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Published in: Current Atherosclerosis Reports 3/2011

01-06-2011

Genetic Mechanisms Mediating Atherosclerosis Susceptibility at the Chromosome 9p21 Locus

Authors: Michael S. Cunnington, Bernard Keavney

Published in: Current Atherosclerosis Reports | Issue 3/2011

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Abstract

Recent genome-wide association studies have demonstrated that common genetic variants in a region of chromosome 9p21 confer risk of coronary artery disease (CAD) and other atherosclerotic conditions. Although the absolute increase in risk is small (some 20–30% increase in risk of CAD per copy of the deleterious alleles), the common occurrence of the variants means that their effect on the population risk of disease is estimated to be substantial. Studies investigating the relationship between risk variants and both “classical” and “emerging” atherosclerotic risk factors have found no evidence of association. This suggests that the effect of the 9p21 locus on atherosclerotic risk is mediated via a hitherto unknown pathway potentially amenable to therapeutic modulation. Investigation of potential disease mechanisms at this locus is therefore a focus of intense interest. In this review, we discuss the progress that has been made in the study of mechanisms and highlight the outstanding research questions.
Literature
1.
go back to reference The Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447(7145):661–78.CrossRef The Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447(7145):661–78.CrossRef
2.
go back to reference Helgadottir A, Thorleifsson G, Manolescu A, et al. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science. 2007;316:1491–3.PubMedCrossRef Helgadottir A, Thorleifsson G, Manolescu A, et al. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science. 2007;316:1491–3.PubMedCrossRef
3.
go back to reference McPherson R, Pertsemlidis A, Kavaslar N, et al. A common allele on chromosome 9 associated with coronary heart disease. Science. 2007;316:1488–91.PubMedCrossRef McPherson R, Pertsemlidis A, Kavaslar N, et al. A common allele on chromosome 9 associated with coronary heart disease. Science. 2007;316:1488–91.PubMedCrossRef
4.
go back to reference Samani NJ, Erdmann J, Hall AS, et al. Genomewide association analysis of coronary artery disease. N Engl J Med. 2007;357(5):443–53.PubMedCrossRef Samani NJ, Erdmann J, Hall AS, et al. Genomewide association analysis of coronary artery disease. N Engl J Med. 2007;357(5):443–53.PubMedCrossRef
5.
go back to reference Broadbent HM, Peden JF, Lorkowski S, et al. Susceptibility to coronary artery disease and diabetes is encoded by distinct, tightly linked SNPs in the ANRIL locus on chromosome 9p. Hum Mol Genet. 2008;17(6):806–14.PubMedCrossRef Broadbent HM, Peden JF, Lorkowski S, et al. Susceptibility to coronary artery disease and diabetes is encoded by distinct, tightly linked SNPs in the ANRIL locus on chromosome 9p. Hum Mol Genet. 2008;17(6):806–14.PubMedCrossRef
6.
go back to reference Emanuele E, Lista S, Ghidoni R, et al.: Chromosome 9p21.3 genotype is associated with vascular dementia and Alzheimer’s disease. Neurobiol Aging 2009, In Press. Emanuele E, Lista S, Ghidoni R, et al.: Chromosome 9p21.3 genotype is associated with vascular dementia and Alzheimer’s disease. Neurobiol Aging 2009, In Press.
7.
go back to reference Uno S, Zembutsu H, Hirasawa A, et al. A genome-wide association study identifies genetic variants in the CDKN2BAS locus associated with endometriosis in Japanese. Nat Genet. 2010;42(8):707–10.PubMedCrossRef Uno S, Zembutsu H, Hirasawa A, et al. A genome-wide association study identifies genetic variants in the CDKN2BAS locus associated with endometriosis in Japanese. Nat Genet. 2010;42(8):707–10.PubMedCrossRef
8.
go back to reference Helgadottir A, Thorleifsson G, Magnusson KP, et al. The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm. Nat Genet. 2008;40(2):217–24.PubMedCrossRef Helgadottir A, Thorleifsson G, Magnusson KP, et al. The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm. Nat Genet. 2008;40(2):217–24.PubMedCrossRef
9.
