Association between ABO haplotypes and the risk of venous thrombosis: impact on disease risk estimation

Abstract

Genetic risk score (GRS) analysis is an increasingly popular approach to derive individual risk prediction models for complex diseases. In the context of venous thrombosis (VT), any GRS shall integrate information at the ABO blood group locus, the latter being one of the major susceptibility locus for this disease. However, there is yet no consensus about which single nucleotide polymorphisms (SNPs) must be investigated when one is interested in properly assessing the association of ABO locus with VT risk. Using comprehensive haplotype analyses of ABO blood group tagging SNPs in up to 5,425 cases and 8,445 controls from 6 studies, we demonstrated that using only rs8176719 (tagging O1) to correctly assess the impact of ABO locus on VT risk is suboptimal as 5% of rs8176719-delG carriers are not exposed at higher VT risk. Instead, we recommend to use 4 SNPs, rs2519093 (tagging A1), rs1053878 (A2), rs8176743 (B) and rs41302905 (O2) in any analysis aimed at assessing the impact of ABO locus on VT risk to avoid any risk misestimation. Compared to O1 haplotype that can be inferred from these 4 SNPs, the A2 haplotype is associated with a modest increase in VT risk (odds ratio ~1.2), A1 and B haplotypes are associated with a ~1.8 fold increased risk while O2 tend to be slightly protective (odds ratio ~0.80). In addition, our analyses clearly showed that while the A1 an B blood group are associated with increased vWF and FVIII plasma levels only the A1 blood group is associated wih ICAM plasma levels but in an opposite direction, leaving additional avenues to be explored in order to fully understand the whole spectrum of biological effect of ABO locus on cardiovascular traits.

Characterization of the human ABO genotypes and their association to common inflammatory and cardiovascular diseases in the UK Biobank

“…This also agrees with the underlying disease mechanism, where part or all of the deep vein thrombus is dislodged and transported through the right side of the heart before arresting in the pulmonary vasculature causing PE 42 . A recent study by Goumidi and colleagues, assessed the risk of venous thrombosis (VT) in relation to ABO genotypes, and subclassified A into A1 and A2 and O into O1 and O2 respectively 43 . They found a difference in risk between A1 and A2 , where only A1 is posing an increased risk for VT compared to O , and not A2 that only showed a trend toward a moderately increased risk.…”

A year of Covid-19 GWAS results from the GRASP portal reveals potential SARS-CoV-2 modifiers

“…Using haplotype analyses with blood group tagging variants, we determined the blood groups tagged by the lead variant associated with susceptibility (rs9411378). For the 5 main blood groups, we used the following tagging variants 23 : rs41302905 (tagging for O2), rs8176743 (tagging for B), rs1053878 (tagging for A2), rs8176719 (tagging for O1) and rs2519093 (tagging for A1). As a result, we observed that the Covid-19 susceptibility variant was fully tagging A1 and A2 haplotypes, and partially tagging B haplotypes (20% of B haplotypes) ( Figure S49 ), suggesting an increased risk of infection for A1 and A2 carriers.…”

Are ABO Gene Alleles Responsible for Cardiovascular Diseases and Venous Thromboembolism and Do They Play a Role in COVID?

“…Amongst the non-modifiable risk factors, genetic variations in conjunction with traditional modifiable risk factors may significantly influence the trajectory of an individual's CVD risk [3]. Studies on the association between ABO blood group and CVD have consistently demonstrated that possession of the O blood group, the most common phenotype in most populations [4], confers protection against an individual developing a cardiovascular event [5][6][7][8][9][10][11]. The A and B blood groups are most frequently seen in Caucasian and Asian populations, respectively [4].…”

“…There is also a well-documented interaction between ABO blood group and venous thromboembolism (VTE) [7,[13][14][15]. The A2 blood subgroup, which is less common than A1 and rare in Asian populations [5], has been reported to be associated with a modest VTE risk (Odds Ratio 1.2) whereas the A1 and B subgroups confer a 1.8-fold increased risk [7].…”

“…There is also a well-documented interaction between ABO blood group and venous thromboembolism (VTE) [7,[13][14][15]. The A2 blood subgroup, which is less common than A1 and rare in Asian populations [5], has been reported to be associated with a modest VTE risk (Odds Ratio 1.2) whereas the A1 and B subgroups confer a 1.8-fold increased risk [7]. The non-O blood groups are associated with ~25-30% higher plasma levels of factor VIII and von Willebrand Factor (vWF) which are felt to be the major contributing factors to the increased risk of VTE [7,16].…”