Is CDKN2B-AS1 rs10757278 GG linked to higher coronary artery disease risk?

The 9p21.3 locus is a critical regulatory hub linking genetic variation directly to vascular pathology and clinical cardiovascular events.

Mechanistic pathways of the 9p21 locus

• Transcription factor disruption: The homozygous risk (GG) genotype of the rs10757278 variant, located within the long non-coding RNA CDKN2B-AS1 (ANRIL) region, disrupts a STAT1 transcription factor binding site in an inflammatory-responsive enhancer.
• Loss of negative feedback: This disruption prevents interferon-gamma-induced STAT1 binding, halting normal suppression of CDKN2B-AS1. This shifts splicing away from protective circular forms (circANRIL) and toward pro-atherogenic linear ANRIL isoforms.
• Epigenetic silencing: ANRIL acts as an epigenetic scaffold to recruit Polycomb Repressive Complexes (PRC1 and PRC2), which silence the adjacent tumor suppressor genes CDKN2A (encoding $\text{p16}^{\text{INK4a}}$) and CDKN2B (encoding $\text{p15}^{\text{INK4b}}$).

Vascular cell-cycle and aging phenotypes

• Cell-cycle dysregulation: Because CDKN2A and CDKN2B are cyclin-dependent kinase inhibitors that control the $\text{G}_1$/S transition, their silencing promotes abnormal vascular smooth muscle cell (VSMC) proliferation and impairs macrophage reverse cholesterol transport.
• Accelerated vascular aging: Alterations in this axis elevate $\text{p16}$ and $\text{p15}$ expression to trigger cellular senescence in vascular tissue. The accumulation of these senescent cells leads to arterial stiffness, plaque instability, and compromised vascular repair.

Clinical coronary artery disease risk

• Plaque vulnerability: The combination of VSMC proliferation and impaired cholesterol transport accelerates lipid-rich plaque formation while reducing structural plaque stability.
• Elevated clinical risk: Carrying the rs10757278 GG genotype roughly doubles the odds of developing coronary artery disease (CAD) or acute coronary syndrome (OR ~1.9–2.5). Large-scale meta-analyses show a log-additive relative risk of approximately 1.6- to 1.7-fold compared to non-carriers.

Bottom line

• The CDKN2B-AS1 rs10757278 GG variant is a major driver of coronary artery disease. It disrupts STAT1 binding to dysregulate ANRIL and epigenetically silence CDKN2A and CDKN2B, accelerating vascular cell-cycle dysfunction, cellular senescence, and plaque accumulation.