go back to reference Wrensch M, Jenkins RB, Chang JS, et al. Variants in the CDKN2B and RTEL1 regions are associated with high-grade glioma susceptibility. Nat Genet. 2009;41(8):905–8.PubMedCrossRef Wrensch M, Jenkins RB, Chang JS, et al. Variants in the CDKN2B and RTEL1 regions are associated with high-grade glioma susceptibility. Nat Genet. 2009;41(8):905–8.PubMedCrossRef
10.
go back to reference Cluett C, McDermott MM, Guralnik J, et al. The 9p21 myocardial infarction risk allele increases risk of peripheral artery disease in older people. Circ Cardiovasc Genet. 2009;2(4):347–53.PubMedCrossRef Cluett C, McDermott MM, Guralnik J, et al. The 9p21 myocardial infarction risk allele increases risk of peripheral artery disease in older people. Circ Cardiovasc Genet. 2009;2(4):347–53.PubMedCrossRef
11.
go back to reference Gschwendtner A, Bevan S, Cole JW, et al. Sequence variants on chromosome 9p21.3 confer risk for atherosclerotic stroke. Ann Neurol. 2009;65(5):531–9.PubMedCrossRef Gschwendtner A, Bevan S, Cole JW, et al. Sequence variants on chromosome 9p21.3 confer risk for atherosclerotic stroke. Ann Neurol. 2009;65(5):531–9.PubMedCrossRef
12.
go back to reference Palomaki GE, Melillo S, Bradley LA. Association between 9p21 genomic markers and heart disease: a meta-analysis. JAMA. 2010;303(7):648–56.PubMedCrossRef Palomaki GE, Melillo S, Bradley LA. Association between 9p21 genomic markers and heart disease: a meta-analysis. JAMA. 2010;303(7):648–56.PubMedCrossRef
13.
go back to reference Hinohara K, Nakajima T, Takahashi M, et al. Replication of the association between a chromosome 9p21 polymorphism and coronary artery disease in Japanese and Korean populations. J Hum Genet. 2008;53(4):357–9.PubMedCrossRef Hinohara K, Nakajima T, Takahashi M, et al. Replication of the association between a chromosome 9p21 polymorphism and coronary artery disease in Japanese and Korean populations. J Hum Genet. 2008;53(4):357–9.PubMedCrossRef
14.
go back to reference Ding H, Xu Y, Wang X, et al. 9p21 is a shared susceptibility locus strongly for coronary artery disease and weakly for ischemic stroke in Chinese Han population. Circ Cardiovasc Genet. 2009;2(4):338–46.PubMedCrossRef Ding H, Xu Y, Wang X, et al. 9p21 is a shared susceptibility locus strongly for coronary artery disease and weakly for ischemic stroke in Chinese Han population. Circ Cardiovasc Genet. 2009;2(4):338–46.PubMedCrossRef
15.
go back to reference Cunnington MS, Mayosi BM, Hall DH, et al. Novel genetic variants linked to coronary artery disease by genome-wide association are not associated with carotid artery intima-media thickness or intermediate risk phenotypes. Atherosclerosis. 2009;203(1):41–4.PubMedCrossRef Cunnington MS, Mayosi BM, Hall DH, et al. Novel genetic variants linked to coronary artery disease by genome-wide association are not associated with carotid artery intima-media thickness or intermediate risk phenotypes. Atherosclerosis. 2009;203(1):41–4.PubMedCrossRef
16.
go back to reference Ye S, Willeit J, Kronenberg F, et al. Association of genetic variation on chromosome 9p21 with susceptibility and progression of atherosclerosis: a population-based, prospective study. J Am Coll Cardiol. 2008;52(5):378–84.PubMedCrossRef Ye S, Willeit J, Kronenberg F, et al. Association of genetic variation on chromosome 9p21 with susceptibility and progression of atherosclerosis: a population-based, prospective study. J Am Coll Cardiol. 2008;52(5):378–84.PubMedCrossRef
17.
