Genome-wide association studies in the past 5 years have identified multiple genetic risk variants predisposing to coronary artery disease.
In these studies, the phenotype has been either CAD defined as 50% obstruction of one or more vessels determined by coronary angiography (cardiac catheterization or multi-sliced CT) or MI. In all studies, the phenotype of CAD has been used interchangeably with that of MI. This is because MI is almost always caused by a thrombus superimposed on coronary atherosclerosis. Studies in our laboratory at University of Ottawa Heart Institute and studies conducted by others have shown that 9p21, the first genetic risk factor identified for CAD, is primarily a risk factor for atherosclerosis with little or no risk for MI.
Genetic risk variants and MI
After the formation of an international consortium — Coronary Artery Disease Genome-wide Replication and Meta-Analysis (CARDIoGRAM) — we performed a study headed by Muredach P. Reilly, MBBCH, MSCE, of the University of Pennsylvania, to search for genetic risk variants that predispose specifically to MI. Coronary atherosclerosis can progress to significant obstruction, but fatal MI usually results from a thrombus superimposed on atherosclerosis often induced by plaque rupture.
In CARDIoGRAM, a genome-wide association study (GWAS) was performed, genotyping with either the 500,000 or 1 million single-nucleotide polymorphism (SNP) array. The cases selected had documented CAD on coronary angiography with or without MI. Besides the direct genotyping, additional SNPs were imputed, for a total of 2.4 million. The GWAS was performed in two stages. In stage 1, a meta-analysis of six GWAS was performed, which included comparing the genotypes of patients with angiographic documented CAD and MI to those having CAD without MI. The sample size consisted of 4,572 patients with CAD and MI compared with 2,739 patients with CAD without MI — providing a total sample size of 7,311. Forty-nine DNA markers (SNPs) showed an association to patients with MI and angiographic CAD. These markers were taken forward for replication in stage 2, which included an independent population of 1,211 cases with CAD and MI and 905 cases with CAD without MI, for a total sample size of 2,116.
Meta-analysis of the combined groups (stages 1 and 2) showed genome-wide significance for several SNPs (P=7.6×10-9) in the region of 9q34.2. The markers showing an association with MI were all in the same region located at 9q34.2, the ABO blood group locus. Further analysis showed this locus was associated with increased risk for patients with MI and CAD; however, there was no risk associated with cases having CAD without MI. Furthermore, there was no association between this locus and known risk factors for CAD, indicating it mediates its risk independently of traditional risk factors for MI.
The final analysis showed that blood group A or B increases the risk for MI by approximately 20%. More than 50% of the population is either blood group A or B. In contrast, blood group O is not associated with any increased risk for MI.
Interpreting recent advances
The finding that blood group A or B was associated with an increased risk for MI agrees with historical epidemiological data of more than 5 decades. It has been claimed for some time that blood group O offered protection for MI compared with blood groups A or B. The locus for these blood groups at 9q34.2 is responsible for a single gene. The A, B and O are different forms of the same gene, which in proper nomenclature, A, B and O are referred to as alleles. The A and B genes encode for a protein (alpha 1-3N-acetylgalactosaminyltransferase), which transfers a carbohydrate moiety onto von Willebrand’s factor (vWF), which inhibits proteolysis. This leads to prolonged plasma half-life of vWF, predisposing to coronary thrombosis, which is presumably the cause of the MI. In contrast, the O gene encodes for a transferase protein that is mutated and, as a result, lacks the activity to transfer the carbohydrate moiety onto vWF. Thus, there is no increased risk for MI in those with blood group O.
This study provides a simple but illustrative example of MI triggered by thrombosis. Whether the thrombus associated with blood group A or B is triggered by plaque rupture remains to be determined. However, in this study, all of the patients who had MI also had CAD and, thus, the substrate for plaque rupture.
These findings, besides providing evidence that thrombosis induces MI, also have implications for prevention and treatment. Aspirin, an antiplatelet agent, is well established to prevent MI and death from CAD.
These data raise the hypothesis that aspirin would be appropriate preventive therapy in those who have blood group A or B, particularly if they also have other risk factors for CAD. This could be a significant health problem, considering that more than 50% of the population is group A or B.
Further studies are required to determine the frequency of thrombosis associated with blood group A or B. Furthermore, graft closure or stent thrombosis in patients undergoing these procedures may be more common in blood group A or B. Those with blood group A or B gene would be expected to benefit from an antiplatelet agent such as aspirin. Considering aspirin decreases MI and death in patients with CAD, it is a worthy public health problem to pursue for the future.
Robert Roberts, MD, is president and CEO of the University of Ottawa Heart Institute and director of the Ruddy Canadian Cardiovascular Genetics Centre at the University of Ottawa Heart Institute. He is also a member of the Cardiology Today Editorial Board. Brandon A. Roberts, MD, MSc, is a resident in internal medicine at Louisiana State University.
For more information:
- Preuss M. Circ Cardiovasc Genet. 2010;3:475-483.
- Reilly MP. Lancet. 2011;377:383-392.
Disclosure: Drs. Roberts and Roberts report no relevant financial disclosures.