A positive family history is one of the strongest cardiovascular risk factor. However, an intensive search of the molecular mechanisms explaining the inherited predisposition of coronary artery disease (CAD) and myocardial infarction (MI) has remained largely elusive for more than two decades.
Initial attempts to unravel the genetics of MI were based on the prevalent understanding of the disease process. Candidate gene studies tested the hypothesis that proteins known to be involved in the pathogenesis of atherosclerosis carry mutations or variants that affect their function and ultimately the risk of developing CAD. However, despite over 5.000 publications on this topic, variants in only a limited number of genes mainly affecting LDL cholesterol (LDL-C) were convincingly shown to be associated with disease risk.
The scientific breakthrough for genetic studies of complex diseases like CAD and MI came with the availability of genome wide SNP arrays and subsequent genome-wide associations studies (GWAS).
Since 2007 several GWAS on CAD/MI have been published and today a total of 164 genetic risk loci for CAD/MI have been identified.
We have recently celebrated one decade of GWAS with a symposium in Lübeck.
For some of these CAD risk loci the underlying pathomechanisms have been identified in challenging studies.
For example, one of the first DNA variant which was identified by our group through GWAS on chromosome 1p13 increases the relative risk of coronary artery disease by 29% per allele. A few months later, the same genetic variant was also found — again through a genome wide association approach — to increase serum levels of low-density lipoprotein (LDL) cholesterol. At that time, little was known about the genes at the 1p13 locus, so the functional link between the DNA variant and the increase in LDL cholesterol and coronary risk was puzzling. Challenging basic research carried out by Musunuru et al. now sheds light on the underlying pathway and identified the C/EBP-sortilin 1 pathway as novel target for prevention and treatment of atherosclerosis. The discovery of this pathway provides an example of how genome wide association studies can initiate new biologic discoveries, leading to a better understanding of pathophysiology, which could ultimately translate into new approaches to treatment. All good reasons to undertake GWA studies.
Kessler et al. elucidated the molecular link between rs7692387, which tags the GUCY1A3 locus, and CAD risk; the lead SNP is located in an intronic region and modulates GUCY1A3 promoter activity, as shown by luciferase assays. Interestingly, the transcription factor ZEB1 binds preferentially to the non-risk allele, leading to increased GUCY1A3 expression, higher sGC levels and higher sGC activity upon stimulation with NO. In conjunction with mouse data, Kessler and colleagues subsequently linked augmented sGC expression to lower risk of CAD. Additionally, the importance of the pathway was confirmed by the fact that a loss-of-function mutation in GUCY1A3 caused premature CAD and MI in one of our extended families.