go back to reference •• Holdt LM, Beutner F, Scholz M, et al.: ANRIL expression is associated with atherosclerosis risk at chromosome 9p21. Arterioscler Thromb Vasc Biol 2010, 30(3): 620–627. This study demonstrated an association between 9p21 atherosclerosis risk variants and expression of ANRIL transcripts in peripheral blood mononuclear cells from 1098 patients with CAD, but no consistent association with expression of CDKN2A, CDKN2B, or MTAP. Results were replicated in 41 atherosclerotic plaques and ANRIL expression was also correlated with the severity of atherosclerosis. Differential effects were seen on expression of different ANRIL transcripts.PubMedCrossRef •• Holdt LM, Beutner F, Scholz M, et al.: ANRIL expression is associated with atherosclerosis risk at chromosome 9p21. Arterioscler Thromb Vasc Biol 2010, 30(3): 620–627. This study demonstrated an association between 9p21 atherosclerosis risk variants and expression of ANRIL transcripts in peripheral blood mononuclear cells from 1098 patients with CAD, but no consistent association with expression of CDKN2A, CDKN2B, or MTAP. Results were replicated in 41 atherosclerotic plaques and ANRIL expression was also correlated with the severity of atherosclerosis. Differential effects were seen on expression of different ANRIL transcripts.PubMedCrossRef
18.
go back to reference Dandona S, Stewart AFR, Chen L, et al. Gene dosage of the common variant 9p21 predicts severity of coronary artery disease. J Am Coll Cardiol. 2010;56(6):479–86.PubMedCrossRef Dandona S, Stewart AFR, Chen L, et al. Gene dosage of the common variant 9p21 predicts severity of coronary artery disease. J Am Coll Cardiol. 2010;56(6):479–86.PubMedCrossRef
19.
go back to reference Horne BD, Carlquist JF, Muhlestein JB, et al. Association of variation in the chromosome 9p21 locus with myocardial infarction versus chronic coronary artery disease. Circ Cardiovasc Genet. 2008;1(2):85–92.PubMedCrossRef Horne BD, Carlquist JF, Muhlestein JB, et al. Association of variation in the chromosome 9p21 locus with myocardial infarction versus chronic coronary artery disease. Circ Cardiovasc Genet. 2008;1(2):85–92.PubMedCrossRef
20.
go back to reference Patel RS, Su S, Neeland IJ, et al.: The chromosome 9p21 risk locus is associated with angiographic severity and progression of coronary artery disease. Eur Heart J 2010: Epub ahead of print. Patel RS, Su S, Neeland IJ, et al.: The chromosome 9p21 risk locus is associated with angiographic severity and progression of coronary artery disease. Eur Heart J 2010: Epub ahead of print.
21.
go back to reference Shen GQ, Li L, Rao S, et al. Four SNPs on chromosome 9p21 in a South Korean population implicate a genetic locus that confers high cross-race risk for development of coronary artery disease. Arterioscler Thromb Vasc Biol. 2008;28(2):360–5.PubMedCrossRef Shen GQ, Li L, Rao S, et al. Four SNPs on chromosome 9p21 in a South Korean population implicate a genetic locus that confers high cross-race risk for development of coronary artery disease. Arterioscler Thromb Vasc Biol. 2008;28(2):360–5.PubMedCrossRef
22.
go back to reference Anderson JL, Horne BD, Kolek MJ, et al. Genetic variation at the 9p21 locus predicts angiographic coronary artery disease prevalence but not extent and has clinical utility. Am Heart J. 2008;156(6):1155–1162.e2.PubMedCrossRef Anderson JL, Horne BD, Kolek MJ, et al. Genetic variation at the 9p21 locus predicts angiographic coronary artery disease prevalence but not extent and has clinical utility. Am Heart J. 2008;156(6):1155–1162.e2.PubMedCrossRef
23.
go back to reference Hiura Y, Fukushima Y, Yuno M, et al. Validation of the association of genetic variants on chromosome 9p21 and 1q41 with myocardial infarction in a Japanese population. Circ J. 2008;72(8):1213–7.PubMedCrossRef Hiura Y, Fukushima Y, Yuno M, et al. Validation of the association of genetic variants on chromosome 9p21 and 1q41 with myocardial infarction in a Japanese population. Circ J. 2008;72(8):1213–7.PubMedCrossRef
24.
go back to reference Musunuru K, Post WS, Herzog W, et al. Association of single nucleotide polymorphisms on chromosome 9p21.3 with platelet reactivity. Circ Cardiovasc Genet. 2010;3(5):445–53.PubMedCrossRef Musunuru K, Post WS, Herzog W, et al. Association of single nucleotide polymorphisms on chromosome 9p21.3 with platelet reactivity. Circ Cardiovasc Genet. 2010;3(5):445–53.PubMedCrossRef
25.
