Trends in Endocrinology & Metabolism
ReviewFunctional genomics of the CDKN2A/B locus in cardiovascular and metabolic disease: what have we learned from GWASs?
Introduction
T2D patients display increased risk for CVDs (see Glossary). The prevalence of both pathologies is increasing despite intense efforts in prevention and disease treatment. The pathogenesis of CVD and T2D involves the interaction of environmental and genetic factors. Identification of the pathophysiological mechanisms and risk factors, allowing lifestyle intervention and pharmacological therapies, is paramount to curb the epidemic propagation of these diseases.
Although T2D and CVD are often clinically linked and share obvious risk factors such as life style, the existence of shared genetic signatures has remained elusive for a long time. In recent years, GWASs focusing on CVD and T2D have provided a wealth of new information allowing the identification of biological pathways not associated with conventional risk factors. GWASs have identified a common susceptibility locus on chromosome 9p21.3 for both T2D and CVD, with the sequence variants rs10757278-G and rs10811661-T, respectively, associated with CAD and T2D [1].
Discovered in 2007 by three independent GWASs 2, 3, 4 and replicated since in several other studies, the chromosome 9p21.3 locus is, to date, one of the most robust genetic markers of CAD and myocardial infarction (MI) in Caucasian [5], Korean, and Japanese populations 6, 7. This locus also associates with atherosclerosis severity, with a substantially higher risk allele frequency in subjects with multivessel disease [8]. Furthermore, an association of rs10757278-G was also demonstrated with abdominal aortic and intracranial aneurysms [9], suggesting a more general impact of this locus on vascular function and remodeling. The strongest association of 9p21.3 variants is with the risk of first rather than subsequent CHD events [10], suggesting an action of this locus on the burden of CAD, rather than on MI due to plaque instability/rupture and thrombosis.
The 9p21.3 locus, spanning a >50-kb genomic region, contains multiple SNPs associated with CVD that are in strong linkage disequilibrium (LD), defining a core risk haplotype robustly associated with CVD [11]. T2D is a well-established risk factor for CVD and especially for atherosclerosis, raising thus the possibility that the region on 9p21.3 predisposes to both CVD and T2D through shared biological mechanisms. However, the CVD SNP rs10757278 and T2D SNP rs10811661 (Figure 1) are in adjacent LD blocks, and the two SNPs are not associated (r2<0.01) in the HapMap of Utah residents with northern and western European ancestry (CEU) data [9]. Moreover, despite the clear genetic signal at this locus, the underlying biological mechanisms are still poorly understood. The genome region containing the SNPs on chromosome 9p21.3 harbors no known protein-coding genes, but expresses the long noncoding RNA ANRIL (antisense noncoding RNA in the inhibitor of CDK4 (INK4) locus). The closest adjacent protein-coding genes including the cyclin-dependent kinase (CDK) inhibitors CDKN2A and CDKN2B, known as tumor suppressors, are considered as potential functional candidates. Moreover, it must be kept in mind that rs10757278 and rs10811661 are separated by <10 kb from CDKN2A and CDKN2B. Candidate gene approaches have also reported variants in this locus associated with ovarian cancer, acute lymphoblastic leukemia, glioma, malignant melanoma, breast cancer, pancreatic cancer, nasopharyngeal neoplasm, and glaucoma [12], showing that this chromosomal area harbors genes involved in a number of different pathophysiological processes. It should be noted that the link with cancer is more expected than with T2D and CVD, considering the well-known function of the CDKN2A/B gene products in cell cycle control (Box 1).
Section snippets
CDKN2A/B gene products and ANRIL expression in human samples
The CDKN2A locus encodes the CDK inhibitor protein (CDKI) p16INK4a and the p53 regulatory protein p14ARF (p19ARF in mice), whereas the CDKN2B gene encodes another CDKI, p15INK4b. All these proteins are involved in cell cycle regulation, aging, senescence, and apoptosis 13, 14.
The protein products of the CDKN2A/B locus, that is, p16INK4a, p14ARF, and p15INK4b, are expressed in normal and atherosclerotic human coronary arteries [15]. In atherosclerotic lesions, these proteins localize to a subset
CDKN2A/B genes in the control of metabolism
Systemic metabolic risk factors for CVD, such as observed in dyslipidemia and diabetes, are rising rapidly worldwide due to the obesity epidemic. CVD complications account for more than 70% of the morbidity associated with these diseases. eQTL studies for CDKN2B have associated the CVD-risk region with reduced CDKN2B expression in human subcutaneous adipose tissue (SAT) and circulating leukocytes [53]. CDKN2B appears to play a significant role in regulating SAT expandability, determinant of
Concluding remarks and future perspectives
9p21.3 SNP variants were tagged by GWASs as a hot spot associated with cardio-metabolic diseases. Although GWAS findings are not yet translated into clinical application for personalized health care of individual patients, they constitute nevertheless a first step towards an improved understanding of disease etiology. Several studies tried to decipher the function of the CDKN2A/B gene products in cardio-metabolic diseases (Figure 2). Nonetheless, even with the progress made, we are far from
Glossary
- Cardiovascular disease (CVD)
- includes all the diseases of the heart and circulation including coronary heart disease (angina and myocardial infarction), heart failure, congenital heart disease, and ischemic stroke.
- Coronary heart diseases (CHDs)
- are a set of complex, prevalent, and related conditions including coronary artery disease (CAD) and myocardial infarction (MI). CHD begins as atherosclerosis, an inflammatory disease that is influenced by multiple environmental and genetic factors. It
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