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      Expresser phenotype determines ABO(H) blood group antigen loading on platelets and von Willebrand factor

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          Abstract

          ABO blood group is associated with cardiovascular disease, with significantly lower risk in blood group O individuals. ABO(H) blood group determinants are expressed on different glycoproteins on platelet surfaces. In addition, ABO(H) structures are also present on VWF glycans. These ABO(H) carbohydrates influence both platelet and VWF function. Previous studies have reported that approximately 5–10% of normal blood donors express abnormally high or low levels of A or B blood group antigens on their platelet surfaces (high expresser phenotype, HXP or low expresser phenotype, LXP respectively). In this study, the biological effects of the ABO Expresser phenotype were investigated. ABO(H) expression on platelets and plasma VWF was studied in a series of 541 healthy blood donors. Overall, 5.6% of our study cohort were classified as HXP, whilst 4.4% satisfied criteria for LXP. We demonstrate that genotype at the ABO blood group locus plays a critical role in modulating the platelet HXP phenotype. In particular, A 1A 1 genotype is a major determinant of ABO high-expresser trait. Our data further show that ABH loading on VWF is also affected by ABO expresser phenotype. Consequently, A antigen expression on VWF was significantly elevated in HXP individuals and moderately reduced in LXP subjects ( P < 0.05). Collectively, these findings suggest that ABO expresser phenotype influences primary hemostasis though several different pathways. Further studies will be required to define whether inter-individual variations in ABO(H) expression on platelets and/or VWF (particularly HXP and LXP) impact upon risk for cardiovascular disease.

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          Molecular genetic basis of the histo-blood group ABO system.

          The histo-blood group ABO, the major human alloantigen system, involves three carbohydrate antigens (ABH). A, B and AB individuals express glycosyltransferase activities converting the H antigen into A or B antigens, whereas O(H) individuals lack such activity. Here we present a molecular basis for the ABO genotypes. The A and B genes differ in a few single-base substitutions, changing four amino-acid residues that may cause differences in A and B transferase specificity. A critical single-base deletion was found in the O gene, which results in an entirely different, inactive protein incapable of modifying the H antigen.
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            Association between ABO blood groups and risk of SARS‐CoV‐2 pneumonia

