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Journal of Molecular Medicine

, Volume 96, Issue 8, pp 765–775 | Cite as

Targeted resequencing of a locus for heparin-induced thrombocytopenia on chromosome 5 identified in a genome-wide association study

  • Anika Witten
  • Juliane Bolbrinker
  • Andrei Barysenka
  • Matthias Huber
  • Frank Rühle
  • Ulrike Nowak-Göttl
  • Edeltraut Garbe
  • Reinhold Kreutz
  • Monika StollEmail author
Original Article

Abstract

Immune-mediated heparin-induced thrombocytopenia (HIT) is the clinically most important adverse drug reaction (ADR) in response to heparin therapy characterized by a prothrombotic state despite a decrease in platelet count. We conducted a genome-wide association study in 96 suspected HIT cases and 96 controls to explore the genetic predisposition for HIT within a case-control pharmacovigilance study followed by replication in additional 86 cases and 86 controls from the same study. One single nucleotide polymorphism (SNP, rs1433265, P = 6.5 × 10−5, odds ratio (OR) 2.79) from 16 identified SNPs was successfully replicated (P = 1.5 × 10−4, OR 2.77; combined data set P = 2.7 × 10−8, OR 2.77) and remained the most strongly associated SNP after imputing locus genotypes. Fine mapping revealed a significantly associated risk-conferring haplotype (P = 4.9 × 10−6, OR 2.41). In order to find rare variants contributing to the association signals, we applied a targeted resequencing approach in a subgroup of 73 HIT patients and 23 controls for the regions with the 16 most strongly HIT-associated SNPs. C-alpha testing was applied to test for the impact of rare variants and we detected two candidate genes, the discoidin domain receptor tyrosine kinase 1 (DDR1, P = 3.6 × 10−2) and the multiple C2 and transmembrane domain containing 2 (MCTP2, P = 4.5 × 10−2). For the genes interactor of little elongation complex ELL subunit 1 (ICE1) and a disintegrin-like and metalloproteinase with thrombospondin type 1 motif, 16 (ADAMTS16) nearby rs1433265, we identified several missense variants. Although replication in an independent population is warranted, these findings provide a basis for future studies aiming to identify and characterize genetic susceptibility factors for HIT.

Key messages

  • We identified and validated a HIT-associated locus on chromosome 5.

  • Targeted NGS analysis for rare variants identifies DDR1 and MCTP2 as novel candidates.

  • In addition, missense variants for ADAMTS16 and ICE1 were identified in the locus.

Keywords

ADR HIT GWAS ADAMTS16 ICE1 

Notes

Acknowledgments

The authors appreciate the technical assistance of Tanja Bauer, Marianne Jansen-Rust, Petra Pietsch, Silke Pollack, and Karen Böhme. We thank all participating hospitals for contributing cases and controls to this study and all patients who participated.

Funding

The Berlin Pharmacovigilance Center Study was funded by the Federal Institute for Drugs and Medical Devices in Bonn, Germany, grant number V-5238/68502-68605.

Supplementary material

109_2018_1661_MOESM1_ESM.docx (2.7 mb)
ESM 1 (DOCX 2.70 mb)

