Is the rs10757278 GG genotype at the CDKN2B-AS1/ANRIL locus linked to vascular aging?

The 9p21.3 locus is a major genetic contributor to cardiovascular pathology. Specifically, the rs10757278 GG risk genotype within the long non-coding RNA ANRIL (CDKN2B-AS1) plays a direct, causative role in driving vascular aging.

Mechanistic pathway

• Transcription factor disruption: The rs10757278 GG risk genotype directly disrupts a critical STAT1 transcription factor binding site within the 9p21 enhancer region.
• Splicing alteration: This disruption alters the transcriptional splicing landscape of ANRIL, shifting the expression balance away from long, protective isoforms and toward shorter, pathogenic splice variants.
• Epigenetic dysregulation: Because ANRIL acts as an epigenetic scaffold that recruits chromatin-modifying complexes (including Polycomb complexes, WDR5, and HDAC3), these isoform shifts alter the epigenetic silencing and transcriptional expression of the neighboring tumor suppressor genes, CDKN2A (p16/INK4a) and CDKN2B (p15/INK4b).

Cellular and vascular aging phenotypes

• Senescence checkpoint activation: Altered expression of CDKN2A and CDKN2B triggers the activation of cellular senescence checkpoint pathways.
• Phenotypic switching: Genotype-mediated downregulation of protective ANRIL isoforms drives vascular smooth muscle cells (VSMCs) to undergo a synthetic, osteochondrogenic phenotypic shift.
• Vascular remodeling: This osteochondrogenic switching and localized cellular senescence in endothelial cells and VSMCs promote arterial calcification, carotid plaque formation, and adverse vascular remodeling, which manifest clinically as advanced vascular aging.

Bottom line

• The rs10757278 GG genotype drives vascular aging by disrupting STAT1 binding and altering ANRIL splicing, which epigenetically deregulates CDKN2A/CDKN2B senescence checkpoints to promote pro-atherogenic, osteochondrogenic vascular remodeling.