Sequence variants within the 9p21 locus of chromosome 9 have been shown to predict increased risk for:

• Early onset myocardial infarction (early MI)^{*,^,1}
• Abdominal aortic aneurysm (AAA)^{†, μ,2}
• Myocardial infarction / coronary heart disease (MI/CHD) in general^{1,^}

The 9p21 polymorphism variants occur within a region thought to be involved in cell-cycle regulatory control ^5,6,7. While the mechanism relating these sequence variants to cardiovascular disease pathophysiology is not yet understood, the disease association has been replicated in several studies ^1,2.

Risk Associated with the 9p21 Genotype:

• 9p21 Carriers Had Up To Two-Fold Higher Risk of Early Onset Myocardial Infarction Events than Noncarriers^±,1 (Figure A)
• 9p21 Carriers Had Up To 74% Higher Risk of Abdominal Aortic Aneurysms than Noncarriers^±,2 (Figure A)

Figure A

9p21-Associated Risk is Independent of Family History and Traditional Risk Factors‡, 3,4 The Population Attributable Risk for 9p21 is Substantial (Figure B) Due to the High Frequency of the Risk-Associated Variant (Figure A) #, 4	Figure B

Based on these data, chromosome 9p21 genotyping may help health care providers identify patients who may be at increased risk for early onset myocardial infarction (early MI), abdominal aortic aneurysm (AAA), or myocardial infarction /coronary heart disease (MI/CHD).

Knowing that 9p21 carriers are at increased risk of early MI or AAA may allow health care providers to take steps to characterize and reduce other risk factors that may contribute to the initiation or progression of sub-clinical or symptomatic disease.

Knowledge of 9p21 carrier status and associated increased risk for early MI or AAA may also be a valuable compliance tool to help health care providers engage patients in treatment recommendations.

For more information about 9p21, download a 9p21 Overview or call Customer Support at 1-800-432-7889, option 3.

Due to the unique nature of genetic testing, physicians may suggest patients consider genetic counseling. Informed consent is recommended and required for patients according to state law. Consent forms are available from Berkeley HeartLab upon request.

Approximately 73% of the Caucasian population carries 9p21 genetic sequence variants associated with risk. Patients who carry 9p21 risk variants will not invariably develop MI, CHD, or AAA. Similarly, patients who do not carry 9p21 risk sequence variants are not protected from developing these diseases.

The 9p21-EarlyMICheck genotyping test detects two single nucleotide polymorphism variants, rs10757278 A>G and rs1333049 G>C, which are in near-perfect linkage disequilibrium (nearly 1.0) and typically in agreement. Approximately 1% of the population experience recombination events which will cause sequence variant determinations from these SNPs to not be consistent.

There are no current data to support that knowledge of 9p21 carrier status affects compliance with treatment recommendations.

^*Early onset MI and MI/CHD study populations consisted of Caucasian men and women (4,587 CHD cases and 12,769 controls) with history of MI.

^†9p21 has been associated with risk of AAA, but not rate of aneurysmal expansion or risk of rupture

^‡9p21-associated risk was stated as independent of traditional risk factors in a Meta-analysis published in JAMA

^#The reported degree of risk and population attributable risk associated with the 9p21 variant and early MI, AAA, and MI/CHD was derived from Caucasian populations

^{^}Early MI and MI/CHD risk association was also established in Asian populations from Korea and Japan that included three studies consisting of 1,872 cases and 4,332 controls ^22,23,24,25

^±Risk results are not adjusted for traditional risk factors

^µAAA study populations consisted of Caucasian men and women with a history of arterial disease and type-2 diabetes from 7 geographically distinct regions in Europe, North America, and New Zealand, a combined analysis of 2,832 cases and 16,732 controls.

The 9p21-EarlyMICheck™ genotyping test was developed and its performance characteristics were determined by Berkeley HeartLab, a CLIA-certified and CAP-accredited laboratory. It has not been reviewed or approved by the FDA.

References and suggested reading:

1. Helgadottir, A et al. (2007). Science 316(5830): 1491-1493.
2. Helgadottir, A et al. (2008). Nat Genet 40(2): 217-224.
3. Palomaki, GE, JAMA. 2010;303(7):648-656.
4. Roberts R. Curr Opin Cardiol 2008;23:629-633.
5. Guttman, M. et al. Nature 458, 223–227 (2009).
6. Pasmant, E. et al. Cancer Res. 67, 3963–3969 (2007)
7. Visel, A.  Nature. Jan 2010. Published online 21 Feb 2010
8. Lloyd-Jones, D. et al. Circulation. 2010; 121:e46-e215.
9. Schunkert, H. et al. Circulation 117, 1675–1684
10. Lemmens, R. et al. Eur. J Hum. Genet. 17,1287–1293 (2009).
11. Shen, G. Q. et al. J. Hum. Genet. 53, 144–150 (2008).
12. Zhou, L. et al. Arterioscler. Thromb. Vasc. Biol. 28, 2085–2089 (2008).
13. Hinohara, K. et al. J. Hum. Genet. 53, 357–359 (2008).
14. Hiura Y, Fukushima et al. Circ J. 2008;72:1213-1217
15. Thompson AR et al. Eur J Hum Genet. 2009;17:391-394
16. Bown MJ Circ Cardiovasc Genet. 2008;1:39-42
17. Lederle F A Archives of Internal Medicine. 2000; 160(10): 1425–1430.
18. Partha P. Majumder Am. J. Hum. Genet. 48:164-170, 1991
19. Scott R A British Journal of Surgery. 2002; 89(3): 283–285.
20. Lederle F Ann Intern Med. 1997; 126(6): 441–449.
21. Hirsch et al. JACC Vol. 47, No. 6 (2006) 1239–312
22. Ding et al. (2009) Circ Cardiovasc Genet 2:338
23. Hiura et al. (2008) Circ J. 72:1213
24. Hinohara et al. (2008) J Hum Genet 53:357
25. Peng et al. (2009) Clin Chem Lab Med 47:917