The widespread use of genome-wide association studies (GWASs) over the last 5 years has spurred an enormous acceleration in discoveries across the entire spectrum of CVD [20
]. Recent GWASs have confirmed ABO
as a locus for venous thromboembolism (VTE), myocardial infarction (MI), and multiple cardiovascular biomarkers ().
ABO SNPs associated with cardiovascular disease and risk factors.
One of the most studied aspects of the ABO
gene is its relationship with von Willebrand factor (VWF) [17
]. In 2003, a family-based linkage screen was carried out to determine the loci involved in VWF variation in 398 Spanish individuals. Markers at the chromosome 9q ABO
locus region harbored the highest LOD value of 3.46 [38
]. Subsequently, several GWASs have shown that carriers of single nucleotide polymorphisms (SNPs) that mark non-O blood group types have higher levels of plasma VWF when compared to O individuals. A recent GWAS of 7856 European participants in the Atherosclerosis Risk In Communities (ARIC) cohort study showed that ABO blood group O carriers had a 25% average reduction in plasma VWF levels when compared with non-O blood group carriers. SNP rs514659, which was used to tag the O blood type, contributed to 15.4% of circulating VWF variance [33
]. Additionally, a genome-wide meta-analysis of 4 cohorts found that rs657152, which also tags the blood group O, was strongly associated with circulating VWF levels and that blood group O individuals had 22–30% lower plasma VWF when compared to non-blood group O individuals [28
]. A relationship between Factor VIII (FVIII) plasma concentrations and ABO blood groups has also been seen. However, in a Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium GWAS, no unique genetic variants within the ABO locus were found to affect FVIII independently of VWF [34
]. As VWF binds and transports FVIII, the correlation between the ABO gene and FVIII is most likely mediated via VWF [39
As increased plasma levels of VWF and Factor VIII are associated with greater risk of thrombosis [40
], many studies have examined the connection between ABO blood group and thrombotic risk. In a GWAS published in 2009, SNPs rs8176750, rs8176746 and rs8176719, which tag the A2, B, and O ABO blood groups, respectively, showed that genetically inferred blood type O had 67% lower risk of VTE than non-O blood groups. Additionally, the A2 blood group had 47% lower risk of VTE when compared to the other non-O blood group phenotypes [32
]. Blood type A2 was also shown to be associated with lower VTE risk in a recently published GWAS involving 1,503 VTE patients in which rs8176704 was used to tag the A2 blood group [23
]. These data suggest that the decreased risk of VTE is a result of reduced H antigen glycosylation, as the A2 allele contains a 1061delC that results in the synthesis of an enzyme that has 30–50 fold less A transferase activity than the A1 allele product [42
]. Blood group genotypes may be more informative than blood group phenotypes in studying the association between blood groups and VTE since genotypes can distinguish between heterozygous and homozygous carriers of A, B, and O alleles and between A1 and A2 alleles [43
]. One GWAS found that the A11 allele, tagged by rs529565 and rs657152, and the B allele, tagged by rs8176749, were associated with 56% and 16% increased risk of VTE, respectively, when compared to the O11 allele. Moreover, when compared with carriers of the O1O1 diplotype, VTE risk was increased by 79% for the A11 diplotype, 82% for the B diplotype, and 170% for the AB diplotype carriers. Overall, non-O categories combined were associated with a 77% increased risk of VTE when compared to the O category [29
]. The effect of ABO genotype on thrombosis risk was also investigated in a case-control study of 471 patients and 471 controls of the Leiden Thrombophilia Study (LETS) which revealed that non-OO genotypes, except homozygous A2 and A2-O combinations, were associated with increased thrombotic risk when compared to OO genotypes. The relative thrombotic risk of AB genotypes and A1-combinations was increased by 90–110% when compared to OO genotypes and the relative thrombotic risk of the homozygous B genotype and B-O combinations was increased by 60% [45
The ABO locus has also been associated with arterial thrombosis in studies of MI. Our group reported that all 11 SNPs that exceeded genome-wide significance for MI in patients with established coronary atherosclerosis mapped to the ABO locus. The risk alleles at rs514659 (odds ratio 1.21; P = 7.62 × 10−9) and rs687289 (odds ratio 1.19; P = 7.75 × 10−9) were perfect tags for the loss of function ABO O blood group demonstrating that functional ABO glycotransferases conferred increased risk of MI. Further analysis found that rs514659 was associated with coronary artery diseases (CADs) when complicated by MI but not with CAD without MI, suggesting that the primary relationship of ABO to clinical CAD is through modulation of coronary thrombosis or plaque rupture in patients with established coronary atherosclerosis rather than through primary promotion of atherosclerosis per se.
The increase in MI risk for non-O blood type individuals has been suggested for some time through epidemiological studies, although there has been debate as to which ABO blood group phenotypes confer the largest increase in risk [8
]. Just recently, He et al. reported results of two large prospective studies of incident coronary heart disease (CHD) as well as a meta-analysis of all prospective data [50
]. The Nurses' Health Study (including 62,073 women ages 30 to 55 at baseline) and the Health Professionals Follow-up Study (including 27,428 men ages 40 to 75 at baseline) were followed up to 2006 and recorded 2,055 cases of CHD in the two cohorts. Individuals with self-reported non-O blood type had an age-adjusted hazard ratio (HR) of 1.09 (95% CI 1.03 to 1.17, P
= 0.005) for risk of developing CHD. Associations between blood type and CHD risk were not modified by age, physical activity, alcohol consumption, smoking status, or diabetes history. A meta-analysis of an additional six prior cohorts, for a combined total of 114,648 individuals and 5,741 CHD cases, also showed a significant pooled relative risk for CHD in patients with non-O blood type of 1.11 (95% CI 1.05 to 1.18, P
= 0.001). Among participants in the cohort, those with type O blood were significantly less likely to develop CHD when compared against types B (HR 1.11, 95% CI 1.01 to 1.23) and AB (HR 1.23, 95% CI 1.10 to 1.37), with a trend toward a higher risk for patients with type A blood (HR 1.05, 95% CI 0.98 to 1.13).
It is plausible that ABO modulation of VWF-related thrombosis accounts for the ABO association with MI. However, ABO antigens are expressed also on distinct platelet proteins, including GPIIb, a subunit of the fibrinogen receptor heterodimer [51
], and may therefore modulate specific platelet functions in arterial thrombosis and MI (see below). In addition, ABO modulation of atherosclerotic plaque rupture and atherosclerosis itself cannot be discounted without further study.