DO: 3393; MONDO: 0012628;
Cytogenetic location: 9p21 Genomic coordinates (GRCh38) : 9:19,900,001-33,200,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9p21 | {Coronary heart disease, susceptibility to, 8} | 611139 | 2 |
For a discussion of genetic heterogeneity of coronary heart disease (CHD), see 607339.
McPherson et al. (2007) used genomewide association scanning to identify a 58-kb interval on chromosome 9p21 that was consistently associated with coronary heart disease in 6 independent samples (more than 23,000 participants) from 4 Caucasian populations. To minimize false positive associations without unduly sacrificing statistical power, McPherson et al. (2007) designed the study to comprise 3 sequential case-control comparisons performed at a nominal significance threshold of P is less than 0.025. The 3 case-control comparisons identified 2 SNPs, rs10757274 and rs2383206, associated with CHD that were located within 20 kb of each other on chromosome 9p21 and were in strong linkage disequilibrium. In validation studies using 3 additional independent cohorts, both SNPs were significantly associated with CHD. Fine mapping studies indicated that the risk allele defined by rs10757274 and rs2383206 comprises a haplotype that spans approximately 58 kb. This interval, which is located near the CDKN2A (600160) and CDKN2B (610347) genes, contained no annotated genes and was not associated with established CHD risk factors such as plasma lipoproteins, hypertension, or diabetes. Resequencing of the 58-kb interval in 2 homozygotes for the risk allele and in 1 homozygote for the reference allele revealed 66 polymorphisms (SNPs plus small insertions or deletions), of which 35 were specific to the risk allele. Only 1 of these variants, a copy number variation in a run of 9 consecutive CAT repeats, mapped to a spliced transcript (BI765545) that appeared to be part of a large noncoding RNA. The mechanistic basis for the association between the risk allele defined by rs10757274 and rs2383206 and coronary heart disease was not known. Homozygotes for the risk allele were estimated to make up 20 to 25% of Caucasians, and have an approximately 30 to 40% increased risk of CHD.
Helgadottir et al. (2007) performed a genomewide association study in a total of 4,587 cases and 12,767 controls from the Icelandic population and identified 3 correlated SNPs. To replicate the observed associations, the authors genotyped the 3 SNPs in an additional 665 Icelandic myocardial infarction (MI) cases and 3,533 controls, and in 3 case-control sample sets of European descent from 3 cities in the United States. The SNP rs10757278 emerged as having the strongest association with the disease. With results from all groups combined, relative to noncarriers, the odds ratios for heterozygous and homozygous carriers of the risk allele G were 1.26 and 1.64, respectively. The corresponding odds ratio for early-onset cases was determined to be 2.02 for homozygous carriers of the risk allele. Assuming an allele frequency of 45.3%, the population-attributable risk is 21% for MI in general and 31% for early-onset cases.
The Wellcome Trust Case Control Consortium (2007) described a joint genomewide association study using the Affymetrix GeneChip 500K Mapping Array Set, undertaken in the British population, which examined approximately 2,000 individuals for each of 7 major diseases and a shared set of approximately 3,000 controls. This analysis identified a powerful association with coronary artery disease on chromosome 9p21.3. Although the strongest signal was seen at rs1333049 (P = 1.8 x 10(-14)), associations were seen for SNPs across more than 100 kb.
Helgadottir et al. (2008) found that, in addition to coronary artery disease, the rs10757278-G SNP is associated with abdominal aortic aneurysm (AAA3; 611891) (odds ratio = 1.31) and intracranial aneurysm (ANIB6; 611891) (odds ratio = 1.29). This was said to be the first variant to be described that affects the risk of AAA and intracranial aneurysm in many populations.
Hinohara et al. (2008) evaluated the association of rs1333049 with coronary artery disease (CAD) in 604 Japanese patients and 1,151 controls and in 679 Korean patients and 706 controls, and found a significant association in both groups (odds ratio = 1.30 and 1.19, and p = 0.00027 and 0.025, respectively). Noting that previous studies had focused on Caucasian populations, the authors concluded that chromosome 9p21 is also a susceptibility locus for CAD in East Asian patients.
