Progress in unraveling the genetics of coronary artery disease and myocardial infarction.

Atherosclerosis is a leading cause of morbidity and mortality. Coronary artery disease (CAD) and its clinical manifestation, myocardial infarction (MI), are equally determined by interacting environmental and (largely unknown) multigenic factors. Genome-wide and candidate gene searches for single nucleotide polymorphism (SNP) associations with CAD/MI (ie, coronary heart disease) often have resulted in nonreproducible or weak associations. Associations with intermediate surrogates have not ensured clinical event predictions. Linked SNP groups (haplotypes) can be more informative than individual SNPs unless the functional gene variant is known with certainty. Recent results of genetic association studies challenge the "common disease-common variant" hypothesis and suggest that multiple, relatively uncommon alleles often determine variation in coronary risk factors (eg, low high-density lipoprotein). Genetic risk scores, generated by considering several functional SNPs or haplotypes in multiple genes within a biologic pathway implicated in coronary heart disease, could improve predictive ability. Despite the complexity of coronary heart disease genetics, steady progress can be expected.