Abstract 11449: Influence of Exonic Variation on Heparin-Induced Thrombocytopenia
Introduction: Heparin-induced thrombocytopenia (HIT) is an immune-mediated, potentially fatal adverse effect of heparin treatment. Here we test the hypotheses that exonic variants are associated with HIT and that genes involved in HIT pathophysiology are enriched with rare exonic variation.
Methods: We identified HIT cases and heparin-exposed controls in an electronic medical record coupled to a DNA biobank. Controls were matched to cases based on age, gender, and heparin anticoagulant (unfractionated versus low molecular weight heparin). Genotypes were determined using the HumanExome BeadChip and individual variants were analyzed for association with HIT using multivariable logistic regression in a dominant model. Aggregated rare variant analyses (unidirectional variable threshold [VT] and bidirectional sequence kernel association test [SKAT]) were performed to identify HIT-associated genes and were restricted to amino-acid coding (AAC) variants (missense, non-synonymous, or frameshift) with minor allele frequency less than 0.01.
Results: We identified 77 HIT cases and 345 matched controls. After adjustment for age, gender, heparin anticoagulant, and first two principal components, the variant most strongly associated with HIT was in the human leukocyte antigen class II, DR alpha gene (HLA-DRA, odds ratio 3.81 [2.12-6.83], p=1.01x10-5). While this association was nominally significant, it did not reach a Bonferroni-corrected significance level. In VT analysis, rare ACC variants were most strongly enriched in HIT cases for the genes IFI44L (interferon-induced protein 44-like, p=0.005) and CXCL11 (chemokine [C-X-C motif] ligand 11, p=0.008). IFI44L and CXCL11 were also enriched in HIT cases in SKAT analysis (p=0.0003 and p=0.0001 respectively).
Conclusions: Using single variant and aggregated rare variant analyses, we implicate variants from HLA-DRA and rare variants from IFI44L and CXCL11 as risk factors for HIT. These genes represent biologically plausible candidates, considering the putative role of class II HLA molecules, T cell chemotaxis, and interferons in immune response to heparin.
Author Disclosures: J.H. Karnes: None. J.C. Denny: None. R.M. Cronin: None. C.M. Shaffer: None. E.A. Bowton: None. J.D. Cowan: None. J.D. Mosley: None. S.L. Van Driest: None. P.E. Weeke: None. Q.S. Wells: None. D.M. Roden: None.
- © 2014 by American Heart Association, Inc.