References

  1. 1.
    Warkentin TE, Levine MN, Hirsh J, Horsewood P, Roberts RS, Gent M, Kelton JG (1995) Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 332(20):1330–1335CrossRefPubMedGoogle Scholar
  2. 2.
    Ortel TL (2009) Heparin-induced thrombocytopenia: when a low platelet count is a mandate for anticoagulation. Hematol Am Soc Hematol Educ Program:225–232Google Scholar
  3. 3.
    Greinacher A (2015) Heparin-induced thrombocytopenia. N Engl J Med 373(19):1883–1884PubMedGoogle Scholar
  4. 4.
    Arepally GM (2017) Heparin-induced thrombocytopenia. Blood 129(21):2864–2872CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Krauel K, Potschke C, Weber C, Kessler W, Furll B, Ittermann T, Maier S, Hammerschmidt S, Broker BM, Greinacher A (2011) Platelet factor 4 binds to bacteria-inducing antibodies cross-reacting with the major antigen in heparin-induced thrombocytopenia. Blood 117(4):1370–1378CrossRefPubMedGoogle Scholar
  6. 6.
    Kelton JG, Warkentin TE, Moore JC, Arnold DM, Nazi I, Arepally GM, Roach JM, Fier I (2012) A prospective study measuring the development of antibodies against platelet factor 4-heparin in healthy males after exposure to heparins. J Thromb Haemost 10(7):1446–1449CrossRefPubMedGoogle Scholar
  7. 7.
    Junqueira DR, Zorzela LM, Perini E (2017) Unfractionated heparin versus low molecular weight heparins for avoiding heparin-induced thrombocytopenia in postoperative patients. Cochrane Database Syst Rev 4:Cd007557PubMedGoogle Scholar
  8. 8.
    Girolami B, Prandoni P, Stefani PM, Tanduo C, Sabbion P, Eichler P, Ramon R, Baggio G, Fabris F, Girolami A (2003) The incidence of heparin-induced thrombocytopenia in hospitalized medical patients treated with subcutaneous unfractionated heparin: a prospective cohort study. Blood 101(8):2955–2959CrossRefPubMedGoogle Scholar
  9. 9.
    Prandoni P, Siragusa S, Girolami B, Fabris F (2005) The incidence of heparin-induced thrombocytopenia in medical patients treated with low-molecular-weight heparin: a prospective cohort study. Blood 106(9):3049–3054CrossRefPubMedGoogle Scholar
  10. 10.
    Girolami B, Girolami A (2006) Heparin-induced thrombocytopenia: a review. Semin Thromb Hemost 32(8):803–809CrossRefPubMedGoogle Scholar
  11. 11.
    Kato S, Takahashi K, Ayabe K, Samad R, Fukaya E, Friedmann P, Varma M, Bergmann SR (2011) Heparin-induced thrombocytopenia: analysis of risk factors in medical inpatients. Br J Haematol 154(3):373–377CrossRefPubMedGoogle Scholar
  12. 12.
    Lubenow N, Hinz P, Thomaschewski S, Lietz T, Vogler M, Ladwig A, Junger M, Nauck M, Schellong S, Wander K, Engel G, Ekkernkamp A, Greinacher A (2010) The severity of trauma determines the immune response to PF4/heparin and the frequency of heparin-induced thrombocytopenia. Blood 115(9):1797–1803CrossRefPubMedGoogle Scholar
  13. 13.
    Warkentin TE, Sheppard JA, Sigouin CS, Kohlmann T, Eichler P, Greinacher A (2006) Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia. Blood 108(9):2937–2941CrossRefPubMedGoogle Scholar
  14. 14.
    Kosfeld RE, Lansing AM, Masri Z, Liu YK (1985) Heparin-induced thrombocytopenia and recurrent thromboembolism in siblings. Am J Hematol 18(4):421–423CrossRefPubMedGoogle Scholar
  15. 15.
    Lee DH, Warkentin TE, Denomme GA, Lagrotteria DD, Kelton JG (1998) Factor V Leiden and thrombotic complications in heparin-induced thrombocytopenia. Thromb Haemost 79(1):50–53CrossRefPubMedGoogle Scholar
  16. 16.
