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


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.





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.


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)


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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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