We identified two loci for distinct CAD phenotypes, ADAMTS7, a novel locus for angiographic CAD but not myocardial infarction, and ABO, a gene for myocardial infarction in patients with angiographic CAD, but not for angiographic CAD itself. Further, our data suggest that the ABO GWAS signal for myocardial infarction in patients with angiographic CAD is mediated by the glycotransferase-deficient isoform that encodes the ABO blood group O phenotype.
Clinical CAD phenotypes are heritable but highly complex. The association of several published loci for myocardial infarction5
might be mediated by diverse pathological processes including those that promote atherosclerosis, precipitate plaque rupture, or facilitate arterial thrombosis. Our use of coronary angiography reduced heterogeneity in coronary atherosclerosis within patients with CAD while allowing discrimination of risk alleles for plaque rupture or myocardial infarction from those for atherosclerosis. Although most published loci for myocardial infarction had significant signals for angiographic CAD compared with controls, none were associated with myocardial infarction in patients with angiographic CAD. This finding suggests that these loci relate to myocardial infarction indirectly via coronary atherosclerosis rather than having a specific role in vulnerable plaque and myocardial infarction. In fact, independent studies support this concept for the 9p21 locus. Consistent with our data, Horne and colleagues12
showed that this locus did not predict incident or prevalent myocardial infarction in patients with CAD but was strongly associated with the presence of angiographic CAD versus controls.
Our discovery of ADAMTS7
as a novel locus for CAD might have been facilitated by use of coronary angiography because, unlike clinically defined cases, the definition of angiographic CAD required a pre-specified burden of coronary atherosclerosis. All ADAMTS
genes have a similar domain structure, consisting of a preproregion, a reprolysin-type catalytic domain, a disintegrin-like domain, a thrombospondin type-1 module, a cysteine-rich domain, a spacer domain, and a COOH-terminal thrombospondin type-1 module. ADAMTS7 degrades cartilage oligomeric matrix protein and has been implicated in inflammatory arthritis and bone growth. Overexpression of ADAMTS7 accelerates migration of vascular smooth muscle cells in vitro and exacerbates neointimal thickening after carotid artery injury in vivo, perhaps through degradation of cartilage oligomeric matrix protein.27
These data implicate ADAMTS7 in the proliferative response to vascular injury, a process that has parallels to the progressive phase of atherosclerosis.7
These mechanistic findings coincide with the lack of association of ADAMTS7
SNPs with early-onset myocardial infarction. Together they raise the provocative possibility that some proteins, such as ADAMTS7, could increase plaque size but not affect plaque stability. Overall, ADAMTS7
might be a novel therapeutic target for progression of atherosclerosis but seems less likely to be one for prevention of myocardial infarction in high-risk patients.
Discovery of ABO
as the top locus for myocardial infarction in patients with angiographic CAD is notable, in view of decades of work suggesting a relation between ABO blood groups and both thrombosis and coronary heart disease.28,29
gene encodes proteins (transferase A, a 1-3-N-acetylgalactosaminyltransferase; transferase B, a 1-3-galactosyltransferase) related to the ABO blood group system.30
Blood group O is caused by a deletion of guanine-258 near the N-terminus of the protein. This deletion causes a frameshift, which results in translation of a protein with no glycosyltransferase activity.30
In a meta-analysis,29
Wu and colleagues reported ORs for non-O relative to the O blood group of 1·79 (1·56–2·05) for venous thrombo embolism, 1·25 (1·14–1·36) for myocardial infarction, but only 1·03 (0·89–1·19) for angina.29
Ketch and colleagues31
reported that patients with non-O blood groups had higher thrombus burden despite less extensive coronary atherosclerosis at the time of acute myocardial infarction. These data, coupled with our genetic findings, strongly suggest a primary relation of non-O ABO glycotransferase activity with coronary thrombosis rather than atherosclerosis. ABO-related thrombosis is thought to be mediated by ABO carbohydrate-modification of von Willebrand Factor (VWF) resulting in impaired proteolysis and higher circulating von Willebrand Factor and Factor VIII.32
Tregouet and co-workers identified ABO
as the most significant locus in a GWAS of venous thrombo-embolism.33
The top ABO
SNPs for venous thromboembolism, rs657152 and rs505922, have strong associations with myocardial infarction in patients with angiographic CAD in our data (eg, rs505922 p=1·032×10−8
) and are in strong linkage disequilibrium with our top ABO
SNP signals for myocardial infarction (eg, r2
1·0 with rs514659 (, , webappendix
p 6). We note that the top SNPs (rs687621 and rs687289) in a GWAS34
of plasma von Willebrand Factor and Factor VIII are in complete linkage disequilibrium with rs514659 and blood group O and also reach genome-wide significance for myocardial infarction in patients with angiographic CAD (). Thus, common ABO
genetic variation, linked to blood group O, reduced glycotransferase activity and lower circulating von Willebrand Factor and Factor VIII, lowers risk of myocardial infarction in the setting of angiographic CAD, while also protecting against venous thromboembolism.
The relation between ABO
and atherosclerotic cardiovascular disease, however, might be more complex than modulation of thrombosis. Other GWAS also identified ABO
as a locus for low-density lipoprotein (LDL-C),35
inflammatory risk biomarkers E-selectin, P-selectin, and sol-ICAM126,36–38
as well as angiotensin-converting enzyme39
(). Indeed, ABO blood group associations with plasma cholesterol were described several decades ago. In PennCath, however, ABO
SNP associations with myocardial infarction in patients with angiographic CAD were not attenuated by adjustment for ABO
SNPs related to LDL-C, ICAM-1, and E-selectin (webappendix
p 6). Taken together, these factors suggest that ABO
might modulate various distinct pathways related to cardiovascular risk factors, atherosclerosis, and thrombosis.
Our study has potential limitations. The multistudy design might have introduced selection bias and confounding. The absence of genomic control inflation, however, argues against confounding caused by genetic differences in source populations. Angiography cannot detect early subclinical atherosclerosis in controls resulting in misclassification of controls as free of CAD. Misclassification is potentially a greater drawback in our study within patients with angiographic CAD, in which those without myocardial infarction might subsequently develop myocardial infarction. Patients with angiographic CAD who had myocardial infarction, however, tended to be younger than those who did not have myocardial infarction, despite having broadly similar risk factors. This finding suggests that additional factors beyond age and traditional risk must contribute to myocardial infarction among patients with angiographic CAD. Overall, heterogeneity and misclassification would tend to bias to wards the null, would not affect our novel findings, but would limit the power for additional discoveries.
Our results indicate that specific genetic variants predispose to the development of coronary atherosclerosis whereas others predispose to subsequent plaque rupture and acute myocardial infarction. Further, many published loci for myocardial infarction are likely to relate to the initiation and progression of coronary atherosclerosis rather than having a specific role in vulnerable plaque and myocardial infarction. Translation of GWAS discoveries for CAD into prognostic and therapeutic benefit will need greater insights into the relation between each locus and the phenotypes of atherosclerosis, plaque rupture, and thrombosis.