(Physique S6) The rs3742704 was also significantly associated with the formation of positive PF4/heparin IgG antibodies in a recessive model (OR 3.09 [CI 1.14C8.13], p=0.02). warranted to assess their influence on the risk of developing HIT. Introduction Heparin-induced thrombocytopenia (HIT) is an antibody-mediated condition of platelet activation in patients receiving unfractionated heparin (UFH) and low molecular weight heparin (LMWH)(1). HIT develops in up Brefeldin A to 0.5C5% of patients treated with heparin anticoagulants, has a greater than 30% mortality rate, and results in catastrophic thromboembolic complications, including life- and limb-threatening thrombosis(2C5). Further complicating the use of heparin anticoagulants, prevention of HIT-related thrombosis is currently possible only after manifestations of HIT are evident and the disease process has already begun(6, 7). The inability to predict HIT thus represents a liability with heparin administration and identification of patients with a high HIT risk could allow for prevention of HIT. HIT is closely associated with the development of antibodies to complexes of heparin and platelet factor 4 (PF4), a protein normally found in the alpha granules of platelets(8). Although several studies have identified genetic polymorphisms such as the Fc receptor RIIA (and were not included unless located within 10 kilobases of a specified candidate gene. A total of 1 1,412 SNPs with minor allele frequencies (MAFs) greater than 0.01 were tested and we implemented a Bonferroni cutoff of alpha=3.5410?5 (0.05/1,412). In an additional exploratory analysis, imputed classical HLA alleles were tested for association with HIT in an unadjusted additive model. Table 1 List of candidate genes with description and rationale for inclusion in study. association;(43, 44) immune-mediated adverse drug reaction requires antigen presentation Open in a separate window HIT indicates heparin-induced thrombocytopenia; HLA, human leukocyte antigen; SNP, single nucleotide polymorphism. 1)Indicates SNPs of any minor allele frequency within 10,000 base pairs of 3 and 5 end of gene. Replication of GWAS SNPs To test the association of genotyped SNPs and HIT, multivariate logistic regression was used. Age and gender-adjusted odds ratios (OR) and 95% confidence intervals (CI) were generated with HIT defined as the outcome compared to both groups without HIT (Abpos and Abneg patients) and compared to Abneg patients in a recessive model. Results were considered significant with a two-sided alpha=0.05. SNP Association with PF4/heparin Antibody Development In the SHIP cohort, we assessed the association between GWAS-associated SNPs and PF4/heparin IgG titer levels (enzyme immunoassay OD levels) as well as formation of positive PF4/heparin antibody assessments. Two IgG measurements were available for each patient and mean PF4/heparin IgG ODs were analyzed as continuous variables after square root transformation. Association of SNPs with PF4/heparin IgG levels were decided using linear regression adjusted for age and gender with alpha=0.05. Effect sizes of SNPs are reported using coefficients () and standard errors (SEs). To evaluate the association between SNPs (exposure) and anti-PF4/heparin Ab status (dependent variable), conditional logistic regression models with fixed effects were used, adjusting for age and gender. ORs and CIs for positive anti-PF4/heparin status was Brefeldin A tested for association with SNP genotype in a recessive model and determined by exact methods with median-unbiased estimates. Statistical analyses were performed in R. Results Genome-Wide Association Study in the EMR Discovery Population A total of 73 HIT cases were identified from BioVU and 67 of these cases were successfully genotyped after QC filters. The mean 4Ts score for HIT cases was 5.2 (standard deviation [SD] 0.8). (Table 2) The clinical Mouse monoclonal to CD41.TBP8 reacts with a calcium-dependent complex of CD41/CD61 ( GPIIb/IIIa), 135/120 kDa, expressed on normal platelets and megakaryocytes. CD41 antigen acts as a receptor for fibrinogen, von Willebrand factor (vWf), fibrinectin and vitronectin and mediates platelet adhesion and aggregation. GM1CD41 completely inhibits ADP, epinephrine and collagen-induced platelet activation and partially inhibits restocetin and thrombin-induced platelet activation. It is useful in the morphological and physiological studies of platelets and megakaryocytes characteristics of patients with HIT diagnosis are presented in Supplemental Table S2. We identified 884 controls from BioVU that were matched to HIT cases by exposure to UFH or LMWH Brefeldin A and were successfully genotyped. The number of consecutive days of exposure to UFH or LMWH was significantly increased in HIT cases versus controls (9.7 [SD 6.0]) versus 3.4 [SD 4.0], p 0.01). No other significant differences were observed in baseline characteristics between cases and controls. Table 2 Baseline characteristics in cases versus controls of genotyped samples for GWAS.