In a case-control study of 416 Italian MI patients and 308 controls, Shen et al. (2008) found significant association with 4 SNPs on chromosome 9p21 (rs10757274, rs2383206, rs2383207, and {dbSNP 10757278}) that remained significant after adjusting for covariates for MI, and identified a GGGG risk haplotype and an AAAA protective haplotype. When the case cohort was divided into patients with a positive family history and those without, significant association was identified only in the group with a positive family history. Shen et al. (2008) concluded that chromosome 9p21 confers risk for development of MI in the Italian population.
In a European case-control study involving 4,251 patients with coronary artery disease and 4,443 controls, Broadbent et al. (2008) replicated association (p values ranging from 3 x 10(-11) to 8 x 10(-13); odds ratios from 1.26 to 1.29) for 7 SNPs on chromosome 9p21 (rs10116277, rs6475606, rs10757274, rs2383206, rs2383207, rs10757278, and rs1333049). The authors showed that the consistent association was a result of a 'yin-yang' haplotype pattern spanning 53 kb, and noted that a large antisense noncoding RNA gene (CDKN2BAS; 613149) colocates with the high-risk haplotype and is expressed in tissues and cell types that are affected by atherosclerosis. Simultaneous testing of CAD and type 2 diabetes-associated SNPs at chromosome 9p21 (see 125853) indicated that these associations were independent of each other.
Harismendy et al. (2011) identified 33 enhancers in 9p21; the interval is the second densest gene desert for predicted enhancers and 6 times denser than the whole genome (P less than 6.55 x 10(-33)). The CAD risk alleles of SNPs rs10811656 and rs10757278 are located in one of these enhancers and disrupt a binding site for STAT1 (600555). Lymphoblastoid cell lines homozygous for the CAD risk haplotype show no binding of STAT1, and in lymphoblastoid cell lines homozygous for the CAD nonrisk haplotype, binding of STAT1 inhibits CDKN2BAS expression, which is reversed by short interfering RNA knockdown of STAT1. Using a new, open-ended approach to detect long-distance interactions, Harismendy et al. (2011) found that in human vascular endothelial cells the enhancer interval containing the CAD locus physically interacts with the CDKN2A/B locus (see 600431), the MTAP gene (156540), and an interval downstream of IFNA21 (147584). In human vascular endothelial cells, interferon-gamma (147570) activation strongly affects the structure of the chromatin and the transcriptional regulation in the 9p21 locus, including STAT1 binding, long-range enhancer interactions, and altered expression of neighboring genes. Harismendy et al. (2011) concluded that their findings established a link between CAD genetic susceptibility and the response to inflammatory signaling in a vascular cell type.
Visel et al. (2010) showed that deletion of the 70-kb noncoding interval on mouse chromosome 4 orthologous to the chromosome 9p21 interval associated with human coronary artery disease (CAD) affects cardiac expression of neighboring genes, as well as proliferation properties of vascular cells. Mice with homozygous deletion of the 70-kb interval (delta-70-kb) were viable but showed increased mortality both during development and as adults. Cardiac expression of 2 genes near the noncoding interval, Cdkn2a (600160) and Cdkn2b (600431), was severely reduced in delta-70-kb homozygous mice, indicating that distant-acting gene regulatory functions are located in the noncoding CAD risk interval. Allele-specific expression of Cdkn2b transcripts in heterozygous mice showed that the deletion affects expression through a cis-acting mechanism. Primary cultures of aortic smooth muscle cells from homozygous delta-70-kb mice exhibited excessive proliferation and diminished senescence, a cellular phenotype consistent with accelerated CAD pathogenesis. Visel et al. (2010) concluded that, taken together, their results provided direct evidence that the CAD risk interval has a pivotal role in the regulation of cardiac CDKN2A/B expression, and suggested that this region affects coronary artery disease progression by altering the dynamics of vascular cell proliferation.
