The Association of atherothrombosis and thrombophilias – genetic aspects

Czech version

Authors: Tomáš Kvasnička
Authors‘ workplace: Trombotické centrum Ústavu lékařské biochemie a laboratorní diagnostiky 1. LF UK a VFN Praha, přednosta prof. MUDr. Tomáš Zima, DrSc, MBA
Published in: Vnitř Lék 2014; 60(10): 880-884
Category: Reviews

Overview

Thrombosis in the arterial or venous vascular systems is preceded by a complex interplay between environmental and genetic factors, and it is the underlying cause of several common complex diseases. The genomewide association approach has proved successful in identifying loci associated with cardiovascular disease and related risk factors. However, much work remains to identifyning the culprit genes and causal variants as well as the mechanisms whereby they influence disease development and progression. In-depth studies of previously identified disease-associated loci are expected to improve our understanding of the pathophysiology of cardiovascular disease and identify novel targets for treatment. In the field of atherothrombosis and thrombophilia are significant results from association studies focused on the area of coronary artery disease, ischemic stroke, venous thromboembolism.

Key words:
atherosclerosis – atherothrombosis – coronary artery disease – genomewide association study (GWAS) – myocardial infarction – single nucleotide polymorphism (SNP) – thrombophilia – venous thromboembolism

Sources

1. 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): 661–678.

2. Hindorff LA, Sethupathy P, Junkins HA et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci USA 2009; 106(23): 9362–9367.

3. Lusis AJ, Mar R, Pajukanta P Genetics of atherosclerosis. Annu Rev Genomics Hum Genet 2004; 5: 189–218.

4. Libby P, Ridker PM, Hansson GK Inflammation in atherosclerosis: from pathophysiology to practice. J Am Coll Cardiol 2009; 54(23): 2129–2138.

5. Helgadottir A, Thorleifsson G, Manolescu A et al. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science 2007; 316(5830): 1491–1493.

6. Schunkert H, Gotz A, Braund P et al. Repeated replication and a prospective meta-analysis of the association between chromosome 9p21.3 and coronary artery disease. Circulation 2008; 117(13): 1675–1684.

7. 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): 806–814.

8. Jarinova O, Stewart AF, 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.

9. 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.

10. Kathiresan S, Voight BF, Purcell S et al. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat Genet 2009; 41(3): 334–341.

11. Nielsen MS, Jacobsen C, Olivecrona G et al. Sortilin/neurotensin receptor-3 binds and mediates degradation of lipoprotein lipase. J Biol Chem 1999; 274(13): 8832–8836.

12. Rader DJ, Cohen J, Hobbs HH. Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. J Clin Invest 2003; 111(12): 1795–1803.

13. Clarke R, Peden JF, Hopewell JC et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med 2009; 361(26): 2518–2528.

14. Erqou S, Kaptoge S, Perry PL et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA 2009; 302(4): 412–423.

15. Bosserhoff AK, Moser M, Buettner R. Characterization and expression pattern of the novel MIA homolog TANGO. Gene Expr Patterns 2004; 4(4): 473–479.

16. Holzel M, Rohrmoser M, Schlee M et al. Mammalian WDR12 is a novel member of the Pes1-Bop1 complex and is required for ribosome biogenesis and cell proliferation. J Cell Biol 2005; 170(3): 367–378.

17. Allen PB, Greenfield AT, Svenningsson P et al. Phactrs 1–4: A family of protein phosphatase 1 and actin regulatory proteins. Proc Natl Acad Sci USA 2004; 101(18): 7187–7192.

18. Gleissner CA, von Hundelshausen P, Ley K. Platelet chemokines in vascular disease. Arterioscler Thromb Vasc Biol 2008; 28(11): 1920–1927.

19. Stellos K, Bigalke B, Langer H et al. Expression of stromal-cellderived factor-1 on circulating platelets is increased in patients with acute coronary syndrome and correlates with the number of CD34+ progenitor cells. Eur Heart J 2009; 30(5): 584–593.

20. Abbott GW, Sesti F, Splawski I et al. MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell 1999; 97(2): 175–187.

21. Erdmann J, Grosshennig A, Braund PS et al. New susceptibility locus for coronary artery disease on chromosome 3q22.3. Nat Genet 2009; 41(3): 280–282.

22. Elliott P, Chambers JC, Zhang W et al. Genetic Loci associated with C-reactive protein levels and risk of coronary heart disease. JAMA 2009; 302(1): 37–48.

23. Gudbjartsson DF, Bjornsdottir US, Halapi E et al. Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nat Genet 2009; 41(3): 342–347.

24. Takaki S, Sauer K, Iritani BM et al. Control of B cell production by the adaptor protein lnk. Definition of a conserved family of signal-modulating proteins. Immunity 2000; 13(5): 599–609.

25. Takizawa H, Nishimura S, Takayama N et al. Lnk regulates integrin alphaIIb beta3 outside-in signaling in mouse platelets, leading to stabilization of thrombus development in vivo. J Clin Invest 2010; 120(1): 179–190.

26. Tregouet DA, Heath S, Saut N et al. Common susceptibility alleles are unlikely to contribute as strongly as the FV and ABO loci to VTE risk: results from a GWAS approach. Blood 2009; 113(21): 5298–5303.

27. Bezemer ID, Bare LA, Doggen CJ et al. Gene variants associated with deep vein thrombosis. JAMA 2008; 299(11): 1306–1314.

28. Coenen MJ, Trynka G, Heskamp S et al. Common and different genetic background for rheumatoid arthritis and celiac disease. Hum Mol Genet 2009; 18(21): 4195–4203.

29. Ikram MA, Seshadri S, Bis JC et al. Genomewide association studies of stroke. N Engl J Med 2009; 360(17): 1718–1728.

30. Debette S, Bis JC, Fornage M et al. Genome-wide association studies of MRI-defined brain infarcts: meta-analysis from the CHARGE Consortium. Stroke 2010; 41(2): 210–217.

31. Chasman DI, Paré G, Mora S et al. Forty-three loci associated with plasma lipoprotein size, concentration, and cholesterol content in genome-wide analysis. PLoS Genet 2009; 5(11): e1000730. Dostupné z DOI: <http://doi: 10.1371/journal.pgen.1000730>.

32. Abbas Dehghan, Qiong Yang, Annette Peters et al. Association of novel genetic loci with circulating fibrinogen levels. Circ Cardiovasc Genet 2009; 2(2): 125–133.

33. Dupuis J, Langenberg C, Prokopenko I et al. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 2010; 42(2): 105–116.

34. Saxena R, Hivert MF, Langenberg C et al. Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge. Nat Genet 2010; 42(2): 142–148.

35. Manolio TA, Collins FS, Cox NJ et al. Finding the missing heritability of complex diseases. Nature 2009; 461(7265): 747–753.