The 9p21 Story


February 13, 2008

On January 6, 2008, Nature Genetics published online a very important study on cardiovascular genomics by Helgadottir and colleagues.[1] This study addressed two 9p21 markers which previously had been shown by these DeCode investigators and many other groups to be associated with myocardial infarction (MI)/coronary artery disease[2,3,4,5] and type 2 diabetes mellitus, respectively.[6,7,8] In May 2007, the clustering of these distinct diseases to markers in the genome less than 10,000 base pairs away was particularly striking and was labeled as possibly representing the "seat of the soul of the genome."[9]

The purpose of the current study was to determine whether the 9p21 variants were associated with both MI and diabetes mellitus. In a very creative move to extend the findings, the study authors assessed the single nucleotide polymorphism (SNP) variants for any relationship with other forms of vascular disease: abdominal aortic aneurysm (AAA), intracranial aneurysm, peripheral artery disease, and "large artery disease," loosely defining cerebrovascular disease.

The results were both striking and important.[1] The 2 SNP variants, neither of which are located in a gene, are in 2 distinct linkage disequilibrium bins separated by a recombination hot spot. The salient findings were 2-fold: (1) The MI and diabetes SNPs did not cosegregate; they were separate and distinct even though they were proximally located; and (2) the MI SNP was also associated with AAA and intracranial aneurysm, representing a marked extension from atherosclerotic coronary artery disease to a vascular phenotype not even associated with atherosclerosis: intracranial aneurysm.

Previously, the odds ratio of the 9p21 variant for MI and coronary artery disease was approximately 1.3 for heterozygotes.[2,3] The odds ratio in this study for both AAA and intracranial aneurysm in heterozygotes with the variant was similarly about 1.3, indicating consistent magnitude of risk across these varied vascular phenotypes.[1] The AAA risk was only for the presence and not for progression or rupture of the aneurysm. The odds ratios for peripheral arterial disease and the surrogate for cerebrovascular disease among heterozygotes were 1.14 and 1.15, respectively, and were lower and became statistically nonsignificant when patients with known coronary artery disease were excluded. Although the other atherosclerotic phenotypes were not statistically significant in the current study, it is hard to find a biological explanation for why only the coronary arteries and abdominal aortic aneurysm would be linked without invoking other arterial beds.

The most important implication of the study is that the 9p21 variants are associated with multiple vascular phenotypes, all of which are life-threatening (MI, AAA, intracranial aneurysm), and that the link extends beyond just the process of atherosclerosis. We still do not have any idea of how these SNPs, which simply tag a bin of the genome, are exerting their effects at the mechanistic level, particularly because the SNPs reside outside of any gene. Thus, there is considerable work to do. In the meantime, a controversy has been engendered. Should individuals now be genomically screened for 9p21 SNPs for assessment of risk for AAA or intracranial aneurysm, which, until now, has not been possible?

With approximately 21% of individuals of European ancestry homozygous for the 9p21 vascular SNP,[2] the population's attributable risk for multiple serious diseases is exceptionally high. It would be premature to recommend 9p21 screening and follow-up imaging of the aorta and intracerebral circulation. Specific studies to validate such a strategy would be necessary in regard to preventing such fatal or serious vascular events. Nonetheless, it is exciting to think that genomics could eventually be used to indicate risk of developing critical vascular conditions that we cannot otherwise predict.


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