            In December 2019, a cluster of acute respiratory illness caused by a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) occurred in Wuhan, China. 1 , 2 Epidemiological and clinical characteristics, risk factors for mortality of patients infected with SARS‐CoV‐2, and risk factors in the susceptibility to SARS‐CoV‐2 included age and chronic disease have been reported. 3 , 4 , 5 , 6 However, the use of biological markers to predict the susceptibility to SARS‐CoV‐2 has not been well described. So far, only one study has reported that ABO blood groups were associated with the susceptibility to SARS‐CoV‐2· 7 In the present study, after eliminating other confounding risk factors (including age, gender and comorbidities), we further investigated and confirmed the association of ABO blood groups and risk of SARS‐CoV‐2 pneumonia in patients from the Central Hospital of Wuhan, as well as two hospitals in Wuhan, China. Patients diagnosed with SARS‐CoV‐2 who died or were discharged between February 1 and March 25, 2020, were included in this retrospective cohort study. The study was approved by the Ethics Committee of the Central Hospital of Wuhan, and the need for informed consent was waived. 8 Epidemiological information, clinical data, underlying comorbidities, CT images of lungs, laboratory findings and clinical outcomes were extracted from electronic medical records. The blood group distribution data of the other two hospitals (Wuhan Jinyintan Hospital and Renmin Hospital of Wuhan University) and healthy controls in Wuhan came from the paper published online. 7 Data were expressed as percentages (%). We used chi‐squared tests or Fisher's exact tests in order to compare the various groups. The ABO blood group in 265 patients infected with SARS‐CoV‐2 from the Central Hospital of Wuhan showed a distribution of 39·3 %, 25·3 %, 9·8 % and 25·7 % for A, B, AB and O, respectively (Table I). The proportion of blood group A in patients infected with SARS‐CoV‐2 was significantly higher than that in healthy controls (39·3 % vs. 32·3 %, P = 0·017), 7 while the proportion of blood group O in patients infected with SARS‐CoV‐2 was significantly lower than that in healthy controls (25·7 % vs. 33·8 %, P < 0·01). Table I The ABO blood group distribution in patients infected with SARS‐CoV‐2 and healthy controls in Wuhan. Blood Group A B AB O Controls (Wuhan Area, n = 3694), % 1188 (32·3 %) 920 (24·9 %) 336 (9·1 %) 1250 (33·8 %) Central Hospital of Wuhan (n = 265), % 104 (39·3) 67 (25·3) 26 (9·8) 68 (25·7) χ 2 5·645 0·019 0·152 7·447 P 0·017 0·891 0·696 < 0·01 Age distribution (n = 265), % Less than 40 years (n = 69) 24 (34·8) 17 (24·6) 8 (11·6) 20 (29·0) χ 2 0·213 0·003 0·509 0·714 P 0·644 0·959 0·476 0·398 Between 41–59 years (n = 79) 29 (36·7) 20 (25·3) 8 (10·1) 22 (27·9) χ 2 0·732 0·007 0·099 1·242 P 0·392 0·933 0·753 0·265 Over 60 years (n = 117) 51 (43·6) 30 (25·6) 10 (8·6) 26 (22·2) χ 2 6·752 0·033 0·041 6·871 P < 0·01 0·856 0·839 < 0·01 Gender distribution (n = 265), % Male (n = 113) 48 (42·5) 30 (26·6) 9 (8·0) 26 (23·0) χ 2 5·323 0·158 0·170 5·771 P 0·021 0·691 0·680 0·016 Female (n = 152) 56 (36·8) 37 (24·3) 17 (11·2) 42 (27·6) χ 2 1·462 0·025 0·764 2·521 P 0·227 0·875 0·382 0·112 Chronic disease, % Cerebrovascular disease (n = 55) 19 (34·6) 15 (27·3) 6 (10·9) 15 (27·3) χ 2 0·141 0·162 0·215 1·045 P 0·707 0·687 0·643 0·307 Coronary heart disease (n = 51) 18 (35·3) 14 (27·5) 7 (13·7) 12 (23·5) χ 2 0·226 0·174 1·296 2·393 P 0·634 0·676 0·255 0·122 Heart failure (n = 16) 2 (12·5) 6 (37·5) 1 (6·3) 7 (43·8) χ 2 2·826 1·349 0·000 0·699 P 0·093 0·245 1·000 0·403 Hypertension (n = 115) 48 (41·7) 26 (22·6) 10 (8·7) 31 (27·0) χ 2 4·668 0·315 0·022 2·367 P 0·031 0·575 0·883 0·124 Diabetes (n = 66) 26 (39·4) 19 (28·8) 4 (6·1) 17 (25·8) χ 2 1·552 0·522 0·726 1·895 P 0·213 0·470 0·394 0·169 Digestive disorder (n = 90) 33 (36·7) 26 (28·9) 7 (7·8) 23 (25·6) χ 2 0·816 0·744 0·185 2·700 P 0·366 0·389 0·667 0·100 COPD (n = 11) 4 (36·4) 4 (36·4) 1 (9·1) 2 (18·2) χ 2 0·089 0·769 0·000 0·604 P 0·766 0·380 1·000 0·437 Solid tumour (n = 27) 13 (48·2) 8 (29·6) 1 (3·7) 5 (18·5) χ 2 3·134 0·320 0·405 2·815 P 0·077 0·572 0·525 0·093 Chronic renal disease (n = 41) 15 (36·6) 12 (29·3) 2 (4·9) 12 (29·3) χ 2 0·364 0·708 0·439 0·379 P 0·546 0·400 0·508 0·538 Hepatitis (n = 7) 6 (85·7) 1 (14·3) 0 (0) 0 (0) χ 2 6·883 0·422 0·032 2·224 P < 0·01 0·516 0·858 0·136 Deaths (n = 57), % 20 (35·1) 15 (26·3) 8 (14·0) 14 (24·6) χ 2 0·220 0·060 1·644 2·162 P 0·639 0·807 0·200 0·141 COPD, chronic obstructive pulmonary disease. John Wiley & Sons, Ltd This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency. We next investigated whether age, gender and chronic disease influence the ABO blood group distribution (Table I). The results showed that, among blood group A (43·6 % vs. 32·2 % in controls, P < 0·01) and blood group O (22·2 % vs. 33·8 % in controls, P < 0·01), patients over 60 years of age were consistent with all the above patients. Similarly, we also found that A (42·5 % vs. 32·2 %, P = 0·021) and O (23·0 % vs. 33·8 %, P = 0·016) distribution of blood groups in male patients was consistent with all the above patients. In all chronic diseases, we found that the proportion of hypertension (41·7 % vs. 32·2 %, P = 0·031) and hepatitis (85·7 % vs. 32·2 %, P < 0·01) in blood group A was much higher than that in the control group; however, there is currently no literature supporting that hypertension and hepatitis increase the risk of infection of SARS‐CoV‐2. In dead patients, we found no differences between blood types. Finally, we integrated the data of the three hospitals in Wuhan for analysis (Table II). 7 We still find that the proportion of blood group A in patients infected with SARS‐CoV‐2 was significantly higher than that in healthy controls (38·0 % vs. 32·2 %, P < 0·001), while the proportion of blood group O in SARS‐CoV‐2 infected patients was significantly lower than in healthy controls (25·7 % vs. 33·8 %, P < 0·001). The distribution ratio of blood type A and O between various ages and genders was almost consistent with the trend of all patients. Table II The ABO blood group distribution in patients infected with SARS‐CoV‐2 from three Wuhan hospitals. Blood Group A B AB O Controls (Wuhan Area, n = 3694), % 1188 (32·2) 920 (24·9) 336 (9·1) 1250 (33·8) Three Wuhan Hospitals (n = 2153), % 819 (38·0) 561 (26·1) 219 (10·2) 554 (25·7) χ 2 20·859 0·953 1·833 36·445 P <0·001 0·329 0·176 <0·001 Age distribution (n = 2153), % Less than 40 years (n = 342) 124 (36·3) 95 (27·8) 29 (8·5) 94 (27·5) χ 2 2·395 1·372 0·145 5·688 P 0·122 0·241 0·704 0·017 Between 41–59 years (n = 784) 304 (38·8) 196 (25·0) 79 (10·1) 205 (26·2) χ 2 12·739 0·003 0·740 17·439 P <0·001 0·956 0·390 <0·001 Over 60 years (n = 1027) 391 (38·1) 270 (26·3) 111 (10·8) 255 (24·8) χ 2 12·617 0·818 2·749 30·034 P <0·001 0·366 0·097 <0·001 Gender distribution (n = 2153), % Male (n = 1143) 451 (39·5) 305 (26·7) 110 (9·6) 277 (24·2) χ 2 20·749 1·461 0·291 37·271 P <0·001 0·227 0·590 <0·001 Female (n = 1010) 368 (36·4) 256 (25·4) 109 (10·8) 277 (27·4) χ 2 6·549 0·082 2·664 14·878 P 0·010 0·774 0·103 <0·001 Three Wuhan hospitals: the Central Hospital of Wuhan, Wuhan Jinyintan Hospital and Renmin Hospital of Wuhan University. John Wiley & Sons, Ltd This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency. In this study, we demonstrated that blood group A patients were at higher risk of hospitalization following SARS‐CoV‐2 infection, while blood group O patients had lower risk, which suggested that the ABO blood type could be used as a biomarker to predict the risk of SARS‐CoV‐2 infection. Coincidentally, previous studies found that ABO blood type distribution also had significant differences in other viral infections. Chen et al. reported that blood group O individuals were less likely to become infected by SARS coronavirus, 9 Batool et al. found that blood group O might have some influence in protecting against blood‐transmitted infection, and people having blood group A were more prone to contract  hepatitis B  and HIV. 10 Jing et al. found that blood group B was associated with a lower risk of HBV infection. 11 Guillon et al. reported that the S protein/angiotensin‐converting enzyme 2‐dependent adhesion of these cells to an angiotensin‐converting enzyme 2 expressing cell line was specifically inhibited by human natural anti‐A antibodies, which might block the interaction between the virus and its receptor. 12 This could explain why blood group A is susceptible, while blood group O is not. However, there may be other factors that need further study. In summary, based on our research, and confirmed by reported data, people with blood group A had a significantly higher risk of SARS‐CoV‐2 infection, whereas blood group O had a significantly lower risk of SARS‐CoV‐2 infection. People with blood type A should strengthen protection to reduce the risk of infection; however, people with blood type O should not take the virus lightly, and must still take precautions to avoid increasing the risk of infection. The underlying molecular mechanism of our findings will need further study. Funding information This study was supported by the Health and Family Planning Commission of Wuhan City (WX18M02). Conflict of interest No reports. Authors' contribution Conceived and designed the experiments: J.L., M.Y. and A.D. Performed the experiments: J.L., X.W. and A.D. Analysed the data: J.L., X.W., J.C. and A.D. Wrote the paper: J.L. J.L. and X.W. contributed equally.
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              ABO(H) blood groups and vascular disease: a systematic review and meta-analysis.