26.
go back to reference Gil J, Peters G. Regulation of the INK4b-ARF-INK4a tumour suppressor locus: all for one or one for all. Nat Rev Mol Cell Biol. 2006;7(9):667–77.PubMedCrossRef Gil J, Peters G. Regulation of the INK4b-ARF-INK4a tumour suppressor locus: all for one or one for all. Nat Rev Mol Cell Biol. 2006;7(9):667–77.PubMedCrossRef
27.
go back to reference Holdt LM, Sass K, Gäbel G, et al.: Expression of Chr9p21 genes CDKN2B (p15INK4b), CDKN2A (p16INK4a, p14ARF) and MTAP in human atherosclerotic plaque. Atherosclerosis 2010, In Press. Holdt LM, Sass K, Gäbel G, et al.: Expression of Chr9p21 genes CDKN2B (p15INK4b), CDKN2A (p16INK4a, p14ARF) and MTAP in human atherosclerotic plaque. Atherosclerosis 2010, In Press.
28.
go back to reference Dzau VJ, Braun-Dullaeus RC, Sedding DG. Vascular proliferation and atherosclerosis: New perspectives and therapeutic strategies. Nat Med. 2002;8(11):1249–56.PubMedCrossRef Dzau VJ, Braun-Dullaeus RC, Sedding DG. Vascular proliferation and atherosclerosis: New perspectives and therapeutic strategies. Nat Med. 2002;8(11):1249–56.PubMedCrossRef
29.
go back to reference Fuster JJ, Fernandez P, Gonzalez-Navarro H, et al. Control of cell proliferation in atherosclerosis: insights from animal models and human studies. Cardiovasc Res. 2010;86(2):254–64.PubMedCrossRef Fuster JJ, Fernandez P, Gonzalez-Navarro H, et al. Control of cell proliferation in atherosclerosis: insights from animal models and human studies. Cardiovasc Res. 2010;86(2):254–64.PubMedCrossRef
30.
31.
go back to reference Minamino T, Komuro I. Vascular cell senescence: contribution to atherosclerosis. Circ Res. 2007;100(1):15–26.PubMedCrossRef Minamino T, Komuro I. Vascular cell senescence: contribution to atherosclerosis. Circ Res. 2007;100(1):15–26.PubMedCrossRef
32.
go back to reference Hannon GJ, Beach D. pl5INK4B is a potentia| effector of TGF-beta-induced cell cycle arrest. Nature. 1994;371(6494):257–61.PubMedCrossRef Hannon GJ, Beach D. pl5INK4B is a potentia| effector of TGF-beta-induced cell cycle arrest. Nature. 1994;371(6494):257–61.PubMedCrossRef
33.
go back to reference Kalinina N, Agrotis A, Antropova Y, et al. Smad expression in human atherosclerotic lesions: evidence for impaired TGF-beta/Smad signaling in smooth muscle cells of fibrofatty lesions. Arterioscler Thromb Vasc Biol. 2004;24(8):1391–6.PubMedCrossRef Kalinina N, Agrotis A, Antropova Y, et al. Smad expression in human atherosclerotic lesions: evidence for impaired TGF-beta/Smad signaling in smooth muscle cells of fibrofatty lesions. Arterioscler Thromb Vasc Biol. 2004;24(8):1391–6.PubMedCrossRef
34.
go back to reference Christopher SA, Diegelman P, Porter CW, Kruger WD. Methylthioadenosine phosphorylase, a gene frequently codeleted with p16cdkN2a/ARF, acts as a tumor suppressor in a breast cancer cell line. Cancer Res. 2002;62(22):6639–44.PubMed Christopher SA, Diegelman P, Porter CW, Kruger WD. Methylthioadenosine phosphorylase, a gene frequently codeleted with p16cdkN2a/ARF, acts as a tumor suppressor in a breast cancer cell line. Cancer Res. 2002;62(22):6639–44.PubMed
35.
