Investigating the impact of ABO blood group status on immune activity using data from the Milieu Intérieurcohort
Citation:
Lou, Tianai, Investigating the impact of ABO blood group status on immune activity using data from the Milieu Intérieurcohort, Trinity College Dublin, School of Medicine, Immunology, 2024Download Item:
Abstract:
The ABO blood group system is an important clinical determinant in transfusion medicine for the prevention of haemolytic transfusion reactions, and it has been linked to differential susceptibility to non-communicable diseases, such as thrombotic vascular diseases (TVDs) and type 2 diabetes. In addition, ABO blood groups are also associated with differential risk to infectious diseases, including Helicobacter pylori and Norwalk virus infection; based on data from the COVID-19 pandemic, individuals with blood Type O have been consistently shown to be more protected against infection and illness compared to non-O individuals.
The ABO blood group system has also been associated with varying levels of chemokines, cytokines, and plasma proteins, which are important in immune defence against pathogens. Studies have found that Type O donors have higher levels of cell adhesion molecules and lower levels of clotting factors in their serum compared with non-O donors. However, systematic assessment of whether ABO blood group status is associated with altered immune responses, which may play a role in differential susceptibility to infection and disease severity, has not been carried out. Here, we used data from the Milieu Intérieur cohort (MIC) of 1000 healthy donors of Western European ancestry, evenly stratified by sex and age (20-69 years), to investigate potential differences in whole blood induced immune response to viral and bacterial ligands. We used the rs8176719 SNP in the ABO gene to classify MIC donors as either Type O or non-O and then used multiple regression models to compare levels of immune potential in both groups.
Assessing 229 plasma proteins (quantified by Luminex) from 400 MIC donors, 11 differential plasma proteins were found between Type O and non-O donors. Consistent with previous studies, we observed increased levels of soluble E-selectin (sE-selectin) and decreased levels of von Willebrand Factor (vWF) in O donors compared with non-O donors (both p< 0.0001, FDR correction). Further stratifying our cohort into ABO blood group genotypes (AA, AO, BB, BO, AB, OO) using 2 SNPs of rs8176719 and rs8176746, we observed that ABO blood group status affects the levels of sE-selectin and vWF in an allele dose-dependent manner, with homozygous O donors having highest levels of sE-selectin, and homozygous non-O donors having highest levels of vWF.
To investigate whether ABO blood group status affects the whole blood induced immune response, we assessed 560 immune genes previously quantified by NanoString and 13 induced cytokines measured by Luminex after whole blood stimulation with a panel of PRR ligands, in the 1000 MI donors. Using multiple regression models, we observed 5 differentially upregulated immune genes in Type O donors in response to live Influenza A virus stimulation, including CSF1R, CD1D, APP, CD36 and GUSB. After stimulation with BCG, we found 3 differentially expressed genes between Type O and non-O donors, CFB, JAK1 and TRAF3. We also found higher levels of IL-1ß protein after BCG stimulation in Type O donors. In response to 7 other stimuli, including Null, LPS, polyIC, SEB, HKSA, HKEC and HKCA, induced immune gene expression and cytokine levels were similar between Type O and non-O individuals.
DNA methylation is known to play an important role in gene regulation; we therefore investigated potential epigenetic differences between Type O and non-O individuals We first assessed genome-wide DNA methylation at over 850,000 CpG sites quantified by Infinium MethylationEPIC BeadChip in all MIC donors. Using epigenome-wide association analysis (EWAS), we observed no differences in DNA methylation in most genes between O and non-O donors; however, we identified 23 methylation CpG sites strongly associated with ABO blood group status, all located in the ABO gene. Intriguingly, we found that ABO promoter regions of Type O donors are significantly less methylated than the ABO promotor regions of non-O donors. Using mediation analysis, we showed that differences in methylation partially mediate the effects of blood group on plasma protein levels.
Overall, this study has identified for the first time, a unique methylation profile between Type O and Type non-O individuals; ABO promoter regions in Type O donors are less methylated than promoter regions in non-O donors. It is possible that decreased methylation of the ABO gene in Type O individuals contributes to the increased levels of sE-selectin and reduced levels of vWF, which may in turn, alter the risk of CVD and infection.
Description:
APPROVED
Author: Lou, Tianai
Advisor:
O'Farrelly, ClionaDuffy, Darragh
Sugrue, Jamie
Publisher:
Trinity College Dublin. School of Medicine. Discipline of ImmunologyType of material:
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Full text availableKeywords:
ABO blood groups, E-selectin, vWF, Immune responsesMetadata
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