Department of Pharmacy Practice and Science, University of Arizona College of Pharmacy, Tucson, Arizona.
Sarver Heart Center, Tucson, Arizona.
Pharmacotherapy. 2017 Sep;37(9):1164-1171. doi: 10.1002/phar.1983. Epub 2017 Sep 4.
Heparin-induced thrombocytopenia (HIT) is an unpredictable, life-threatening, immune-mediated reaction to heparin. Variation in human leukocyte antigen (HLA) genes is now used to prevent immune-mediated adverse drug reactions. Combinations of HLA alleles and killer cell immunoglobulin-like receptors (KIR) are associated with multiple autoimmune diseases and infections. The objective of this study is to evaluate the association of HLA alleles and KIR types, alone or in the presence of different HLA ligands, with HIT. HIT cases and heparin-exposed controls were identified in BioVU, an electronic health record coupled to a DNA biobank. HLA sequencing and KIR type imputation using Illumina OMNI-Quad data were performed. Odds ratios for HLA alleles and KIR types and HLAKIR interactions using conditional logistic regressions were determined in the overall population and by race/ethnicity. Analysis was restricted to KIR types and HLA alleles with a frequency greater than 0.01. The p values for HLA and KIR association were corrected by using a false discovery rate q<0.05 and HLAKIR interactions were considered significant at p<0.05. Sixty-five HIT cases and 350 matched controls were identified. No statistical differences in baseline characteristics were observed between cases and controls. The HLA-DRB301:01 allele was significantly associated with HIT in the overall population (odds ratio 2.81 [1.57-5.02], p=2.1×10 , q=0.02) and in individuals with European ancestry, independent of other alleles. No KIR types were associated with HIT, although a significant interaction was observed between KIR2DS5 and the HLA-C1 KIR binding group (p=0.03). The HLA-DRB301:01 allele was identified as a potential risk factor for HIT. This class II HLA gene and allele represent biologically plausible candidates for influencing HIT pathogenesis. We found limited evidence of the role of KIR types in HIT pathogenesis. Replication and further study of the HLA-DRB3*01:01 association is necessary.
肝素诱导的血小板减少症（HIT）是一种不可预测的、危及生命的、免疫介导的肝素不良反应。人类白细胞抗原（HLA）基因的变异现在被用于预防免疫介导的药物不良反应。HLA 等位基因和杀伤细胞免疫球蛋白样受体（KIR）的组合与多种自身免疫性疾病和感染有关。本研究的目的是评估 HLA 等位基因和 KIR 类型单独或在存在不同 HLA 配体的情况下与 HIT 的关联。在 BioVU 中鉴定了 HIT 病例和肝素暴露对照，BioVU 是一个与 DNA 生物库相连接的电子健康记录。使用 Illumina OMNI-Quad 数据进行 HLA 测序和 KIR 类型推断。使用条件逻辑回归在总体人群和按种族/族裔确定 HLA 等位基因和 KIR 类型的比值比以及 HLAKIR 相互作用。分析仅限于频率大于 0.01 的 KIR 类型和 HLA 等位基因。使用错误发现率 q<0.05 校正 HLA 和 KIR 关联的 p 值，并且认为 HLAKIR 相互作用在 p<0.05 时有统计学意义。鉴定了 65 例 HIT 病例和 350 例匹配对照。病例和对照之间的基线特征无统计学差异。HLA-DRB301:01 等位基因在总体人群（比值比 2.81 [1.57-5.02]，p=2.1×10 ，q=0.02）和欧洲血统个体中与 HIT 显著相关，与其他等位基因无关。没有 KIR 类型与 HIT 相关，尽管 KIR2DS5 和 HLA-C1 KIR 结合组之间观察到显著相互作用（p=0.03）。HLA-DRB301:01 等位基因被确定为 HIT 的潜在危险因素。这种 II 类 HLA 基因和等位基因代表影响 HIT 发病机制的生物学上合理的候选物。我们发现 KIR 类型在 HIT 发病机制中的作用证据有限。有必要对 HLA-DRB3*01:01 关联进行复制和进一步研究。
