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CARDIoGRAM: A genetic landfall for CAD
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The year 2011 should go down in history as a genetic landfall for coronary artery disease.
In the past few months, more than 20 new genetic variants predisposing to CAD have been identified. Several investigators have postulated that the prevention of CAD may be accomplished in this century. Epidemiologists have presented evidence for several decades that genetic predisposition accounts for about 50% of risk for CAD. In premature CAD, evidence is overwhelming that genetic predisposition is the major risk component. For the genetics of rare single-gene disorders (occurring in <1% of the population), the past 2 decades have been a golden era, yielding the identification of more than 2,000 genes.
Early mapping for CAD risks
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Chromosomal mapping of the location of genes responsible for single-gene disorders is possible through genotyping of affected pedigrees with a few hundred DNA markers, followed by linkage analysis and identification of the genes through positional cloning. Although our knowledge of these disorders such as hypertrophic cardiomyopathy has been markedly enriched, common disorders such as CAD had to await the development of new technology. Common disorders — unlike rare single-gene disorders — are due to multiple genes, each expected to contribute only a small portion of the total risk. Another way of thinking of genetic risk for diseases, such as CAD or diabetes, is to assume that the total genetic risk depends on the number of predisposing genes one inherits for that disease. However, to map the location of these diseases requires hundreds of thousands of DNA markers and high throughput platforms comparing thousands of cases to controls rather than families. Most of the genetic variants predisposing to disease are believed due to single nucleotide polymorphisms (SNPs), which occur every 1,000 bps throughout the genome, for a total of 3 million SNPs per individual. These SNPs, besides predisposing to disease, are also responsible for most of the human variations such as in height or hair color.
The technology to pursue common disorders became available in 2005 with the development of microarrays with hundreds of thousands of SNPs as DNA markers. Utilizing this microarray and high throughput platform, the Ottawa Heart Genomics Study performed a genome-wide association study (GWAS). Cases of CAD (<55 years for males; <65 years for females) were defined on the basis of >50% coronary obstruction in one or more vessels. Controls were selected from healthy elderly individuals (>65 years for males; >70 years for females). In collaboration with investigators in Dallas, Houston and Denmark, the first genetic variant predisposing to CAD was identified on the short arm of chromosome 9, referred to as 9p21. In the same issue of Science, independently and simultaneously, the Icelandic group (DeCode) identified 9p21 as a risk variant using the phenotype of MI as a surrogate for CAD. The 9p21 region has a risk variant for CAD that was soon confirmed across the world to be a risk factor not just in Caucasians but all ethnic groups, except African Americans. The 9p21 variant, when present as two copies, increases risk by approximately 50% (and as one copy by 25%). It is very common, occurring in 75% of the population.
The CARDIoGRAM consortium
The GWAS launched a new era in the search for genetic variants predisposing to common diseases. Between 2007 and 2010, eleven new variants predisposing to CAD were mapped and confirmed in several large GWAS. It was now evident that most diseases would be associated with many genetic variants having small effects. This would require even larger discovery and replication samples sizes than previously expected. This led to the formation of an international consortium of GWAS dedicated to genes predisposing to CAD. The consortium took the acronym of CARDIoGRAM (Coronary Artery Disease Genome-wide Replication And Meta Analysis). The formation of the consortium was spearheaded by Nilesh Samani, MD, of Leicester, UK, and Heribert Schunkert, MD, of Lübeck, Germany, consisting of 14 groups spanning North America and Europe with GWAS data for CAD. The project was overseen by an executive committee, steering committee and various working subcommittees, and was coordinated through weekly telephone conferences and daily emails.
The combined effort had a discovery sample size of 22,233 cases and a control sample size of 64,762 (with a replication sample size of 56,682). It is a mammoth project that, for cardiology, is arguably comparable to the Human Genome Project. The total cost for recruiting the participant phenotyping, genotyping and analysis borne by each of the institutions and collaborating groups must have run into hundreds of millions of dollars. This is reflected in the more than 100 authors contributing to the publication of the study, all of whom contributed in a major way to the success of this project.
Results and implications
The results have been spectacular, as 13 novel genetic variants were identified, along with the confirmation of 10 variants previously published, for a total of 23 variants predisposing to CAD. The novel genetic variants are shown in Table 1 and the confirmed previously published variants in Table 2.
Several features are notable about the genetic variants for CAD. The frequency of the variants in the population varies from 13% to 91%. The RR varies from 6% to 17%. The OR for early-onset was much higher than that seen for late-onset CAD. There was no difference in the OR between males and females. The maximum number of variants per individual with 23 variants would be 46, and we observed a minimal number of 15 and a maximum number of 37 per individual. A mean weighted risk score was significantly higher for cases than controls (P<10-20). The top 10th percentile or lowest 10th percentile of the weighted risk score was associated with ORs for CAD of 1.88 and 0.55, respectively, compared with the 50th percentile.
This study has doubled the number of genetic variants associated with increased risk for CAD. The other major finding was that of the 23 variants, only six act through known risk factors. This has tremendous implications for the understanding of the pathogenesis of CAD, and more importantly, its prevention and treatment. These genetic risk factors, not previously suspected, provide both the road map and the impetus to explore these DNA regions and discover the molecular networks through which they contribute to the pathogenesis of CAD and its sequelae. The search for such molecular pathways is the beginning of a new and exciting era in the pathogenesis of CAD. The molecular systems or pathways through which these genetic variants act will serve undoubtedly, in some instances, provide targets for new therapy. It is self-evident that future screening will have to incorporate this new knowledge if they hope to provide comprehensive prevention. These new genetic risk factors provide well-founded hope for development of new therapies. The postulate of preventing CAD in this century could be a reality.
For more information:
- McPherson R. Science. 2007;316:1488-1491.
- Schunkert H. Nat Genet. 2011;43:333-338.
Robert Roberts, MD, is the 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.