    Carlsson LE, Lubenow N, Blumentritt C, Kempf R, Papenberg S, Schroder W, Eichler P, Herrmann FH, Santoso S, Greinacher A (2003) Platelet receptor and clotting factor polymorphisms as genetic risk factors for thromboembolic complications in heparin-induced thrombocytopenia. Pharmacogenetics 13(5):253–258CrossRefPubMedGoogle Scholar
  17. 17.
    Horsewood P, Kelton JG (2000) Investigation of a platelet factor 4 polymorphism on the immune response in patients with heparin-induced thrombocytopenia. Platelets 11(1):23–27CrossRefPubMedGoogle Scholar
  18. 18.
    Harris K, Nguyen P, Van Cott EM (2008) Platelet PlA2 polymorphism and the risk for thrombosis in heparin-induced thrombocytopenia. Am J Clin Pathol 129(2):282–286CrossRefPubMedGoogle Scholar
  19. 19.
    Pouplard C, Cornillet-Lefebvre P, Attaoua R, Leroux D, Lecocq-Lafon C, Rollin J, Grigorescu F, Nguyen P, Gruel Y (2012) Interleukin-10 promoter microsatellite polymorphisms influence the immune response to heparin and the risk of heparin-induced thrombocytopenia. Thromb Res 129(4):465–469CrossRefPubMedGoogle Scholar
  20. 20.
    Rollin J, Pouplard C, Gratacap MP, Leroux D, May MA, Aupart M, Gouilleux-Gruart V, Payrastre B, Gruel Y (2012) Polymorphisms of protein tyrosine phosphatase CD148 influence FcgammaRIIA-dependent platelet activation and the risk of heparin-induced thrombocytopenia. Blood 120(6):1309–1316CrossRefPubMedGoogle Scholar
  21. 21.
    Rollin J, Pouplard C, Leroux D, May MA, Gruel Y (2013) Impact of polymorphisms affecting the ACP1 gene on levels of antibodies against platelet factor 4-heparin complexes. J Thromb Haemost 11(8):1609–1611CrossRefPubMedGoogle Scholar
  22. 22.
    Pamela S, Anna ML, Elena D, Giovanni M, Emanuele A, Silvia V, Carmen B, Andreas G, Fabrizio F (2013) Heparin-induced thrombocytopenia: the role of platelets genetic polymorphisms. Platelets 24(5):362–368CrossRefPubMedGoogle Scholar
  23. 23.
    Slavik L, Svobodova G, Ulehlova J, Krcova V, Hlusi A, Prochazkova J, Hutyra M (2015) Polymorphism of the Fcgamma receptor II as a possible predisposing factor for heparin-induced thrombocytopenia. Clin Lab 61(8):1027–1032PubMedGoogle Scholar
  24. 24.
    Rollin J, Pouplard C, Gruel Y (2016) Risk factors for heparin-induced thrombocytopenia: focus on Fcgamma receptors. Thromb Haemost 116(5):799–805CrossRefPubMedGoogle Scholar
  25. 25.
    Karnes JH, Cronin RM, Rollin J, Teumer A, Pouplard C, Shaffer CM, Blanquicett C, Bowton EA, Cowan JD, Mosley JD, Van Driest SL, Weeke PE, Wells QS, Bakchoul T, Denny JC, Greinacher A, Gruel Y, Roden DM (2015) A genome-wide association study of heparin-induced thrombocytopenia using an electronic medical record. Thromb Haemost 113(4):772–781CrossRefPubMedGoogle Scholar
  26. 26.
    Linkins LA, Dans AL, Moores LK, Bona R, Davidson BL, Schulman S, Crowther M (2012) Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 141(2 Suppl):e495S–e530SCrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Garbe E, Andersohn F, Bronder E, Salama A, Klimpel A, Thomae M, Schrezenmeier H, Hildebrandt M, Spath-Schwalbe E, Gruneisen A, Meyer O, Kurtal H (2012) Drug-induced immune thrombocytopaenia: results from the Berlin Case-Control Surveillance Study. Eur J Clin Pharmacol 68(5):821–832CrossRefPubMedGoogle Scholar
  28. 28.
    Bolbrinker J, Garbe E, Douros A, Huber M, Bronder E, Klimpel A, Andersohn F, Meyer O, Salama A, Kreutz R (2017) Immobilization and high platelet count are associated with thromboembolic complications in heparin-induced thrombocytopenia. Pharmacoepidemiol Drug Saf 26(10):1149–1155CrossRefPubMedGoogle Scholar
  29. 29.
