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9p21 – Genetic Risk for Cardiovascular Disease

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9p21 – Genetic Risk for Cardiovascular Disease

9p21 – Genetic Risk for Cardiovascular Disease

Genetic differentiation is what makes us unique. It also changes our risk for certain diseases. In regards to cardiovascular disease, one gene stands out as having a consistent association with increased risk of coronary heart disease, heart attacks (MI) and atherosclerosis. That gene is 9p21.

4 separate studies reported the association between 9p21 and cardiovascular disease within weeks of each other in 2007.16 Eight different single nucleotide polymorphisms (SNPs) have been identified to associate with increased risk of cardiovascular disease.

It is interesting to note that the association of 9p21 to cardiovascular disease is independent of other risk factors. 9p21 doesn’t seem to have any effect on cholesterol, hypertension, diabetes or markers of inflammation. Because of this, the mechanism by which 9p21 increases risk is poorly understood.8,9  Another interesting point is that the atherogenic 9p21 Single Nucleotide Polymorphism (SNP) maps to a segment of the chromosome with no known protein coding genes.

 

The 9p21 Gene is associated with:

  • Coronary artery disease (CAD)9,11,17
  • Heart attacks (myocardial infarction [MI])8,18
  • Abdominal aortic aneurysms7
  • Intracrandial aneurysms7
  • Peridontitis19
  • Stroke6

Approximately 21% of individuals in the population are homozygous for this SNP meaning that both of their genes have the higher risk variant. Their estimated risk of suffering heart attack is 1.64 times compared to those without the high-risk SNP. In looking this SNP in the setting of early-onset heart attacks, the risk is doubled8.

 

How Does 9p21 Increase Heart Attack Risk?

Initially, the 9p21 SNP didn’t make sense. However, more information has come out which, at least partially, explains why 9p21 increases risk for cardiovascular disease.

Signal Transducer and Activator of Transcription 1 (STAT1) is a transcription factor protein. This means that it helps turn certain genes on and off. It is activated by several ligands such as IL-6, TNFa, PDGF, and many others.20 STAT1 has a key role in many gene expressions that cause survival of the cell, viability or pathogen response. It plays a very important role in inflammation. Inflammation is a major contributor to atherosclerosis and angiogenesis in endothelial tissue.

There are 33 gene enhancers located in the 9p21 region that are implicated in inflammatory pathways.1 The interaction of 9p21 with STAT1, CDKN2A/B, and INF-g increase the genetic susceptibility to coronary heart disease and the response to inflammatory signaling in vascular cells.10  STAT1 is a downstream effector of the pathway that mediates response to inflammation, which is associated with angiogenesis12 and atherosclerosis pathogenesis13 in endothelial tissue. Thus, in endothelial tissues, the biological effects of the rs10811656 and rs10757278 risk alleles disrupting the ECAD9 STAT1 binding site might be augmented during activation of the inflammatory response.

Two SNPs located in one of these enhancers disrupt a binding site for STAT1, a signal transduction protein that regulates inflammation. This enhancer locus physically interacts with the CDKN2A/B locus and an interval downstream of IFNA21, The gene that encodes interferon-γ in human vascular endothelial cells. The activation of interferon-γ affects transcriptional regulation of the 9p21 locus, including STAT1 binding, suggesting a link between genetic susceptibility to coronary artery disease and response to inflammatory signaling in vascular cells. Yet another driver of disease may be the aforementioned noncoding RNA element ANRIL.

 

How To Improve Your Risk If you Have 9p21

Obviously, you can’t change your genetics any more than a leopard can change its spots. The good news is that you CAN change whether or not this gene is causing a problem and increasing your risk.

A study by Ron et al. evaluated 8,114 participants from the global INTERHEART Study and assessed 4 different 9p21 SNPs. They evaluated the association of 9p21 with MI in those participants who ate a “prudent” diet vs those who ate less fruits and vegetables. They discovered that those who ate high amounts of the prudent diet virtually negated their risk of MI associated with their higher risk due to 9p21 (odds ratio = 1.02). The FINRISK Study revealed similar findings.15 

Another trial evaluated the association of Sugar Sweetened Beverages (SSB) and 9p21. They found a clear and strong association between MI and SSB in those with 9p21. Those who drank the most SSB (highest tertile) had an odds ratio of 1.45 (45% increased risk of MI) compared to those in the lowest intake (lowest tertile) with an odds ratio of 0.96 (4% reduced risk of MI).21

As with so many things in medicine, a healthy lifestyle can make all the difference. The Traditional Mediterranean Diet (TMD) and the DASH-2 diet have been shown to be beneficial for improving health. The principles within these nutritional approaches appear to extend to patients at higher risk of cardiovascular disease because of the 9p21 gene. The principles behind these nutritional approaches are outlined in our Revolution Nutrition Plan.

