Inherited Risk Factors for Thrombotic Diseases in Children: The Genome-Wide Perspective

 

 Buy Article Permissions and Reprints

ABSTRACT

As a result of technological advances in the field of high-throughput genomics, there has been a remarkable transition in studying the nature of complex genetic disorders. The genetic analysis of prothrombotic risk factors has shifted from candidate gene to genome-wide association studies (GWAS) in adults. GWAS established a framework in which up to 90% of common genetic variation can be analyzed in a single experiment. Given the ubiquity of the GWAS approach in the adult population, it will become essential for clinicians and researchers in the field of pediatrics to interpret results derived from genetic high-throughput studies. Here, we review the current knowledge regarding genetic factors affecting prothrombotic risk in children and adults. Advantages and pitfalls of the GWAS approach are discussed, including the use of intermediate phenotypes, deep resequencing, and the differences between family-based and association studies. Intelligently designed and well-powered studies incorporating stringent phenotype assessment will contribute to decipher the genetic basis of stroke and venous thrombosis in children.

REFERENCES

• 1 Bezemer I D, van der Meer FJM, Eikenboom JCJ, Rosendaal F R, Doggen CJM. The value of family history as a risk indicator for venous thrombosis.  Arch Intern Med. 2009;  169 (6) 610-615
  Google Scholar
• 2 Vandenbroucke J P, Koster T, Briët E, Reitsma P H, Bertina R M, Rosendaal F R. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation.  Lancet. 1994;  344 (8935) 1453-1457
  Google Scholar
• 3 Gregg J P, Yamane A J, Grody W W. Prevalence of the factor V-Leiden mutation in four distinct American ethnic populations.  Am J Med Genet. 1997;  73 (3) 334-336
  Google Scholar
• 4 Souto J C, Almasy L, Borrell M et al.. Genetic susceptibility to thrombosis and its relationship to physiological risk factors: the GAIT study. Genetic Analysis of Idiopathic Thrombophilia.  Am J Hum Genet. 2000;  67 (6) 1452-1459
  Google Scholar
• 5 McCarthy M I, Abecasis G R, Cardon L R et al.. Genome-wide association studies for complex traits: consensus, uncertainty and challenges.  Nat Rev Genet. 2008;  9 (5) 356-369
  Google Scholar
• 6 Bertina R M, Koeleman B P, Koster T et al.. Mutation in blood coagulation factor V associated with resistance to activated protein C.  Nature. 1994;  369 (6475) 64-67
  Google Scholar
• 7 Kenet G, Lütkhoff L K, Albisetti M et al.. Impact of thrombophilia on risk of arterial ischemic stroke or cerebral sinovenous thrombosis in neonates and children: a systematic review and meta-analysis of observational studies.  Circulation. 2010;  121 (16) 1838-1847
  Google Scholar
• 8 Nowak-Göttl U, Weiler H, Hernandez I et al.. Fibrinogen alpha and gamma genes and factor V Leiden in children with thromboembolism: results from 2 family-based association studies.  Blood. 2009;  114 (9) 1947-1953
  Google Scholar
• 9 Vandenbroucke J P, van der Meer F J, Helmerhorst F M, Rosendaal F R. Factor V Leiden: should we screen oral contraceptive users and pregnant women?.  BMJ. 1996;  313 (7065) 1127-1130
  Google Scholar
• 10 Lijfering W M, Middeldorp S, Veeger NJGM et al.. Risk of recurrent venous thrombosis in homozygous carriers and double heterozygous carriers of factor V Leiden and prothrombin G20210A.  Circulation. 2010;  121 (15) 1706-1712
  Google Scholar
• 11 Nowak-Göttl U, Junker R, Kreuz W Childhood Thrombophilia Study Group et al. Risk of recurrent venous thrombosis in children with combined prothrombotic risk factors.  Blood. 2001;  97 (4) 858-862
  Google Scholar
• 12 Juul K, Tybjaerg-Hansen A, Steffensen R, Kofoed S, Jensen G, Nordestgaard B G. Factor V Leiden: The Copenhagen City Heart Study and 2 meta-analyses.  Blood. 2002;  100 (1) 3-10
  Google Scholar
• 13 Markus H S, Ali N, Swaminathan R, Sankaralingam A, Molloy J, Powell J. A common polymorphism in the methylenetetrahydrofolate reductase gene, homocysteine, and ischemic cerebrovascular disease.  Stroke. 1997;  28 (9) 1739-1743
  Google Scholar
• 14 Kelly P J, Rosand J, Kistler J P et al.. Homocysteine, MTHFR 677C—>T polymorphism, and risk of ischemic stroke: results of a meta-analysis.  Neurology. 2002;  59 (4) 529-536
  Google Scholar
• 15 Wilhelmsen L, Svärdsudd K, Korsan-Bengtsen K, Larsson B, Welin L, Tibblin G. Fibrinogen as a risk factor for stroke and myocardial infarction.  N Engl J Med. 1984;  311 (8) 501-505
  Google Scholar
• 16 Uitte de Willige S, de Visser MCH, Houwing-Duistermaat J J, Rosendaal F R, Vos H L, Bertina R M. Genetic variation in the fibrinogen gamma gene increases the risk for deep venous thrombosis by reducing plasma fibrinogen gamma' levels.  Blood. 2005;  106 (13) 4176-4183
  Google Scholar
• 17 Kardys I, Uitterlinden A G, Hofman A, Witteman JCM, de Maat MPM. Fibrinogen gene haplotypes in relation to risk of coronary events and coronary and extracoronary atherosclerosis: the Rotterdam Study.  Thromb Haemost. 2007;  97 (2) 288-295
