Is the chromosome 9p21 rs10757278 GG genotype associated with higher coronary artery disease risk?

Chromosome 9p21.3 is among the most reproducible inherited CAD-susceptibility loci. For a 57-year-old man, rs10757278 GG indicates increased relative susceptibility, but does not determine whether CAD will occur and should be interpreted alongside conventional risk factors and baseline risk.

Clinical association

• GG homozygosity is supported as a marker of higher CAD risk. Adjusted studies reported odds ratios of 2.08 (95% CI 1.19–3.66) for Polish premature CAD, 3.05 (1.09–8.57) for Chinese early-onset CAD, and 1.91 (1.35–2.68) for Chinese angiography-defined acute coronary syndrome.
• Consistent directional evidence comes from meta-analytic G-allele data: per-G-allele CAD OR approximately 1.36 (95% CI 1.27–1.45). The apparent GG effect varies with ancestry, disease definition, reference genotype, and covariate adjustment.

Vascular-remodeling mechanisms

• The locus is noncoding and tags a 9p21 risk haplotype rather than proving that rs10757278 is itself the causal nucleotide. Risk-haplotype biology is linked to reduced ANRIL/CDKN2B-AS1, p16^INK4a^ (CDKN2A), and p15^INK4b^ (CDKN2B) expression in primary vascular smooth-muscle cells.
• Reduced cell-cycle restraint is associated with increased smooth-muscle proliferation. Engineered and iPSC-derived models further report dedifferentiation, impaired adhesion/contractility, and calcification-prone osteochondrogenic phenotypes—changes compatible with maladaptive arterial-wall remodeling.
• rs10757278 also lies in a vascular regulatory region in which risk variation can disrupt interferon-γ-responsive STAT1 binding, altering chromatin contacts and inflammatory transcriptional responses.
• Senescence is biologically credible through ANRIL–CDKN2A/CDKN2B signaling, but is not established as a direct GG-specific vascular phenotype; available models may instead show diminished senescence.

Bottom line

• GG is a well-supported genetic marker of increased CAD susceptibility, with moderately supported links to proliferative, phenotypically dysregulated vascular remodeling. Senescence remains a plausible but incompletely demonstrated part of that pathway.