Genetic variant predisposes to CAD

Issue: November 2013

ByRobert Roberts, MD, FRSC, FRCPC, MACC, LLD (Hon.), FAHA

ByBrandon A. Roberts, MSc, MD

ByWilliam L. Roberts, MHA, CPA

ByCalvin W. Roberts, MD

In a large genome-wide association study, a genetic variant predisposing to CAD was identified on the short arm of chromosome 6 (6p21.3).

Common genetic risk variant identified

This study utilized as its discovery population 13,949 patients phenotyped to determine whether they qualified as cases or controls. The patients described as cases (n=7,123) were those who had either coronary angiography with obstruction of ≥50% in one or more coronary vessels or a documented MI. The patients described as controls were asymptomatic elderly individuals (n=6,826; men older than 65 years; women older than 70 years) without MI, and if coronary angiography were performed coronary obstruction was required to be <50% in all vessels. The population was genotyped with more than 5 million single nucleotide polymorphisms (SNPs), for which the SNPs serve as DNA markers. The overall analysis compared the frequency of each SNP in cases and controls, and those SNPs significantly more common in cases are regarded as markers reflecting a DNA region carrying a genetic risk for CAD. Since initial genotyping is performed with nearly 1 million SNPs, the P value for significance in genome-wide association studies (GWAS) is conventionally recognized as P≤5 x 10-8 (arbitrarily referred to as genome-wide significant).

Robert Roberts

The results of the initial discovery population confirmed 16 genetic risk variants previously identified to be associated with increased risk for CAD and 21 novel SNPs. The novel SNPs were taken forward for potential replication in an independent population of 11,302 individuals (n=5,211 cases; n=5,828 controls). Replication in an independent population is a prerequisite to confirm genetic risk variants identified in the discovery population. Replication showed a novel risk variant associated with increased risk of CAD with a P value of ≤1.12 x 10-9, which is genome-wide significant. The SNP is located on the small arm of chromosome 6 (6p21.3).

This is a common genetic risk variant occurring in 55% of the population (OR=1.16). The 6p21.3 chromosomal region is very intriguing as it contains the major histocompatibility complex (MHC) genes. However, genotyping for the HLA, HLC genes did not improve the strength of the association over that of the marker SNP. This would indicate that no HLA gene per se is responsible for the association with CAD.

Impetus for further research

This is the first study to show definitively that a polymorphism in the DNA region containing the MHC genes is associated with increased risk for CAD. This could have profound implications for the pathogenesis of atherosclerosis. It has been known for some time that atherosclerosis represents an inflammatory response to oxidized cholesterol after penetrating the endothelial membrane. The MHC cluster of genes is associated with several autoimmune diseases such as lupus and rheumatoid arthritis. The MHC genes are associated with innate and adaptive immune processes. This finding of 6p21.3 provides the impetus to pursue the positive SNP associated with CAD and define the molecular pathways by which inflammation contributes to the pathogenesis of atherosclerosis or MI.

Discovery of this genetic risk variant in the MHC region further supports a direct role for inflammation in atherosclerosis.

Davies RW. Circ Cardiovasc Genet. 2012;5:217-225.

Robert Roberts, MD, FRCPC, MACC, is president and CEO of the University of Ottawa Heart Institute. He is also professor of medicine at the University of Ottawa and director of the Ruddy Canadian Cardiovascular Genetics Centre. He can be reached at 40 Ruskin St., Ottawa, Ontario, Canada, K1Y 4W7; email: rroberts@ottawaheart.ca.

Disclosure: Roberts reports no relevant financial disclosures.