Broadbent, H. M., Peden, J. F., Lorkowski, S., Goel, A., Ongen, H., Green, F., Clarke, R., Collins, R., Franzosi, M. G., Tognoni, G., Seedorf, U., Rust, S., Eriksson, P., Hamsten, A., Farrall, M., Watkins, H. Susceptibility to coronary artery disease and diabetes is encoded by distinct, tightly linked SNPs in the ANRIL locus on chromosome 9p. Hum. Molec. Genet. 17: 806-814, 2008. [PubMed: 18048406] [Full Text: https://doi.org/10.1093/hmg/ddm352]
Harismendy, O., Notani, D., Song, X., Rahim, N. G., Tanasa, B., Heintzman, N., Ren, B., Fu, X.-D., Topol, E. J., Rosenfeld, M. G., Frazer, K. A. 9p21 DNA variants associated with coronary artery disease impair interferon-gamma signalling response. Nature 470: 264-268, 2011. [PubMed: 21307941] [Full Text: https://doi.org/10.1038/nature09753]
Helgadottir, A., Thorleifsson, G., Magnusson, K. P., Gretarsdottir, S., Steinthorsdottir, V., Manolescu, A., Jones, G. T., Rinkel, G. J. E., Blankensteijn, J. D., Ronkainen, A., Jaaskelainen, J. E., Kyo, Y., and 56 others. The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm. Nature Genet. 40: 217-224, 2008. [PubMed: 18176561] [Full Text: https://doi.org/10.1038/ng.72]
Helgadottir, A., Thorleifsson, G., Manolescu, A., Gretarsdottir, S., Blondal, T., Jonasdottir, A., Jonasdottir, A., Sigurdsson, A., Baker, A., Palsson, A., Masson, G., Gudbjartsson, D. F., and 23 others. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science 316: 1491-1493, 2007. [PubMed: 17478679] [Full Text: https://doi.org/10.1126/science.1142842]
Hinohara, K., Nakajima, T., Takahashi, M., Hohda, S., Sasaoka, T., Nakahara, K., Chida, K., Sawabe, M., Arimura, T., Sato, A., Lee, B.-S., Ban, J., Yasunami, M., Park, J.-E., Izumi, T., Kimura, A. Replication of the association between a chromosome 9p21 polymorphism and coronary artery disease in Japanese and Korean populations. J. Hum. Genet. 53: 357-359, 2008. [PubMed: 18264662] [Full Text: https://doi.org/10.1007/s10038-008-0248-4]
McPherson, R., Pertsemlidis, A., Kavaslar, N., Stewart, A., Roberts, R., Cox, D. R., Hinds, D. A., Pennacchio, L. A., Tybjaerg-Hansen, A., Folsom, A. R., Boerwinkle, E., Hobbs, H. H., Cohen, J. C. A common allele on chromosome 9 associated with coronary heart disease. Science 316: 1488-1491, 2007. [PubMed: 17478681] [Full Text: https://doi.org/10.1126/science.1142447]
Shen, G.-Q., Rao, S., Martinelli, N., Li, L., Olivieri, O., Corrocher, R., Abdullah, K. G., Hazen, S. L., Smith, J., Barnard, J., Plow, E. F., Girelli, D., Wang, Q. K. Association between four SNPs on chromosome 9p21 and myocardial infarction is replicated in an Italian population. J. Hum. Genet. 53: 144-150, 2008. [PubMed: 18066490] [Full Text: https://doi.org/10.1007/s10038-007-0230-6]
Visel, A., Zhu, Y., May, D., Afzal, V., Gong, E., Attanasio, C., Blow, M. J., Cohen, J. C., Rubin, E. M., Pennacchio, L. A. Targeted deletion of the 9p21 non-coding coronary artery disease risk interval in mice. Nature 464: 409-412, 2010. [PubMed: 20173736] [Full Text: https://doi.org/10.1038/nature08801]
Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447: 661-678, 2007. [PubMed: 17554300] [Full Text: https://doi.org/10.1038/nature05911]