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

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.