 

 

References

  1. Nature. 2011 Feb 10; 470(7333): 264–268.
  2. Roberts R. Genetics of premature myocardial infarction. Curr Atheroscler Rep. 2008 Jun;10(3):186-93.
  3. Shen GQ1, Rao S, Martinelli N, Li L, Olivieri O, Corrocher R, Abdullah KG, Hazen SL, Smith J, Barnard J, Plow EF, Girelli D, Wang QK.Association between four SNPs on chromosome 9p21 and myocardial infarction is replicated in an Italian population. Genome-wide single nucleotide polymorphism (SNP) association studies recently identified four SNPs (rs10757274, rs2383206, rs2383207, and rs10757278) on chromosome 9p21 were associated with myocardial infarction (MI) with odd ratio of 1.24, 1.31, 1.26, and 1.28.
  4. Helgadottir A1, Thorleifsson G, Magnusson KP, Grétarsdottir S, Steinthorsdottir V, Manolescu A, Jones GT, Rinkel GJ, Blankensteijn JD, Ronkainen A, Jääskeläinen JE, Kyo Y, Lenk GM, Sakalihasan N, Kostulas K, Gottsäter A, Flex A, Stefansson H, Hansen T, Andersen G, Weinsheimer S, Borch-Johnsen K, Jorgensen T, Shah SH, Quyyumi AA, Granger CB, Reilly MP, Austin H, Levey AI, Vaccarino V, Palsdottir E, Walters GB, Jonsdottir T, Snorradottir S, Magnusdottir D, Gudmundsson G, Ferrell RE, Sveinbjornsdottir S, Hernesniemi J, Niemelä M, Limet R, Andersen K, Sigurdsson G, Benediktsson R, Verhoeven EL, Teijink JA, Grobbee DE, Rader DJ, Collier DA, Pedersen O, Pola R, Hillert J, Lindblad B, Valdimarsson EM, Magnadottir HB, Wijmenga C, Tromp G, Baas AF, Ruigrok YM, van Rij AM, Kuivaniemi H, Powell JT, Matthiasson SE, Gulcher JR, Thorgeirsson G, Kong A, Thorsteinsdottir U, Stefansson K.The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm. Study population included 16732 controls, 2836 individuals diagnosed with Abdominal Aortic Aneurysm, Results indicate that rs10757278-G is associated with Abdominal Aortic Aneurysm has an odd ratio of 1.31.
  5. Genomics of Cardiovascular Disease. NEJM 2011;365:2098-109
  6. Anderson CD, Biffi A, Rost NS, Cortellini L, Furie KL, Rosand J. Chromosome 9p21 in ischemic stroke: population structure and meta-analysis. Stroke 2010;41:1123–1131
  7. 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;40:217–224
  8. Helgadottir A, Thorleifsson G, Manolescu A, et al. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science 2007;316:1491–1493
  9. McPherson R, Pertsemlidis A, Kavaslar N, et al. A common allele on chromosome 9 associated with coronary heart disease. Science 2007;316:1488–1491
  10. Visel A, Zhu Y, May D, et al. Targeted deletion of the 9p21 non-coding coronary artery disease risk interval in mice. Nature 2010;464:409–412
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  13. Am Heart J. 1999 Nov; 138(5 Pt 2):S419-20.
  14. J Am Coll Cardiol 2014;63:2234-45.
  15. Do R, Xie C, Zhang X, et al. The effect of chromosome 9p21 variants on cardiovascular disease may be modified by dietary intake: evidence from a case/control and a prospective study. PLoS Med 201;8:e1001106.
  16. Circulation: Cardiovascular Genetics. 2008;1:81–84
  17. N Engl J Med. 2007; 357: 443–453.
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  19. Schaefer AS, Richter GM, Groessner-Schreiber B, Noack B, Nothnagel M, El Mokhtari NE, Loos BG, Jepsen S, Schreiber S: Identification of a shared genetic susceptibility locus for coronary heart disease and periodontitis. PLoS Genet. 2009, 5: e1000378-10.1371/journal.pgen.1000378.
  20. Journal of Clinical Immunology. 36 (7): 641–8.
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