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 Ruhle, Ulrike Nowak-Gottl, Edeltraut Garbe, Reinhold Kreutz, Monika Stoll*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

11 Citations (Web of Science)

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 x 10(-5), odds ratio (OR) 2.79) from 16 identified SNPs was successfully replicated (P = 1.5 x 10(-4), OR 2.77; combined data set P = 2.7 x 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 x 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 x 10(-2)) and the multiple C2 and transmembrane domain containing 2 (MCTP2, P = 4.5 x 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. 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.
Original languageEnglish
Pages (from-to)765-775
Number of pages11
JournalJournal of Molecular Medicine
Volume96
Issue number8
DOIs
Publication statusPublished - 1 Aug 2018

Keywords

  • ADR
  • HIT
  • GWAS
  • ADAMTS16
  • ICE1
  • MOLECULAR-WEIGHT HEPARIN
  • IMMUNE-RESPONSE
  • RISK-FACTORS
  • THROMBOEMBOLIC COMPLICATIONS
  • UNFRACTIONATED HEPARIN
  • EXPERT PROBABILITY
  • PROSPECTIVE COHORT
  • ADAMTS GENES
  • POLYMORPHISMS
  • ANTIBODIES

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