Histo-blood group ABO system transferase plasma levels and risk of future venous thromboembolism: The HUNT Study

• Elevated plasma levels of histo-blood group ABO system transferase are associated with increased risk of future venous thromboembolism.

• The association is only partly explained by plasma levels of von Willebrand factor or coagulation factor VIII.

The non-O blood group is a well-established risk factor for venous thromboembolism (VTE). However, the association between plasma levels of the histo-blood group ABO system transferase (BGAT), the gene product of the ABO locus, and VTE risk remains unclear. We aimed to investigate the association between plasma BGAT levels and risk of future VTE, and whether this relationship was mediated by plasma von Willebrand factor (VWF) or coagulation factor VIII (FVIII) as VWF is glycosylated by BGAT. Incident VTE-cases (n=294) and randomly sampled age- and-sex-weighted subcohort (n=1,066) were derived from the third survey of the Trøndelag Health Study (HUNT3). Baseline plasma samples (2006-08) were subjected to the SomaScan® aptamer-based-7K platform for protein measurements. Weighted Cox regression was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) across BGAT quartiles. We found that ABO haplotypes (A1/A2/B/O1/O2) explained ~80% of the BGAT plasma variability. Participants with BGAT levels in the highest quartile had 2-fold higher VTE risk (HR 2.12, 95%CI:1.39-3.22) compared with those with BGAT in the lowest quartile in age-, sex- and sample batch-adjusted models. The associations were particularly pronounced for unprovoked VTE (HR 3.71, 95%CI:1.79-7.67) and deep vein thrombosis (HR 3.28, 95%CI:1.63-6.59). The HRs were similar after further adjustment for body mass index, C-reactive protein, and estimated estimated glomerular filtration rate, and moderately attenuated when adding VWF or FVIII plasma levels to the models. Our findings indicate that elevated BGAT plasma levels are associated with increased risk of future VTE beyond what is explained by VWF and FVIII.