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

Abstract

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.

Pathogenesis of heparin-induced thrombocytopenia

“…Other supporting data come from findings of a restricted T cell repertoire in patients with HIT 42,43 and the requirement for T cells in the murine HIT immune response. [44][45][46] Recent genome wide association (GWAS) studies, though involving small numbers of patients, identified several candidate genes, 47,48 including an HLA-DRB3*01:01 allele associated with a greater risk of developing HIT 49 ; these findings will require validation in larger cohorts.…”

Elucidation of Cellular Contributions to Heparin-Induced Thrombocytopenia Using Omic Approaches

“…GWAS investigates the association between millions of genetic variants and a phenotype of interest. Despite clear successes in GWAS in identifying genetic polymorphisms associated with other phenotypes/diseases, very few GWAS studies have been performed for HIT (Karnes et al, 2015;Witten et al, 2018). One study identified a SNP in chromosome 5 in AC106799.2 as a risk allele for HIT (Witten et al, 2018).…”

“…The common omics disciplines including genomics, transcriptomics, proteomics, metabolomics, and metagenomics, all have made great strides to answer questions in a wide range of biological topics. In the HIT field, however, these techniques have been under-utilized with studies employing only genome-wide association (Karnes et al, 2015;Karnes et al, 2017a;Witten et al, 2018) and arraybased transcriptomic (Haile et al, 2017) approaches. This review will outline the current understanding of HIT pathogenesis within the context of specific cell types.…”

Quantitative and Qualitative Platelet Derangements in Cardiac Surgery and Extracorporeal Life Support

“…HIT's risk factors are both host and drug related; the female gender has been linked to a doubled risk of developing HIT [94] while a younger age (<40 years) seems to entail a milder risk [95]. Furthermore, recent genome-wide association studies (GWAS) have highlighted candidate gene variants (i.e., the HLA-DRB3*01:01 allele) associated with a risk of HIT [96][97][98]. Among the drug related factors, the duration of heparin exposure plays a major role with a shorter span carrying a lower risk [99].…”