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The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm

Abstract

Recently, two common sequence variants on 9p21, tagged by rs10757278-G and rs10811661-T, were reported to be associated with coronary artery disease (CAD)1,2,3,4 and type 2 diabetes (T2D)5,6,7, respectively. We proceeded to further investigate the contributions of these variants to arterial diseases and T2D. Here we report that rs10757278-G is associated with, in addition to CAD, abdominal aortic aneurysm (AAA; odds ratio (OR) = 1.31, P = 1.2 × 10−12) and intracranial aneurysm (OR = 1.29, P = 2.5 × 10−6), but not with T2D. This variant is the first to be described that affects the risk of AAA and intracranial aneurysm in many populations. The association of rs10811661-T to T2D replicates in our samples, but the variant does not associate with any of the five arterial diseases examined. These findings extend our insight into the role of the sequence variant tagged by rs10757278-G and show that it is not confined to atherosclerotic diseases.

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References

  1. Helgadottir, A. et al. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science 316, 1491–1493 (2007).

    Article  CAS  Google Scholar 

  2. McPherson, R. et al. A common allele on chromosome 9 associated with coronary heart disease. Science 316, 1488–1491 (2007).

    Article  CAS  Google Scholar 

  3. The 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).

  4. Samani, N.J. et al. Genomewide association analysis of coronary artery disease. N. Engl. J. Med. 357, 443–453 (2007).

    Article  CAS  Google Scholar 

  5. Zeggini, E. et al. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316, 1336–1341 (2007).

    Article  CAS  Google Scholar 

  6. Scott, L.J. et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316, 1341–1345 (2007).

    Article  CAS  Google Scholar 

  7. Saxena, R. et al. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316, 1331–1336 (2007).

    Article  CAS  Google Scholar 

  8. International HapMap Consortium. A haplotype map of the human genome. Nature 437, 1299–1320 (2005).

  9. Kim, W.Y. & Sharpless, N.E. The regulation of INK4/ARF in cancer and aging. Cell 127, 265–275 (2006).

    Article  CAS  Google Scholar 

  10. Falk, E., Shah, P.K. & Fuster, V. Coronary plaque disruption. Circulation 92, 657–671 (1995).

    Article  CAS  Google Scholar 

  11. Schievink, W.I. Intracranial aneurysms. N. Engl. J. Med. 336, 28–40 (1997).

    Article  CAS  Google Scholar 

  12. Lederle, F.A., Johnson, G.R. & Wilson, S.E. Abdominal aortic aneurysm in women. J. Vasc. Surg. 34, 122–126 (2001).

    Article  CAS  Google Scholar 

  13. Lederle, F.A. et al. The aneurysm detection and management study screening program: validation cohort and final results. Aneurysm Detection and Management Veterans Affairs Cooperative Study Investigators. Arch. Intern. Med. 160, 1425–1430 (2000).

    Article  CAS  Google Scholar 

  14. Thompson, R.W. Reflections on the pathogenesis of abdominal aortic aneurysms. Cardiovasc. Surg. 10, 389–394 (2002).

    Article  Google Scholar 

  15. Brady, A.R., Thompson, S.G., Fowkes, F.G., Greenhalgh, R.M. & Powell, J.T. Abdominal aortic aneurysm expansion: risk factors and time intervals for surveillance. Circulation 110, 16–21 (2004).

    Article  Google Scholar 

  16. Chatzizisis, Y.S. et al. Role of endothelial shear stress in the natural history of coronary atherosclerosis and vascular remodeling: molecular, cellular, and vascular behavior. J. Am. Coll. Cardiol. 49, 2379–2393 (2007).

    Article  CAS  Google Scholar 

  17. Hashimoto, T., Meng, H. & Young, W.L. Intracranial aneurysms: links among inflammation, hemodynamics and vascular remodeling. Neurol. Res. 28, 372–380 (2006).

    Article  Google Scholar 

  18. Moore, J.E. Jr., Xu, C., Glagov, S., Zarins, C.K. & Ku, D.N. Fluid wall shear stress measurements in a model of the human abdominal aorta: oscillatory behavior and relationship to atherosclerosis. Atherosclerosis 110, 225–240 (1994).

