Influence of Human Leukocyte Antigen (HLA) Alleles and Killer Cell Immunoglobulin-Like Receptors (KIR) Types on Heparin-Induced Thrombocytopenia (HIT).
Influence of Human Leukocyte Antigen (HLA) Alleles and Killer Cell Immunoglobulin-Like Receptors (KIR) Types on Heparin-Induced Thrombocytopenia (HIT).
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DOI：
10.1002/phar.1983
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发表时间：
2017-09
期刊：
影响因子：
4.1
通讯作者：
Roden DM
中科院分区：
文献类型：
--
作者：
Karnes JH;Shaffer CM;Cronin R;Bastarache L;Gaudieri S;James I;Pavlos R;Steiner HE;Mosley JD;Mallal S;Denny JC;Phillips EJ;Roden DM
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相关。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、免疫介导的肝素反应。本研究的目的是评估HLA等位基因和KIR类型，单独或在不同的HLA配体的存在下，与HIT的关联。我们在BioVU（一种与DNA生物库相连的电子健康记录）中确定了HIT病例和肝素暴露对照。我们进行了HLA测序，并从Illumina® OMNI-Quad数据中估算了KIR类型。我们使用条件Logistic回归确定了总体人群中HLA等位基因和KIR类型以及HLA*KIR相互作用的比值比（OR），并按人种/种族进行分析。分析仅限于KIR类型和频率大于0.01的HLA等位基因。使用错误发现率（FDR）q<0.05校正HLA和KIR关联的P值，并且在p<0.05时认为HLA*KIR相互作用是显著的。我们确定了65例HIT病例和350例对照。我们观察到病例组和对照组之间的基线特征没有统计学差异。HLA-DRB 3 *01：01等位基因与总体人群中的HIT显著相关（OR 2.81[1.57-5.02]，p=2.1x10−4，q=0.02），在欧洲血统的个体中，与其他等位基因无关。没有KIR类型与HIT相关，尽管我们观察到KIR 2DS 5和HLA-C1 KIR结合组之间的显著相互作用（p=0.03）。我们确定HLA-DRB 3 *01：01等位基因为HIT的潜在危险因素。这种II类HLA基因和等位基因代表了影响HIT发病机制的生物学上合理的候选者。我们发现有限的证据表明KIR类型在HIT发病机制中的作用。HLA-DRB 3 *01：01关联的复制和进一步研究是必要的。
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. Heparin-induced thrombocytopenia (HIT) is an unpredictable, life-threatening, immune-mediated reaction to heparin. 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. We identified HIT cases and heparin-exposed controls in BioVU, an electronic health record coupled to a DNA biobank. We performed HLA sequencing and imputed KIR types from Illumina® OMNI-Quad data. We determined odds ratios (ORs) for HLA alleles and KIR types and HLA*KIR interactions using conditional logistic regressions in the overall population and by race/ethnicity. Analysis was restricted to KIR types and HLA alleles with a frequency greater than 0.01. P values for HLA and KIR association were corrected using a false discovery rate (FDR) q<0.05 and HLA*KIR interactions were considered significant at p<0.05. We identified 65 HIT cases and 350 matched controls. We observed no statistical differences in baseline characteristics between cases and controls. The HLA-DRB3*01:01 allele was significantly associated with HIT in the overall population (OR 2.81[1.57–5.02], p=2.1x10−4, q=0.02) and in individuals with European ancestry, independent of other alleles. No KIR types were associated with HIT, although we observed a significant interaction between KIR2DS5 and the HLA-C1 KIR binding group (p=0.03). We identify the HLA-DRB3*01:01 allele 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.
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DOI：
10.1073/pnas.0409500102
发表时间：
2005-03-15
影响因子：
11.1
作者：
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DOI：
10.1197/jamia.m3037
发表时间：
2009-11-01
影响因子：
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