              Associations between vascular disease and ABO(H) blood groups have a long history, but no consensus exists regarding its magnitude and significance, or whether it relates to all disorders equally. An accurate calculation of risk would allow direct assessment of whether the effects of non-O status on thrombosis risk are of the magnitude predicted by its effect on von Willebrand factor/FVIII levels. We conducted a systematic review and meta-analysis of studies reporting associations with non-O blood groups. This gave pooled odds ratios of 1.25 [95% confidence interval (CI) 1.14-1.36] for myocardial infarction (MI), 1.03 (95% CI 0.89-1.19) for angina, 1.45 (95% CI 1.35-1.56) for peripheral vascular disease, 1.14 (95% CI 1.01-1.27) for cerebral ischemia of arterial origin, and 1.79 (95% CI 1.56 to 2.05) for venous thromboembolism (VTE). However, restriction to prospective MI studies only did not confirm the association (OR 1.01; 95% CI 0.84-1.23), although these studies may have failed to capture early-onset disease. For VTE, using a combined group of OO/A(2)A(2)/A(2)O as index, the combination of A(1)A(1)/A(1)B/BB gave an OR of 2.44 (95% CI 1.79-3.33) and A(1)O/ BO/A(2)B an OR of 2.11 (95% CI 1.66-2.68). This study confirms the historical impression of linkage between some vascular disorders and non-O blood group status. Although the odds ratios are similar to those predicted by the effect of ABO(H) on von Willebrand factor levels, further work is required to assess risk prospectively and to refine the effect of reducing O(H) antigen expression on thrombosis. However, as non-O and particularly A(1)A(1), A(1)B, BB constitute a significant proportion of the population attributable fraction of VTE, there may be a role for more widespread adoption of ABO(H) typing in testing strategies.
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                Author and article information