go back to reference Talmud PJ, Cooper JA, Palmen J, et al. Chromosome 9p21.3 coronary heart disease locus genotype and prospective risk of chd in healthy middle-aged men. Clin Chem. 2008;54(3):467–74.PubMedCrossRef Talmud PJ, Cooper JA, Palmen J, et al. Chromosome 9p21.3 coronary heart disease locus genotype and prospective risk of chd in healthy middle-aged men. Clin Chem. 2008;54(3):467–74.PubMedCrossRef
36.
go back to reference • Liu Y, Sanoff HK, Cho H, et al.: INK4/ARF Transcript expression is associated with chromosome 9p21 variants linked to atherosclerosis. PLoS One 2009, 4(4): e5027. This study found a significant association between genotype at a CAD risk SNP and reduced expression of CDKN2A, ARF, and CDKN2B in peripheral blood T cells from 170 healthy volunteers. No association with expression of these genes was detected for another CAD risk SNPs in the same population.PubMedCrossRef Liu Y, Sanoff HK, Cho H, et al.: INK4/ARF Transcript expression is associated with chromosome 9p21 variants linked to atherosclerosis. PLoS One 2009, 4(4): e5027. This study found a significant association between genotype at a CAD risk SNP and reduced expression of CDKN2A, ARF, and CDKN2B in peripheral blood T cells from 170 healthy volunteers. No association with expression of these genes was detected for another CAD risk SNPs in the same population.PubMedCrossRef
37.
go back to reference •• Cunnington MS, Santibanez Koref MF, Mayosi BM, et al.: Chromosome 9p21 SNPs associated with multiple disease phenotypes correlate with ANRIL expression. PLoS Genet 2010, 6(4): e1000899. This study showed that CAD risk alleles were all highly associated with reduced expression of ANRIL in peripheral blood from 487 healthy volunteers, yet only a small proportion were significantly associated with CDKN2A and CDKN2B expression. Most of the variation in total expression levels of these genes was due to trans effects (80%–95%), and although total expression levels of the genes are positively correlated SNPs had inverse effects on ANRIL and CDKN2B expression, supporting a role of antisense transcription in CDKN2B regulation. Multiple SNPs independently influenced ANRIL expression in cis.PubMedCrossRef •• Cunnington MS, Santibanez Koref MF, Mayosi BM, et al.: Chromosome 9p21 SNPs associated with multiple disease phenotypes correlate with ANRIL expression. PLoS Genet 2010, 6(4): e1000899. This study showed that CAD risk alleles were all highly associated with reduced expression of ANRIL in peripheral blood from 487 healthy volunteers, yet only a small proportion were significantly associated with CDKN2A and CDKN2B expression. Most of the variation in total expression levels of these genes was due to trans effects (80%–95%), and although total expression levels of the genes are positively correlated SNPs had inverse effects on ANRIL and CDKN2B expression, supporting a role of antisense transcription in CDKN2B regulation. Multiple SNPs independently influenced ANRIL expression in cis.PubMedCrossRef
38.
go back to reference • Jarinova O, Stewart AFR, Roberts R, et al.: Functional analysis of the chromosome 9p21.3 coronary artery disease risk locus. Arterioscler Thromb Vasc Biol 2009, 29(10): 1671–1677. This study compared whole blood expression of ANRIL, CDKN2A and CDKN2B in 63 healthy individuals homozygous for the 9p21 risk allele and 61 healthy individuals homozygous for the non-risk allele. The risk allele was associated with reduced expression of the long ANRIL transcript and increased expression of short ANRIL transcripts, but there was no significant association with CDKN2A or CDKN2B expression.PubMedCrossRef Jarinova O, Stewart AFR, Roberts R, et al.: Functional analysis of the chromosome 9p21.3 coronary artery disease risk locus. Arterioscler Thromb Vasc Biol 2009, 29(10): 1671–1677. This study compared whole blood expression of ANRIL, CDKN2A and CDKN2B in 63 healthy individuals homozygous for the 9p21 risk allele and 61 healthy individuals homozygous for the non-risk allele. The risk allele was associated with reduced expression of the long ANRIL transcript and increased expression of short ANRIL transcripts, but there was no significant association with CDKN2A or CDKN2B expression.PubMedCrossRef
39.
