Although the June 2000 New York Times headline, “Genetic Code of Human Life is Cracked by Scientists,” appeared to herald the arrival of the ‘genetic age,’ according to Eric J. Topol, MD, Scripps Translational Science Institute, La Jolla, CA, it has been the numerous and stunning breakthroughs in single nucleotide polymorphisms (SNP) in the last year that has ushered in the “age of the genome.” A SNP is a DNA sequence variation that occurs when a single nucleotide differs between members of a species in at least 1% of the population. SNPs are useful for comparing regions of the genome between cohorts with and without a particular disease.

The identification of SNPs has created a ‘genomic gold rush’ to discover associations between a disease process and SNP variants. Over 40 diseases have undergone genome-wide association studies (GWAS) to identify common genetic factors that influence health and disease. In a GWAS that was undertaken in the British population that examined approximately 2000 individuals for each of seven major diseases and a shared set of approximately 3000 controls, 24 independent association signals at P < 5 × 10^-7 were identified, including one in bipolar disorder, one in coronary artery disease, nine in Crohn's disease, three in rheumatoid arthritis, seven in type 1 diabetes, and three in type 2 diabetes [Wellcome Trust Case Control Consortium. Nature 2007].

Whole genome information, when combined with clinical and other phenotype data, offers the potential for increased understanding of basic biological processes that affect human health, improve risk prediction, disease prevention, and patient care. Ultimately, the realization of the promise of personalized medicine, which Dr. Topol believes will be readily available by the year 2015, would permit clinicians to deliver optimal therapies to their patients.

There are six diseases that have an extensive genomic definition: type 2 diabetes, Crohn's disease, breast cancer, age-related macular degeneration, prostate cancer, and systemic lupus erythematosus. Of particular interest to cardiologists, SNPs have been defined for myocardial infarction (MI), coronary artery disease (CAD), atrial fibrillation (AF), lipoprotein disorders, and hypercholesterolemia.

Two common sequence variants on chromosome 9p21, tagged by rs10757278-G and rs10811661-T, affect the risk of MI [Helgadottir A et al. Science 2007]. Approximately 21% of individuals in the population are homozygous for these variants, and their estimated risk of suffering an MI is 1.64 times as great as that of non-carriers. The same sequence variant on 9p21 that is associated with MI is also associated with abdominal aortic aneurysms and intracranial aneurysms [Helgadottir A et al. Nat Genet 2008]. However, to date there are no studies that show how these markers develop into the disease state.

Another recent GWAS has identified variants on chromosome 9p21.3 that affect the risk of CAD. The risk allele (C) of the lead SNP, rs1333049, was significantly associated with CAD (p<0.05). In a pooled analysis, the odds ratio per copy of the risk allele was 1.29 (95% CI, 1.22 to 1.37; p=0.0001). An autosomal-additive mode of inheritance best explained the underlying association [Schunkert H et al. Circulation 2008].

Two sequence variants on chromosome 4q25 that are adjacent to PITX2 (which has a critical function in left-right asymmetry of the heart) confer risk of A F. The association is inversely related to age. About 35% of individuals of European descent have at least one of the variants, and the risk of AF increases by 1.72 and 1.39 per copy [Gudbjartsson DF et al. Nature 2007]. Nine validated SNP variants on chromosome 1p13.3 have been associated with modulation in levels of LDL or HDL cholesterol, and the incorporation of them into a genotype score improved clinical risk reclassification in a cardiovascular cohort when added to standard clinical factors [Kathiresan S et al. N Engl J Med 2008; Sandhu MS et al. Lancet 2008].

Dr. Topol believes that this ‘treasure trove’ of genetically linked lipoprotein biology may lead to novel therapeutic interventions if a few caveats can be overcome. He cautioned that we are still working with incomplete coverage of the genome and that structural variants are complex and much larger than initially hypothesized [Korbel JO et al. Science 2007]. Structural variation of the genome involves kilobase- to megabase-sized deletions, duplications, insertions, inversions, and complex combinations of rearrangements. Epigenomics (processes that regulate how and when genes change) and epistasis (when the action of one gene is modified by one or more genes) are not completely understood and may impact the disease process in unpredictable ways. In many cases, the observed effects actually result from multiple SNPs that act in concert within a gene, and thus analysis of a few variants per gene is not likely to be sufficient to identify potential functional effects.

Nonetheless, the ‘age of the genome’ is truly upon us, with private companies beginning to offer genome “scans” that claim to have the ability to predict the risk of many types of diseases. Next to come will be a consumer genome movement and genetic home testing kits. The physician needs to be prepared for the day when patients begin showing up in their offices with individual SNP profiles asking for interpretation of their health risk factors. Dr. Topol's final comment was presented in a slide titled “The Resequencing Imperative”—“..when genome-wide resequencing is practical and affordable, it will be increasingly difficult for the genomic basis of health and disease to be left undetected.”