    Greinacher A, Michels I, Kiefel V, Mueller-Eckhardt C (1991) A rapid and sensitive test for diagnosing heparin-associated thrombocytopenia. Thromb Haemost 66(6):734–736PubMedCrossRefGoogle Scholar
  30. 30.
    Meyer O, Salama A, Pittet N, Schwind P (1999) Rapid detection of heparin-induced platelet antibodies with particle gel immunoassay (ID-HPF4). Lancet 354(9189):1525–1526CrossRefPubMedGoogle Scholar
  31. 31.
    Warkentin TE (2003) Heparin-induced thrombocytopenia: pathogenesis and management. Br J Haematol 121(4):535–555CrossRefPubMedGoogle Scholar
  32. 32.
    Cuker A, Arepally G, Crowther MA, Rice L, Datko F, Hook K, Propert KJ, Kuter DJ, Ortel TL, Konkle BA, Cines DB (2010) The HIT expert probability (HEP) score: a novel pre-test probability model for heparin-induced thrombocytopenia based on broad expert opinion. J Thromb Haemost 8:2642–2650CrossRefPubMedGoogle Scholar
  33. 33.
    Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81(3):559–575CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Pruim RJ, Welch RP, Sanna S, Teslovich TM, Chines PS, Gliedt TP, Boehnke M, Abecasis GR, Willer CJ (2010) LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics (Oxford, England) 26(18):2336–2337CrossRefGoogle Scholar
  35. 35.
    Frazer KA, Ballinger DG, Cox DR, Hinds DA, Stuve LL, Gibbs RA, Belmont JW, Boudreau A, Hardenbol P, Leal SM, Pasternak S, Wheeler DA, Willis TD, Yu F, Yang H, Zeng C, Gao Y, Hu H, Hu W, Li C, Lin W, Liu S, Pan H, Tang X, Wang J, Wang W, Yu J, Zhang B, Zhang Q, Zhao H, Zhao H, Zhou J, Gabriel SB, Barry R, Blumenstiel B, Camargo A, Defelice M, Faggart M, Goyette M, Gupta S, Moore J, Nguyen H, Onofrio RC, Parkin M, Roy J, Stahl E, Winchester E, Ziaugra L, Altshuler D, Shen Y, Yao Z, Huang W, Chu X, He Y, Jin L, Liu Y, Shen Y, Sun W, Wang H, Wang Y, Wang Y, Xiong X, Xu L, Waye MM, Tsui SK, Xue H, Wong JT, Galver LM, Fan JB, Gunderson K, Murray SS, Oliphant AR, Chee MS, Montpetit A, Chagnon F, Ferretti V, Leboeuf M, Olivier JF, Phillips MS, Roumy S, Sallee C, Verner A, Hudson TJ, Kwok PY, Cai D, Koboldt DC, Miller RD, Pawlikowska L, Taillon-Miller P, Xiao M, Tsui LC, Mak W, Song YQ, Tam PK, Nakamura Y, Kawaguchi T, Kitamoto T, Morizono T, Nagashima A, Ohnishi Y, Sekine A, Tanaka T, Tsunoda T, Deloukas P, Bird CP, Delgado M, Dermitzakis ET, Gwilliam R, Hunt S, Morrison J, Powell D, Stranger BE, Whittaker P, Bentley DR, Daly MJ, de Bakker PI, Barrett J, Chretien YR, Maller J, McCarroll S, Patterson N, Pe'er I, Price A, Purcell S, Richter DJ, Sabeti P, Saxena R, Schaffner SF, Sham PC, Varilly P, Altshuler D, Stein LD, Krishnan L, Smith AV, Tello-Ruiz MK, Thorisson GA, Chakravarti A, Chen PE, Cutler DJ, Kashuk CS, Lin S, Abecasis GR, Guan W, Li Y, Munro HM, Qin ZS, Thomas DJ, McVean G, Auton A, Bottolo L, Cardin N, Eyheramendy S, Freeman C, Marchini J, Myers S, Spencer C, Stephens M, Donnelly P, Cardon LR, Clarke G, Evans DM, Morris AP, Weir BS, Tsunoda T, Mullikin JC, Sherry ST, Feolo M, Skol A, Zhang H, Zeng C, Zhao H, Matsuda I, Fukushima Y, Macer DR, Suda E, Rotimi CN, Adebamowo CA, Ajayi I, Aniagwu T, Marshall PA, Nkwodimmah C, Royal CD, Leppert MF, Dixon M, Peiffer A, Qiu R, Kent A, Kato K, Niikawa N, Adewole IF, Knoppers BM, Foster MW, Clayton EW, Watkin J, Gibbs RA, Belmont JW, Muzny D, Nazareth L, Sodergren E, Weinstock GM, Wheeler DA, Yakub I, Gabriel SB, Onofrio RC, Richter DJ, Ziaugra L, Birren BW, Daly MJ, Altshuler D, Wilson RK, Fulton LL, Rogers J, Burton J, Carter NP, Clee CM, Griffiths M, Jones MC, McLay K, Plumb RW, Ross MT, Sims SK, Willey DL, Chen Z, Han H, Kang L, Godbout M, Wallenburg JC, L'Archeveque P, Bellemare G, Saeki K, Wang H, An D, Fu H, Li Q, Wang Z, Wang R, Holden AL, Brooks LD, McEwen JE, Guyer MS, Wang VO, Peterson JL, Shi M, Spiegel J, Sung LM, Zacharia LF, Collins FS, Kennedy K, Jamieson R, Stewart J (2007) A second generation human haplotype map of over 3.1 million SNPs. Nature 449(7164):851–861CrossRefPubMedGoogle Scholar