                Contributors
                jamesodonnell@rcsi.ie
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                27 October 2020
                27 October 2020
                2020
                : 10
                : 18366
                Affiliations
                [1 ]GRID grid.493965.4, Irish Blood Transfusion Service, ; Dublin, Ireland
                [2 ]GRID grid.8217.c, ISNI 0000 0004 1936 9705, Department of Haematology, , Trinity College Dublin, ; Dublin, Ireland
                [3 ]GRID grid.241103.5, ISNI 0000 0001 0169 7725, Department of Haematology, , University Hospital of Wales, ; Cardiff, Wales UK
                [4 ]GRID grid.416409.e, ISNI 0000 0004 0617 8280, National Coagulation Centre, St James’s Hospital, ; Dublin, Ireland
                [5 ]GRID grid.416409.e, ISNI 0000 0004 0617 8280, Cancer Molecular Diagnostics, , Trinity Centre for Health Sciences, St James’s Hospital, ; Dublin, Ireland
                [6 ]GRID grid.4912.e, ISNI 0000 0004 0488 7120, Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, , Royal College of Surgeons in Ireland, ; Ardilaun House 111 St Stephen’s Green, Dublin 2, Ireland
                [7 ]GRID grid.417322.1, ISNI 0000 0004 0516 3853, National Children’s Research Centre, Our Lady’s Children’s Hospital, ; Dublin, Ireland
                Article
                75462
                10.1038/s41598-020-75462-2
                7591562
                33110150
                8a2267de-b67f-4f96-8e6d-a142c0513b73
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 5 July 2020
                : 15 October 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000009, Foundation for the National Institutes of Health;
                Funded by: FundRef http://dx.doi.org/10.13039/501100001602, Science Foundation Ireland;
                Funded by: FundRef http://dx.doi.org/10.13039/100010414, Health Research Board;
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                haematological diseases,vascular diseases
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                haematological diseases, vascular diseases

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