compared to male mice. With age, natural anti-A shifted from IgM to IgG isotype in females but remained predominantly IgM in males (Fig. 1A). In contrast to anti-A, anti-B Ab levels were much lower and remained mostly IgM in both sexes (Fig. 1B). Most natural anti-A Abs were specific to antigen subtypes III/IV; specificity to subtypes I and II was absent or very low. In contrast, following A-antigen sensitization, female and male mice produced comparable quantities of IgM and IgG anti-A Abs (data not shown), with specificities for all subtypes (I-VI).Conclusions: We found a dramatic and previously undescribed sex difference in natural ABO anti-A Ab production in mice. Markedly higher anti-A Ab production together with a distinct propensity for class switching suggest a more complex immune pathway in females than traditionally described for natural Abs to ‘T-independent’ carbohydrate antigens. Future studies will explore mechanisms for these sex differences and relevance to humans. Supported by the Heart and Stroke Foundation of Canada and the Women and Children’s Health Research Institute, University of Alberta.

Abstract 1200: Associations between genetically predicted blood protein biomarkers and pancreatic ductal adenocarcinoma risk

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of most lethal malignancies with few known risk factors and biomarkers. Identification of disease biomarkers is critical for understanding the pathogenesis of this cancer and identifying high risk individuals for close surveillance. Several blood protein biomarkers have been linked to PDAC in previous studies, but these studies have assessed only a limited number of biomarkers usually in small samples. To identify novel circulating protein biomarkers of PDAC, we studied 8,280 cases and 6,728 controls of European descent from the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case-Control Consortium, by using genetic instruments. Protein quantitative trait loci (pQTLs) for 1,226 plasma proteins identified in a large INTERVAL study of 3,301 healthy European descendants were used as instruments to evaluate associations between genetically predicted protein levels and PDAC. For proteins showing a significant association, we further conducted conditional analysis with adjustments for previously identified risk variants to assess whether the observed associations between genetically predicted protein concentrations and PDAC risk were independent of the risk variants identified in genome-wide association studies (GWAS). Furthermore, for the proteins that were associated with PDAC risk, we performed an enrichment analysis of the genes encoding these proteins to examine whether they are enriched in specific pathways, functions or networks. We observed associations between predicted concentrations of 38 proteins and PDAC risk at a false discovery rate of &amp;lt; 0.05, including those of 23 proteins that showed a significant association even after Bonferroni correction (4.08 × 10−5). These include Histo-blood group ABO system transferase encoded by ABO, which has been previously implicated as a potential target gene of PDAC risk variant identified in GWAS. Eight of the identified proteins (Beta-crystallin B2, Dedicator of cytokinesis protein 9, VIP36-like protein, Erythrocyte band 7 integral membrane protein, Tensin-2, Transmembrane protease serine 11D, Alcohol dehydrogenase 1B, and C-X-C motif chemokine 10) were associated with PDAC risk after conditioning on previously reported pancreatic cancer risk variants (odds ratios ranged from 0.79 to 1.52, P-values from 1.28 × 10−3 to 6.47 × 10−4). Pathway enrichment analysis showed that the encoding genes for the implicated proteins were significantly enriched in cancer-related pathways, such as STAT3 and IL-15 production. In conclusion, we identified 38 protein biomarker candidates for PDAC risk, which if validated by additional studies, may contribute to the etiological understanding of PDAC tumor development. Citation Format: Jingjing Zhu, Xiang Shu, Xingyi Guo, Duo Liu, Jiandong bao, Roger Milne, Graham G Giles, Chong Wu, Mengmeng Du, Emily White, Harvey A Risch, Nuria Malats, Eric J. Duell, Phyllis J. Goodman, Donghui Li, Paige Bracci, Verena Katzke, Rachel E Neale, Steven Gallinger, Stephen Van Den Eeden, Alan Arslan, Federico Canzian, Charles Kooperberg, Brian Wolpin, Laura Beane-Freeman, Ghislaine Scelo, Kala Visvanatha, Christopher A. Haiman, Loïc Le Marchand, Herbert Yu, Gloria M Petersen, Rachael Stolzenberg-Solomon, Alison P Klein, Laufey T Amundadottir, Qiuyin Cai, Jirong Long, Xiao-Ou Shu, Wei Zheng, Lang Wu. Associations between genetically predicted blood protein biomarkers and pancreatic ductal adenocarcinoma risk [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1200.

