3 This accords with other data, indicating that the genetic influence is the greatest for early-onset CAD events. Of note, heritable effects are most manifest in younger individuals. 2 The Swedish Twin registry reported on close to 21 000 subjects followed up for >35 years and calculated the heritability of fatal CAD events to be 0.57 and 0.38, for men and women, respectively. In the Framingham Offspring Study, the age-specific incidence of CAD increased by >2-fold after adjustment for conventional CAD risk factors in participants with a family history of premature disease. The heritability of CAD has been estimated between 40% and 60%, on the basis of family and twin studies, a method that yields high precision despite potential bias (Vinkhuyzen et al 1). Despite this success, there has been limited progress in understanding the function of the novel loci the majority of which are in noncoding regions of the genome.Ĭoronary artery disease (CAD) has important genetic underpinnings considered equivalent to that of environmental factors. Overall, recent studies have led to a broader understanding of the genetic architecture of CAD and demonstrate that it largely derives from the cumulative effect of multiple common risk alleles individually of small effect size rather than rare variants with large effects on CAD risk. In contrast to genome-wide association studies, whole-exome sequencing has provided valuable information directly relevant to genes with known roles in plasma lipoprotein metabolism but has, thus far, failed to identify other rare coding variants linked to CAD. Such information also has important applications in clinical medicine and drug discovery by using a Mendelian randomization approach to interrogate the causal nature of many factors found to associate with CAD risk in epidemiological studies. These data have been used successfully to create genetic risk scores that can improve risk prediction beyond conventional risk factors and identify those individuals who will benefit most from statin therapy. Furthermore, a total of 202 independent signals in 109 loci have achieved a false discovery rate ( q<0.05) and together explain 28% of the estimated heritability of CAD. close to 60 common SNPs (minor allele frequency>0.05) associated with CAD risk and reaching genome-wide significance ( P<5×10 −8) have been identified.

The tools applied include genome-wide association studies encompassing >200 000 individuals complemented by bioinformatic approaches, including 1000 Genomes imputation, expression quantitative trait locus analyses, and interrogation of Encyclopedia of DNA Elements, Roadmap, and other data sets. Genetic factors contribute importantly to the risk of coronary artery disease (CAD), and in the past decade, there has been major progress in this area.

Customer Service and Ordering Information.Stroke: Vascular and Interventional Neurology.Journal of the American Heart Association (JAHA).Circ: Cardiovascular Quality & Outcomes.Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB).

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