  Google Scholar
• 18 Lee D H, Henderson P A, Blajchman M A. Prevalence of factor V Leiden in a Canadian blood donor population.  CMAJ. 1996;  155 (3) 285-289
  Google Scholar
• 19 Limdi N A, Beasley T M, Allison D B, Rivers C A, Acton R T. Racial differences in the prevalence of Factor V Leiden mutation among patients on chronic warfarin therapy.  Blood Cells Mol Dis. 2006;  37 (2) 100-106
  Google Scholar
• 20 Yuan M, Tian X, Zheng G, Yang Y. Adaptive transmission disequilibrium test for family trio design.  Stat Appl Genet Mol Biol. 2009;  8 (1) e30
  Google Scholar
• 21 Spielman R S, Ewens W J. The TDT and other family-based tests for linkage disequilibrium and association.  Am J Hum Genet. 1996;  59 (5) 983-989
  Google Scholar
• 22 Helgadottir A, Thorleifsson G, Magnusson K P et al.. The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm.  Nat Genet. 2008;  40 (2) 217-224
  Google Scholar
• 23 Bilguvar K, Yasuno K, Niemelä M et al.. Susceptibility loci for intracranial aneurysm in European and Japanese populations.  Nat Genet. 2008;  40 (12) 1472-1477
  Google Scholar
• 24 Gretarsdottir S, Thorleifsson G, Manolescu A et al.. Risk variants for atrial fibrillation on chromosome 4q25 associate with ischemic stroke.  Ann Neurol. 2008;  64 (4) 402-409
  Google Scholar
• 25 Gudbjartsson D F, Holm H, Gretarsdottir S et al.. A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke.  Nat Genet. 2009;  41 (8) 876-878
  Google Scholar
• 26 Trégouët D A, 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
  Google Scholar
• 27 Morange P E, Bezemer I, Saut N et al.. A follow-up study of a genome-wide association scan identifies a susceptibility locus for venous thrombosis on chromosome 6p24.1  Am J Hum Genet. 2010;  86 (4) 592-595
  Google Scholar
• 28 Buil A, Trégouët D A, Souto J C et al.. C4BPB/C4BPA is a new susceptibility locus for venous thrombosis with unknown protein S-independent mechanism: results from genome-wide association and gene expression analyses followed by case-control studies.  Blood. 2010;  115 (23) 4644-4650
  Google Scholar
• 29 Stec J J, Silbershatz H, Tofler G H et al.. Association of fibrinogen with cardiovascular risk factors and cardiovascular disease in the Framingham Offspring Population.  Circulation. 2000;  102 (14) 1634-1638
  Google Scholar
• 30 Koster T, Rosendaal F R, Reitsma P H, van der Velden P A, Briët E, Vandenbroucke J P. Factor VII and fibrinogen levels as risk factors for venous thrombosis. A case-control study of plasma levels and DNA polymorphisms—the Leiden Thrombophilia Study (LETS).  Thromb Haemost. 1994;  71 (6) 719-722
  Google Scholar
• 31 Danik J S, Paré G, Chasman D I et al.. Novel loci, including those related to Crohn disease, psoriasis, and inflammation, identified in a genome-wide association study of fibrinogen in 17 686 women: the Women's Genome Health Study.  Circ Cardiovasc Genet. 2009;  2 (2) 134-141
  Google Scholar
• 32 Barber M J, Mangravite L M, Hyde C L et al.. Genome-wide association of lipid-lowering response to statins in combined study populations.  PLoS ONE. 2010;  5 (3) e9763
  Google Scholar
• 33 Inouye M, Silander K, Hamalainen E et al.. An immune response network associated with blood lipid levels.  PLoS Genet. 2010;  6 (9)
  Google Scholar
• 34 Soranzo N, Spector T D, Mangino M et al.. A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium.  Nat Genet. 2009;  41 (11) 1182-1190
  Google Scholar
• 35 Johnson A D, Yanek L R, Chen M H et al.. Genome-wide meta-analyses identifies seven loci associated with platelet aggregation in response to agonists.  Nat Genet. 2010;  42 (7) 608-613
  Google Scholar
• 36 Musunuru K, Post W S, Herzog W et al.. Association of SNPs on Chromosome 9p21.3 with Platelet Reactivity: A Potential Mechanism for Increased Vascular Disease. Circ Cardiovasc Genet. 2010 Sep.; Available from: http://dx.doi.org/10.1161/CIRCGENETICS.109.923508
  Google Scholar
• 37 Caldwell M D, Awad T, Johnson J A et al.. CYP4F2 genetic variant alters required warfarin dose.  Blood. 2008;  111 (8) 4106-4112
  Google Scholar
• 38 Daly A K. Pharmacogenomics of anticoagulants: steps toward personal dosage.  Genome Med. 2009;  1 (1) 10
  Google Scholar
• 39 Rieder M J, Reiner A P, Gage B F et al.. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose.  N Engl J Med. 2005;  352 (22) 2285-2293
  Google Scholar
• 40 Mitchell L, Lambers M, Flege S et al.. Validation of a predictive model for identifying an increased risk for thromboembolism in children with acute lymphoblastic leukemia: results of a multicenter cohort study.  Blood. 2010;  115 (24) 4999-5004
  Google Scholar
• 41 Daly A. Genome-wide association studies in pharmacogenomics.  Nat Rev Genet. 2010;  11 241-246
  Google Scholar

Monika StollPh.D. 

Department of Genetic Epidemiology of Vascular Disorders, Leibniz-Institute for Arteriosclerosis Research, Westfälische-Wilhelms-University Muenster

Domagkstr.3, 48149 Muenster, Germany

Email: mstoll@uni-muenster.de