Functional genomics of the CDKN2A/B locus in cardiovascular and metabolic disease: what have we learned from GWASs?

• 9p21.3 SNP variants were tagged by a genome-wide association study (GWAS) as a hot spot associated with cardiovascular disease (CVD) and type 2 diseases.
• It is not clear why this chromosome region is a vital genetic region, or by which pathways this locus might influence cardio-metabolic susceptibility.
• The function of cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) gene products may mechanistically link the 9p21.3 risk locus with CVD and type 2 diabetes (T2D).
• In addition to direct vascular and immune-modulatory roles of CDKN2A/B, this locus may influence cardio-metabolic diseases by affecting metabolic functions.

Genome-wide association studies (GWASs) provide an unprecedented opportunity to examine, on a large scale, the association of common genetic variants with complex diseases like type 2 diabetes (T2D) and cardiovascular disease (CVD), thus allowing the identification of new potential disease loci. Using this approach, numerous studies have associated SNPs on chromosome 9p21.3 situated near the cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) locus with the risk for coronary artery disease (CAD) and T2D. However, identifying the function of the nearby gene products (CDKN2A/B and ANRIL) in the pathophysiology of these conditions requires functional genomic studies. We review the current knowledge, from studies using human and mouse models, describing the function of CDKN2A/B gene products, which may mechanistically link the 9p21.3 risk locus with CVD and diabetes.