Functional Genomics of the 9p21.3 Locus for Atherosclerosis: Clarity or Confusion?

Overview

Journal Curr Cardiol Rep

Publisher Current Science

Specialty Cardiology & Vascular Diseases

Date 2014 Jun 5

PMID 24893939

Citations 21

Authors

Hsiao-Huei Chen

Naif A M Almontashiri

Darlene Antoine

Alexandre F R Stewart

Affiliations

Soon will be listed here.

Abstract

The 9p21.3 locus was the first to yield to genome-wide association studies (GWAS) seeking common genetic variants predisposing to increased risk of coronary artery atherosclerotic disease (CAD). The 59 single nucleotide polymorphisms that show highest association with CAD are clustered in a region 100,000 to 150,000 base pairs 5' to the cyclin-dependent kinase inhibitors CDKN2B (coding for p15(ink4b)) and CDKN2A (coding for p16(ink4a) and p14(ARF)). This region also covers the 3' end of a long noncoding RNA transcribed antisense to CDKN2B (CDKN2BAS, aka ANRIL for antisense noncoding RNA at the ink4 locus) whose expression has been linked to chromatin remodeling at the locus. Despite intensive investigation over the past 7 years, the functional significance of the 9p21.3 locus remains elusive. Other variants at this locus have been associated with glaucoma, glioma, and type 2 diabetes mellitus, diseases that implicate tissue-resident macrophages. Here, we review the evidence that genetic variants at 9p21.3 disrupt tissue-specific enhancers and propose new insights to guide future studies.

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References

Witcher M, Emerson B . Epigenetic silencing of the p16(INK4a) tumor suppressor is associated with loss of CTCF binding and a chromatin boundary. Mol Cell. 2009; 34(3):271-84. PMC: 2723750. DOI: 10.1016/j.molcel.2009.04.001. View

Stewart A, Larkin S, Farrance I, Mar J, Hall D, Ordahl C . Muscle-enriched TEF-1 isoforms bind M-CAT elements from muscle-specific promoters and differentially activate transcription. J Biol Chem. 1994; 269(5):3147-50. View

Musunuru K, Post W, Herzog W, Shen H, OConnell J, McArdle P . Association of single nucleotide polymorphisms on chromosome 9p21.3 with platelet reactivity: a potential mechanism for increased vascular disease. Circ Cardiovasc Genet. 2010; 3(5):445-53. PMC: 3031788. DOI: 10.1161/CIRCGENETICS.109.923508. View

Leask A, Holmes A, Black C, Abraham D . Connective tissue growth factor gene regulation. Requirements for its induction by transforming growth factor-beta 2 in fibroblasts. J Biol Chem. 2003; 278(15):13008-15. DOI: 10.1074/jbc.M210366200. View

Gray L, Fong K, Pavelitz T, Weiner A . Tethering of the conserved piggyBac transposase fusion protein CSB-PGBD3 to chromosomal AP-1 proteins regulates expression of nearby genes in humans. PLoS Genet. 2012; 8(9):e1002972. PMC: 3459987. DOI: 10.1371/journal.pgen.1002972. View

Deloukas P, Kanoni S, Willenborg C, Farrall M, Assimes T, Thompson J . Large-scale association analysis identifies new risk loci for coronary artery disease. Nat Genet. 2012; 45(1):25-33. PMC: 3679547. DOI: 10.1038/ng.2480. View

Wilson P, DAgostino R, Levy D, Belanger A, Silbershatz H, Kannel W . Prediction of coronary heart disease using risk factor categories. Circulation. 1998; 97(18):1837-47. DOI: 10.1161/01.cir.97.18.1837. View

Wong C, Jenne C, Petri B, Chrobok N, Kubes P . Nucleation of platelets with blood-borne pathogens on Kupffer cells precedes other innate immunity and contributes to bacterial clearance. Nat Immunol. 2013; 14(8):785-92. PMC: 4972575. DOI: 10.1038/ni.2631. View

Vijayachandra K, Higgins W, Lee J, Glick A . Induction of p16ink4a and p19ARF by TGFbeta1 contributes to growth arrest and senescence response in mouse keratinocytes. Mol Carcinog. 2008; 48(3):181-186. DOI: 10.1002/mc.20472. View

10.

Parra E, Below J, Krithika S, Valladares A, Barta J, Cox N . Genome-wide association study of type 2 diabetes in a sample from Mexico City and a meta-analysis of a Mexican-American sample from Starr County, Texas. Diabetologia. 2011; 54(8):2038-46. PMC: 3818640. DOI: 10.1007/s00125-011-2172-y. View

11.

Yap K, Li S, Munoz-Cabello A, Raguz S, Zeng L, Mujtaba S . 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):662-74. PMC: 2886305. DOI: 10.1016/j.molcel.2010.03.021. View

12.

Rajaraman P, Melin B, Wang Z, McKean-Cowdin R, Michaud D, Wang S . Genome-wide association study of glioma and meta-analysis. Hum Genet. 2012; 131(12):1877-88. PMC: 3761216. DOI: 10.1007/s00439-012-1212-0. View

13.

Dandona S, Stewart A, Chen L, Williams K, So D, OBrien E . Gene dosage of the common variant 9p21 predicts severity of coronary artery disease. J Am Coll Cardiol. 2010; 56(6):479-86. DOI: 10.1016/j.jacc.2009.10.092. View

14.

Helgadottir A, Thorleifsson G, Magnusson K, Gretarsdottir S, Steinthorsdottir V, Manolescu A . The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm. Nat Genet. 2008; 40(2):217-24. DOI: 10.1038/ng.72. View

15.

Schalkwyk L, Meaburn E, Smith R, Dempster E, Jeffries A, Davies M . Allelic skewing of DNA methylation is widespread across the genome. Am J Hum Genet. 2010; 86(2):196-212. PMC: 2820163. DOI: 10.1016/j.ajhg.2010.01.014. View

16.

Phillips J, Corces V . CTCF: master weaver of the genome. Cell. 2009; 137(7):1194-211. PMC: 3040116. DOI: 10.1016/j.cell.2009.06.001. View

17.

Osman W, Low S, Takahashi A, Kubo M, Nakamura Y . A genome-wide association study in the Japanese population confirms 9p21 and 14q23 as susceptibility loci for primary open angle glaucoma. Hum Mol Genet. 2012; 21(12):2836-42. DOI: 10.1093/hmg/dds103. View

18.

Swirski F, Pittet M, Kircher M, Aikawa E, Jaffer F, Libby P . Monocyte accumulation in mouse atherogenesis is progressive and proportional to extent of disease. Proc Natl Acad Sci U S A. 2006; 103(27):10340-10345. PMC: 1502459. DOI: 10.1073/pnas.0604260103. View

19.

Manning A, Hivert M, Scott R, Grimsby J, Bouatia-Naji N, Chen H . A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance. Nat Genet. 2012; 44(6):659-69. PMC: 3613127. DOI: 10.1038/ng.2274. View

20.

Kim J, Deluna A, Mungrue I, Vu C, Pouldar D, Civelek M . Effect of 9p21.3 coronary artery disease locus neighboring genes on atherosclerosis in mice. Circulation. 2012; 126(15):1896-906. PMC: 3608429. DOI: 10.1161/CIRCULATIONAHA.111.064881. View