Genome-wide association studies have the potential to lead to identification of novel pathways and mechanisms for the pathogenesis of common complex diseases. Previous genome-wide association studies have identified a locus on 1p13 as a risk locus for dyslipidemia and myocardial infarction. However, the responsible mechanisms have remained elusive. Two recent reports implicate SORT1 as the causative gene underlying a human chromosome 1 LDL/coronary artery disease locus but come to opposite conclusions concerning SORTILIN-1’s role in the regulation of VLDL secretion.

Human genome wide association studies have had spectacular success in identifying single nucleotide polymorphisms (SNPs) in or near genes associated with variation in plasma lipid and lipoprotein levels. More than 100 loci have been found that account for a significant part of the genetic variation in triglyceride, low-density lipoprotein (LDL), and high-density lipoprotein cholesterol levels. 1 Many of these loci involve novel genes or regions. Genome-wide association studies of coronary artery disease or myocardial infarction have identified a smaller number of genetic loci, some of which are also associated with changes in traditional lipoprotein risk factors. 2, 3 A notable example has been a widely replicated chromosome 1p13 locus that has been associated with both myocardial infarction and LDL cholesterol levels and that does not contain a gene known to give rise to a Mendelian disorder affecting LDL cholesterol levels. The major alleles at this locus are present in about 65% to 80% of whites, and homozygosity for the major alleles, as opposed to homozygosity for the minor alleles, are associated with a 20% to 40% increase in the risk of myocardial infarction and up to 16 mg/dL higher LDL cholesterol levels. 3-5 The relevant SNPs are localized in a gene cluster containing 4 genes, CELSR2, PSRC1, MYBPHL, and SORT1. A recent study has shown that the SNPs most strongly associated with LDL levels are localized to an intergenic region between CELSR2 and PSRC1 and that the minor allele SNP with strongest association creates a functional C/EBPa binding site. 4 The