The Novel Coronavirus SARS-CoV-2 Vulnerability Association with ABO/Rh Blood Types

Background & Objective:Coronavirus disease 2019 (COVID-19) is the most recent emerging viral disease. Defining the epidemiological aspects and factors influencing the susceptibility of the patients to COVID-19 has been an ongoing struggle. In the present study, we have investigated the connection between ABO histo-blood group phenotypes and the COVID-19.Methods:This study was conducted on 397 patients with confirmed diagnoses of COVID-19 admitted to our center. Also, 500 individuals were selected to form the controls, all of whom had been disclosed to the same medical center in June 2019, before the onset of the outbreak.Results:Our results demonstrated ABO histo-blood phenotypes are correlated with patients’ susceptibility to the infection. A higher rate of infection was observed among patients with the AB histo-blood group, while patients with the O histo-blood group have shown a lower rate of infection. The Rh blood group phenotype was not statistically significant in determining a patient’s vulnerability.Conclusion:Similar to several previous studies about other viral diseases’ association with ABO histo-blood groups, we have concluded that an individual’s ABO histo-blood group phenotype and his/her susceptibility to COVID-19 are indeed connected. So far, only one research has been conducted about this association. Interestingly, while we observed a decreased vulnerability to the disease among patients with an O histo-blood group, we have reached discordant results regarding the increased susceptibility among individuals with an AB histo-blood group, unlike A histo-blood group in the previous study.

High-Levels of ‘Natural’ ABO Antibodies are Produced in Female vs. Male Mice

ABO histo-blood group incompatibility is a barrier in solid organ transplant due to the presence of 'natural' preformed ABO antibodies. However, ABO-incompatible (ABOi) heart transplantation is successful in infants as ABO antibodies are low/absent. A better understanding of the specificity and the production of ABO antibodies may allow for successful ABOi transplantation at older ages. Here, we sought to determine the isotype (IgM/IgG) and subtype (I-VI) specificity of ABO antibodies produced naturally or induced by sensitization in mice as a function of age and sex. BALB/c mice were assessed for natural ABO antibody production over time (n=32/39, female/male; age 1-18 months), or challenged with human A erythrocytes (5 weekly intraperitoneal injection) beginning at 5 weeks of age to measure induced ABO antibody production (n=13/8, female/male; age 1-3 months). Plasma ABO antibody titre was determined by hemagglutination assay; ABO antibody isotype and subtype specificity were assessed by a novel ABH-glycan microarray created in our lab. Female mice produced markedly higher natural anti-A antibodies compared with male mice. With age, natural anti-A antibodies shifted from an IgM to IgG isotype in females but remained predominantly IgM in males (Figure 1). Most natural ABO antibodies were specific to antigen subtypes III/IV; specificity to subtypes I and II was absent or very low. In contrast, following A-antigen sensitization, both female and male mice produced comparable quantities of IgM and IgG anti-A antibodies with specificities for all subtypes (I-VI). Male and female mice show previously undescribed differences in natural ABO antibody production. Markedly higher antibody production together with a distinct propensity to class switching suggest a more complex immune pathway in females than traditionally described for natural antibody to 'T-independent' carbohydrate antigens. Future studies will explore mechanisms for these sex differences and relevance to humans.

ABO, H, Lewis and Secretor histo-blood group-like carbohydrates in pathogenic and non-pathogenic invertebrates

ABO, H, Lewis, and Secretor histo-blood group systems express a repertoire of carbohydrate antigens in human hematopoietic and non-hematopoietic tissues. The oligosaccharide components of these systems are widely distributed in nature, including animal and plants. A set of reports demonstrated that pathogenic and non-pathogenic invertebrates are able to synthesize and or acquire histo-blood group-like carbohydrates from hosts. These abilities seem to be related to strategies for cell invasion as well as scape from host’s innate and adaptive immune responses. This text revised the literature and offers a tentative explanation for the presence of histo-blood group-like carbohydrates in pathogenic and non-pathogenic invertebrates and its importance in terms of evolution.

Histo-blood group antigens and rotavirus vaccine shedding in Nicaraguan infants

ABO, Lewis and secretor histo-blood group antigens (HBGA) are susceptibility factors for rotavirus in a P-genotype dependent manner and can influence IgA seroconversion rates following rotavirus vaccination. To investigate the association between HBGA phenotypes and rotavirus vaccine shedding fecal samples (n = 304) from a total of 141 infants vaccinated with Rotarix (n = 71) and RotaTeq (n = 70) were prospectively sampled in three time frames (≤3, 4–7 and ≥8 days) after first vaccination dose. Rotavirus was detected with qPCR and genotypes determined by G/P multiplex PCR and/or sequencing. HBGAs were determined by hemagglutination and saliva based ELISA. Low shedding rates were observed, with slightly more children vaccinated with RotaTeq (19%) than Rotarix (11%) shedding rotavirus at ≥4 days post vaccination (DPV). At ≥4 DPV no infant of Lewis A (n = 6) or nonsecretor (n = 9) phenotype in the Rotarix cohort shed rotavirus; the same observation was made for Lewis A infants (n = 7) in the RotaTeq cohort. Putative in-vivo gene reassortment among RotaTeq strains occurred, yielding mainly G1P[8] strains. The bovine derived P[5] genotype included in RotaTeq was able to replicate and be shed at long time frames (>13 DPV). The results of this study are consistent with that HBGA phenotype influences vaccine strain shedding as similarly observed for natural infections. Due to the low overall shedding rates observed, additional studies are however warranted.