Genetics of ACS and recurrent MI/cardiac death: are we getting to the heart of the (atherosclerotic) matter?

Coronary artery disease (CAD) is still the most frequent cause of death in Western societies. It is now widely accepted that the classic environmental risk factors for atherosclerosis only partly explain the incidence of CAD and the development of acute coronary syndromes (ACS). Genetic factors that vary among human populations seem to be involved in the clinical manifestations of such patients. Substantial data already showed that genetic variation is likely to influence CAD both directly and through effects on known CAD risk factors, such as hypertension and diabetes. Despite extensive research efforts for more than a decade, the genetic basis of CAD remains largely unknown. Although there have been notable successes, linkage and candidate gene association studies have often failed to deliver definitive results. However, advances are now being made through the application of large-scale, systematic, genome-wide approaches. Due to the HapMap resource, which documents patterns of genome-wide variation and linkage disequilibrium (LD), association studies are being facilitated in terms of both the design and the analysis. Furthermore the availability of dense genotyping chips make it possible that genome-wide association studies are technically and financially possible. In this way genetics can serve as new risk targets and help to stratify patients at risk for CAD. Figure 1 shows the role of genetic testing. Moreover, recently it has been shown that genetic testing is not only useful in disease genetics, but nowadays studies also concentrate on the role of pharmacogenetics. Pharmacogenetics is the search for genetic polymorphisms that affect responses to drug therapy. Since the individual response to specific drugs is also to a large extent inherited, it can therefore have implications for individual drug therapy. Recent findings have particularly highlighted the link between CAD and inflammation and immunity. In particular, a common variant on chromosome 9p21 was recently identified as affecting the risk of myocardial infarction (MI). At least four genome-wide association studies identified chromosome 9p21 as a major locus for risk of CAD or MI. Still little is known about the function of this locus. This region contains the coding sequences of genes for two cyclin-dependent kinase inhibitors, CDKN2A (encoding p16INK4a) and CDKN2B (encoding p15INK4b). Both genes have multiple isoforms, have an important role in the regulation of the cell cycle and are widely expressed, with CDKN2B known to be expressed in the macrophages but not the smooth muscle cells of fibrofatty lesions. The expression of CKDN2B is induced by transforming growth factor-b (TGF-b). The only other known gene nearby is MTAP, which encodes methylthioadenosine phosphorylase, an enzyme that contributes to polyamine metabolism and is important for the salvage of both adenine and methionine. Further research to examine the exact function of this gene is already being performed. Besides its unknown function, it is also not known whether the 9p21 locus confers a risk for recurrent MI or cardiac death. Therefore, Buysschaert et al. investigated, in the Global Registry of Acute Coronary Events (GRACE) programme, which is a large, prospective multinational observational study of patients hospitalized with ACS, if this locus is also associated with recurrent MI and the combined endpoint consisting of recurrent MI or cardiac death after an ACS within the first 6 months following hospitalization. Another goal of their study was to confirm in different populations with ACS that the rs133049 variant on chromosome 9p21 is associated with the risk of ACS. It is primarily a validation study and does not describe a novel discovery; nevertheless, it is a worthwhile and thorough study. It consists of a large population (3473 patients from eight participating centres in three countries). Patients with a clinical diagnosis of