  36. 36.
    Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics (Oxford, England) 21(2):263–265CrossRefGoogle Scholar
  37. 37.
    Delaneau O, Marchini J, Zagury JF (2012) A linear complexity phasing method for thousands of genomes. Nat Methods 9(2):179–181CrossRefGoogle Scholar
  38. 38.
    Howie BN, Donnelly P, Marchini J (2009) A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet 5(6):e1000529CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Marchini J, Howie B, Myers S, McVean G, Donnelly P (2007) A new multipoint method for genome-wide association studies by imputation of genotypes. Nat Genet 39(7):906–913CrossRefPubMedGoogle Scholar
  40. 40.
    Hiersche M, Ruhle F, Stoll M (2013) Postgwas: advanced GWAS interpretation in R. PLoS One 8(8):e71775CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Li H, Durbin R (2009) Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics (Oxford, England) 25(14):1754–1760CrossRefGoogle Scholar
  42. 42.
    McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, Garimella K, Altshuler D, Gabriel S, Daly M, DePristo MA (2010) The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20(9):1297–1303CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Cingolani P, Patel VM, Coon M, Nguyen T, Land SJ, Ruden DM, Lu X (2012) Using Drosophila melanogaster as a model for genotoxic chemical mutational studies with a new program, SnpSift. Front Genet 3:35.  https://doi.org/10.3389/fgene.2012.00035 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Liu X, Wu C, Li C, Boerwinkle E (2016) dbNSFP v3.0: a one-stop database of functional predictions and annotations for human nonsynonymous and splice-site SNVs. Hum Mutat 37(3):235–241CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Neale BM, Rivas MA, Voight BF, Altshuler D, Devlin B, Orho-Melander M, Kathiresan S, Purcell SM, Roeder K, Daly MJ (2011) Testing for an unusual distribution of rare variants. PLoS Genet 7(3):e1001322CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Cuker A (2014) Clinical and laboratory diagnosis of heparin-induced thrombocytopenia: an integrated approach. Semin Thromb Hemost 40(1):106–114PubMedGoogle Scholar
  47. 47.
    Tan CW, Ward CM, Morel-Kopp MC (2012) Evaluating heparin-induced thrombocytopenia: the old and the new. Semin Thromb Hemost 38(2):135–143CrossRefPubMedGoogle Scholar
  48. 48.
    Lillo-Le LA, Boutouyrie P, henc-Gelas M, Le BC, Gautier I, Aiach M, Lasne D (2004) Diagnostic score for heparin-induced thrombocytopenia after cardiopulmonary bypass. J Thromb Haemost 2(11):1882–1888CrossRefGoogle Scholar
  49. 49.
    Uaprasert N, Chanswangphuwana C, Akkawat B, Rojnuckarin P (2013) Comparison of diagnostic performance of the heparin-induced thrombocytopenia expert probability and the 4Ts score in screening for heparin-induced thrombocytopenia. Blood Coagul Fibrinolysis 24(3):261–268CrossRefPubMedGoogle Scholar
  50. 50.
    Cuker A, Gimotty PA, Crowther MA, Warkentin TE (2012) Predictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: a systematic review and meta-analysis. Blood 120(20):4160–4167CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Nagler M, Bachmann LM, ten Cate H, ten Cate-Hoek A (2016) Diagnostic value of immunoassays for heparin-induced thrombocytopenia: a systematic review and meta-analysis. Blood 127(5):546–557CrossRefPubMedGoogle Scholar