go back to reference • Folkersen L, Kyriakou T, Goel A, et al.: Relationship between CAD risk genotype in the chromosome 9p21 locus and gene expression. identification of eight new ANRIL splice variants. PLoS One 2009, 4(11): e7677. This study documented multiple novel ANRIL transcripts in cells derived from different tissues, highlighting the transcript complexity of this locus. No association was found between genotype at an atherosclerosis risk variant and regional or genome-wide expression data in lymphoblastoid cell lines and atherosclerotic tissues.PubMedCrossRef Folkersen L, Kyriakou T, Goel A, et al.: Relationship between CAD risk genotype in the chromosome 9p21 locus and gene expression. identification of eight new ANRIL splice variants. PLoS One 2009, 4(11): e7677. This study documented multiple novel ANRIL transcripts in cells derived from different tissues, highlighting the transcript complexity of this locus. No association was found between genotype at an atherosclerosis risk variant and regional or genome-wide expression data in lymphoblastoid cell lines and atherosclerotic tissues.PubMedCrossRef
40.
go back to reference Pasmant E, Laurendeau I, Heron D, et al. Characterization of a germ-line deletion, including the entire INK4/ARF locus, in a melanoma-neural system tumor family: identification of ANRIL, an antisense noncoding rna whose expression coclusters with ARF. Cancer Res. 2007;67(8):3963–9.PubMedCrossRef Pasmant E, Laurendeau I, Heron D, et al. Characterization of a germ-line deletion, including the entire INK4/ARF locus, in a melanoma-neural system tumor family: identification of ANRIL, an antisense noncoding rna whose expression coclusters with ARF. Cancer Res. 2007;67(8):3963–9.PubMedCrossRef
42.
go back to reference Mercer TR, Dinger ME, Mattick JS. Long non-coding RNAs: insights into functions. Nat Rev Genet. 2009;10(3):155–9.PubMedCrossRef Mercer TR, Dinger ME, Mattick JS. Long non-coding RNAs: insights into functions. Nat Rev Genet. 2009;10(3):155–9.PubMedCrossRef
43.
go back to reference Bracken AP, Kleine-Kohlbrecher D, Dietrich N, et al. The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. Genes Dev. 2007;21(5):525–30.PubMedCrossRef Bracken AP, Kleine-Kohlbrecher D, Dietrich N, et al. The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. Genes Dev. 2007;21(5):525–30.PubMedCrossRef
44.
go back to reference Zindy F, Quelle DE, Roussel MF, Sherr CJ. Expression of the p16(INK4a) tumor suppressor versus other INK4 family members during mouse development and aging. Oncogene. 1997;15(2):203–11.PubMedCrossRef Zindy F, Quelle DE, Roussel MF, Sherr CJ. Expression of the p16(INK4a) tumor suppressor versus other INK4 family members during mouse development and aging. Oncogene. 1997;15(2):203–11.PubMedCrossRef
45.
go back to reference • Visel A, Zhu Y, May D, et al.: Targeted deletion of the 9p21 non-coding coronary artery disease risk interval in mice. Nature 2010, 464(7287): 409–12. This study showed that deletion of a 70-kb non-coding region on mouse chromosome 4, which is orthologous to the 9p21 atherosclerosis risk region in humans, was associated with marked reduction of cardiac Cdkn2a and Cdkn2b expression, indicating that distant-acting gene regulatory functions are located in the deleted region. Aortic sooth muscle cells from knockout mice showed excessive proliferation which may contribute to atherosclerosis development.PubMedCrossRef Visel A, Zhu Y, May D, et al.: Targeted deletion of the 9p21 non-coding coronary artery disease risk interval in mice. Nature 2010, 464(7287): 409–12. This study showed that deletion of a 70-kb non-coding region on mouse chromosome 4, which is orthologous to the 9p21 atherosclerosis risk region in humans, was associated with marked reduction of cardiac Cdkn2a and Cdkn2b expression, indicating that distant-acting gene regulatory functions are located in the deleted region. Aortic sooth muscle cells from knockout mice showed excessive proliferation which may contribute to atherosclerosis development.PubMedCrossRef
46.
