Advances in the genetic basis of coronary artery disease

Abstract

Exciting advances have been made recently in genetic studies of coronary artery disease (CAD), myocardial infarction (MI), and ischemic stroke. One disease-causing gene for CAD and MI has been identified as MEF2A, which is located on chromosome 15q26.3 and encodes a transcriptional factor with a high level of expression in coronary endothelium. Approximately 1% to 2% of CAD patients may carry an MEF2A mutation. Four new susceptibility genes have been identified using genome-wide association studies or genome-wide linkage studies: LTA (encoding cytokine lymphotoxin-alpha) on 6p21.3 for MI; LGALS2 (encoding galectin-2, an LTA-interacting protein) on 22q12-q13 for MI; ALOX5AP (encoding 5-lipoxygenase activating protein involved in synthesizing potent pro-inflammatory leukotrienes) on 13q12-13 for MI and stroke; and PDE4D (encoding phosphodiesterase 4D) on 5q12 for ischemic stroke. These studies identify a new mechanism, the myocyte enhancer factor 2 (MEF2) signaling pathway of vascular endothelium, for the pathogenesis of CAD, and also confirm the role of inflammation in the disease process.

Figure 1

Identification of the first gene, MEF2A, for autosomal dominant coronary artery disease (CAD) and myocardial infarction (MI) on chromosome 15q26.3 (adCAD1). The locations of mutations that cause CAD and MI are shown. A, Ideogram of chromosome 15 showing the location of adCAD1 and MEF2A. B, Domain structure of transcriptional factor MEF2A. (MADS—MCM1, agamous, deficiens, serum response factor; NLS—nuclear localization site.) (Adapted from Wang et al. [3••] and Bhagavatula et al. [16••]; with permission.)

Figure 2

Diagram of the 5-lipoxygenase (5-LO) pathway for biosynthesis of the proinflmamatory leukotrienes (LT) LTA4, LTB4, LTC4, LTD4, and LTE4. (AA—arachidonic acid; BLT1—high-affinity receptor for LTB4; BLT2—low-affinity receptor for LTB4; cPLA2—cytosolic phospholipase A2; CysLT— cysteinyl leukotrienes; FLAP—5-lipoxygenase-activating protein; Hydrolase—LTA4 hydrolase; Transferase—γ-glutamyl transferase; SMC—smooth muscle cell.)