    Article  CAS  Google Scholar 

  19. Adams, H.P. Jr. et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 24, 35–41 (1993).

    Article  Google Scholar 

  20. Weinsheimer, S. et al. Association of kallikrein gene polymorphisms with intracranial aneurysms. Stroke 38, 2670–2676 (2007).

    Article  CAS  Google Scholar 

  21. Flex, A. et al. The −174 G/C polymorphism of the interleukin-6 gene promoter is associated with peripheral artery occlusive disease. Eur. J. Vasc. Endovasc. Surg. 24, 264–268 (2002).

    Article  CAS  Google Scholar 

  22. Barani, J., Nilsson, J.A., Mattiasson, I., Lindblad, B. & Gottsater, A. Inflammatory mediators are associated with 1-year mortality in critical limb ischemia. J. Vasc. Surg. 42, 75–80 (2005).

    Article  Google Scholar 

  23. Jones, G.T. et al. Plasma lipoprotein(a) indicates risk for 4 distinct forms of vascular disease. Clin. Chem. 53, 679–685 (2007).

    Article  CAS  Google Scholar 

  24. Ogata, T. et al. Genetic analysis of polymorphisms in biologically relevant candidate genes in patients with abdominal aortic aneurysms. J. Vasc. Surg. 41, 1036–1042 (2005).

    Article  Google Scholar 

  25. St Jean, P.L. et al. Characterization of a dinucleotide repeat in the 92 kDa type IV collagenase gene (CLG4B), localization of CLG4B to chromosome 20 and the role of CLG4B in aortic aneurysmal disease. Ann. Hum. Genet. 59, 17–24 (1995).

    Article  CAS  Google Scholar 

  26. Steinthorsdottir, V. et al. A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat. Genet. 39, 770–775 (2007).

    Article  CAS  Google Scholar 

  27. Gretarsdottir, S. et al. The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat. Genet. 35, 131–138 (2003).

    Article  CAS  Google Scholar 

  28. Stefansson, H. et al. A common inversion under selection in Europeans. Nat. Genet. 37, 129–137 (2005).

    Article  CAS  Google Scholar 

  29. Mantel, N. & Haenszel, W. Statistical aspects of the analysis of data from retrospective studies of disease. J. Natl. Cancer Inst. 22, 719–748 (1959).

    CAS  Google Scholar 

  30. Grarup, N. et al. Studies of association of variants near the HHEX, CDKN2A/B and IGF2BP2 genes with type 2 diabetes and impaired insulin release in 10,705 Danish subjects validation and extension of genome-wide association studies. Diabetes 56, 3105–3111 (2007); published online 7 September 2007.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the participants whose contribution made this study possible, Noatun (deCODE's sample recruitment center) and the personnel at deCODE core facilities. The recruitment of AAA sample sets and controls from Belgium, Canada and Pennsylvania was funded in part by grants from the US National Heart, Lung and Blood Institute (HL064310 to H.K. and HL044682 to R.E.F.). G.M.L. is a recipient of American Heart Association Predoctoral Fellowships (0510063Z and 0710099Z). The UK AAA sample collection was funded partially from grants from the Medical Research Council and British Heart Foundation. DNA isolation of Dutch AAA samples was funded from a grant from the Novartis Foundation for Cardiovascular Excellence. The Finnish intracranial aneurysm sample collection was funded in part by a US National Institutes of Health grant (NS034395 to G.T.), the American Heart Association, Michigan Affiliate (to G.T.), the University of Kuopio (to A.R.), the University of Helsinki (to J.E.J.) and an American Heart Association Predoctoral Fellowship (0410051Z to S.W.). Y.M. Ruigrok was supported by a grant from the Dr. E. Dekker program of the Netherlands Heart Foundation (2005T014).

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Correspondence to Unnur Thorsteinsdottir or Kari Stefansson.

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Authors from deCODE have stock options in deCODE Genetics. deCODE Genetics has applied for a patent related to this work.

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Helgadottir, A., Thorleifsson, G., Magnusson, K. et al. The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm. Nat Genet 40, 217–224 (2008). https://doi.org/10.1038/ng.72

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