go back to reference • González-Navarro H, Abu Nabah YN, Vinué Á, et al.: p19ARF deficiency reduces macrophage and vascular smooth muscle cell apoptosis and aggravates atherosclerosis. J Am Coll Cardiol 2010, 55(20): 2258–2268. This study showed that ARF knockout in atherosclerosis-prone apoE-null mice accelerated aortic atheroma development, possibly through attenuated apoptosis of macrophages and vascular smooth muscle cells within atherosclerotic lesions. This supports a direct link between ARF, plaque apoptosis, and atherosclerosis.PubMedCrossRef González-Navarro H, Abu Nabah YN, Vinué Á, et al.: p19ARF deficiency reduces macrophage and vascular smooth muscle cell apoptosis and aggravates atherosclerosis. J Am Coll Cardiol 2010, 55(20): 2258–2268. This study showed that ARF knockout in atherosclerosis-prone apoE-null mice accelerated aortic atheroma development, possibly through attenuated apoptosis of macrophages and vascular smooth muscle cells within atherosclerotic lesions. This supports a direct link between ARF, plaque apoptosis, and atherosclerosis.PubMedCrossRef
47.
go back to reference • Yu W, Gius D, Onyango P, et al.: Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA. Nature 2008, 451(7175): 202–206. This study showed that CDKN2B antisense transcription, mapping to the first intron of ANRIL, is associated with down-regulation of CDKN2B expression in leukemia cells and mouse embryonic stem cells, mediated in cis and trans through heterochromatin formation. This suggests that ANRIL may be involved in regulation of CDKN2B expression.PubMedCrossRef Yu W, Gius D, Onyango P, et al.: Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA. Nature 2008, 451(7175): 202–206. This study showed that CDKN2B antisense transcription, mapping to the first intron of ANRIL, is associated with down-regulation of CDKN2B expression in leukemia cells and mouse embryonic stem cells, mediated in cis and trans through heterochromatin formation. This suggests that ANRIL may be involved in regulation of CDKN2B expression.PubMedCrossRef
48.
go back to reference •• Yap KL, Li S, Muñoz-Cabello AM, et al.: Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by Polycomb CBX7 in transcriptional silencing of INK4a. Mol Cell 2010, 38(5): 662–674. This study showed that ANRIL specifically interacts with CBX7, a protein within the polycomb repressive complex 1 that represses transcription of CDKN2A and CDKN2B. This suggests a direct role of ANRIL in regulating the expression of these genes.PubMedCrossRef •• Yap KL, Li S, Muñoz-Cabello AM, et al.: Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by Polycomb CBX7 in transcriptional silencing of INK4a. Mol Cell 2010, 38(5): 662–674. This study showed that ANRIL specifically interacts with CBX7, a protein within the polycomb repressive complex 1 that represses transcription of CDKN2A and CDKN2B. This suggests a direct role of ANRIL in regulating the expression of these genes.PubMedCrossRef
49.
go back to reference Debniak T, Gorski B, Huzarski T, et al. A common variant of CDKN2A (p16) predisposes to breast cancer. J Med Genet. 2005;42(10):763–5.PubMedCrossRef Debniak T, Gorski B, Huzarski T, et al. A common variant of CDKN2A (p16) predisposes to breast cancer. J Med Genet. 2005;42(10):763–5.PubMedCrossRef
Metadata
Title
Genetic Mechanisms Mediating Atherosclerosis Susceptibility at the Chromosome 9p21 Locus
Authors
Michael S. Cunnington
Bernard Keavney
Publication date
01-06-2011
Publisher
Current Science Inc.
Published in
Current Atherosclerosis Reports / Issue 3/2011
Print ISSN: 1523-3804
Electronic ISSN: 1534-6242
DOI
https://doi.org/10.1007/s11883-011-0178-z

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