  52. 52.
    Cuker A, Cines DB (2012) How I treat heparin-induced thrombocytopenia. Blood 119(10):2209–2218CrossRefPubMedGoogle Scholar
  53. 53.
    Sun L, Gimotty PA, Lakshmanan S, Cuker A (2016) Diagnostic accuracy of rapid immunoassays for heparin-induced thrombocytopenia. A systematic review and meta-analysis. Thromb Haemost 115(5):1044–1055CrossRefPubMedGoogle Scholar
  54. 54.
    Linkins LA, Bates SM, Lee AY, Heddle NM, Wang G, Warkentin TE (2015) Combination of 4Ts score and PF4/H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia: prospective cohort study. Blood.  https://doi.org/10.1182/blood-2014-12-618165
  55. 55.
    Leroux D, Hezard N, Lebreton A, Bauters A, Suchon P, de ME, Biron C, Huisse MG, Ternisien C, Voisin S, Gruel Y, Pouplard C (2014) Prospective evaluation of a rapid nanoparticle-based lateral flow immunoassay (STic Expert(®) HIT) for the diagnosis of heparin-induced thrombocytopenia. Br J Haematol 166 (5):774–782. doi:Google Scholar
  56. 56.
    Nellen V, Sulzer I, Barizzi G, Lammle B, Alberio L (2012) Rapid exclusion or confirmation of heparin-induced thrombocytopenia: a single-center experience with 1,291 patients. Haematologica 97(1):89–97CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Yang JJ, Plenge RM (2011) Genomic technology applied to pharmacological traits. JAMA 306(6):652–653CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Negrini S, Becquemont L (2017) Pharmacogenetics of hypersensitivity drug reactions. Therapie 72(2):231–243CrossRefPubMedGoogle Scholar
  59. 59.
    Gunes MF, Akpinar MB, Comertoglu I, Akyol S, Demircelik B, Gurel OM, Aynekin B, Erdemli HK, Ates M, Eryonucu B, Demircan K (2016) The investigation of a Disintegrin and Metalloproteinase with ThromboSpondin Motifs (ADAMTS) 1, 5 and 16 in thoracic aortic aneurysms and dissections. Clin Lab 62(3):425–433PubMedGoogle Scholar
  60. 60.
    Li Z, Nardi MA, Li YS, Zhang W, Pan R, Dang S, Yee H, Quartermain D, Jonas S, Karpatkin S (2009) C-terminal ADAMTS-18 fragment induces oxidative platelet fragmentation, dissolves platelet aggregates, and protects against carotid artery occlusion and cerebral stroke. Blood 113(24):6051–6060CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Nicholson AC, Malik SB, Logsdon JM Jr, Van Meir EG (2005) Functional evolution of ADAMTS genes: evidence from analyses of phylogeny and gene organization. BMC Evol Biol 5:11CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Arning A, Hiersche M, Witten A, Kurlemann G, Kurnik K, Manner D, Stoll M, Nowak-Gottl U (2012) A genome-wide association study identifies a gene network of ADAMTS genes in the predisposition to pediatric stroke. Blood 120(26):5231–5236CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Genetic Epidemiology, Institute of Human GeneticsUniversity Hospital MünsterMünsterGermany
  2. 2.Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of HealthInstitute of Clinical Pharmacology and ToxicologyBerlinGermany
  3. 3.Thrombosis and Hemostasis Unit, Department of Clinical ChemistryUniversity Hospital of Kiel and LübeckKielGermany
  4. 4.Department of Clinical EpidemiologyLeibniz Institute for Prevention Research and Epidemiology – BIPSBremenGermany
  5. 5.Department of Biochemistry, Cardiovascular Research Institute MaastrichtMaastricht UniversityMaastrichtThe Netherlands

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