Two chromosome 9p21 haplotype blocks distinguish between coronary artery disease and myocardial infarction risk

Area of Science:

• Genetics
• Cardiovascular Disease Biology

Background:

• The 9p21 genetic locus is associated with coronary artery disease (CAD) and myocardial infarction (MI) risk.
• Atherosclerotic plaque deposition and MI (plaque rupture/thrombosis) are distinct clinical events.
• Previous studies found no direct link between 9p21 variants and MI in patients already diagnosed with CAD.

Purpose of the Study:

• To investigate whether distinct haplotype blocks at the 9p21 locus differentially predict atherosclerosis and MI.
• To differentiate the roles of 9p21 variants in plaque formation versus plaque rupture events.

Main Methods:

• Haplotype analysis was performed using 24 single-nucleotide polymorphisms (SNPs) in white patients without diabetes.
• Case group: 2352 patients with angiographically confirmed CAD/MI (≥1 stenosis >50%).
• Control group: 2116 asymptomatic individuals over 60 years old. Regression models assessed associations between haplotypes and CAD onset, severity, and MI history.

Main Results:

• Haplotypes in one block (rs1333049) associated with CAD, earlier onset (β=-0.13, P=1.37×10⁻⁴), and greater disease severity (β=0.1823, P=0.006), but not prevalent MI in CAD patients.
• Haplotypes in another block (rs518394) associated with prevalent MI (β=0.239, P=2.05×10⁻⁴) and were inversely linked to disease severity (β=-0.196, P=0.003).
• The MI association for rs518394 haplotypes was replicated in an independent cohort (n=1385, β=0.207, P=0.019).

Conclusions:

• Two distinct haplotype blocks at 9p21 have differential genetic effects.
• One block's variants predispose to the development of atherosclerosis.
• The other block's variants specifically predispose to myocardial infarction in individuals with pre-existing CAD.