Immunogenetics of Outcomes Disparities after Allogeneic HCT

摘要 我们已经在IL6和NKG2通路中发现了影响预后差异的基因变异 非亲缘供者造血细胞移植(HCT)。IL6ST亚单位的患者和供体变体为 与GVHD风险和死亡率增加有关，特别是在非洲和西班牙裔血统的患者中， 与亚裔和高加索血统的患者相比。有关IL6ST和IL6R的信息 证明风险是由影响类型和类型的祖先特定的编码和监管变体传递的 所产生的蛋白质数量。第二个遗传系统NKG2也在同种异体识别中发挥关键作用 HCT。受体HLAE和MICA配体与供体NKG2A、NKG2C、NKG2D受体高度结合 多态的，并因祖先而不同。这两个模型共同展示了理解 配体及其受体，以充分阐明它们的临床重要性。关于IL6和NKG2的贡献的信息 系统对临床结果的影响将阐明传统上与供受者HLA配型相关的风险。 我们将在三个方面测试新的假设：1)确定IL6ST和IL6R变异对表达的影响 和HCT结局；2)定义影响HCT结局的NKG2配体-受体特征，以及3)估计 血细胞移植中与人类白细胞抗原不匹配相关的风险。关于单倍型内容和表达的种族信息- 多样化的移植人群将显著促进对美国结果差异的理解 移植。

Abstract We have identified genetic variants within the IL6 and NKG2 pathways that influence outcomes disparities after unrelated donor hematopoietic cell transplantation (HCT). Patient and donor variants for the IL6ST subunit are associated with increased risk of GVHD and mortality particularly in patients of African and Hispanic ancestry, compared to patients of Asian and Caucasian ancestry. Information on both IL6ST as well as IL6R demonstrate that risks are imparted by ancestry-specific coding and regulatory variants that affect the type and quantity of proteins produced. The second genetic system, NKG2, also plays a critical role in allorecognition in HCT. Recipient HLA-E and MICA ligands together with donor NKG2A, NKG2C, NKG2D receptors are highly polymorphic and differ by ancestry. Together, both models showcase the importance of understanding the ligand and its receptor, to fully clarify their clinical importance. Information on the contribution of IL6 and NKG2 systems to clinical outcome will elucidate the risks traditionally associated with donor-recipient HLA matching. We will test novel hypotheses in three aims: 1) define the impact of IL6ST and IL6R variation on expression and HCT outcome; 2) define NKG2 ligand-receptor features that influence HCT outcomes, and 3) estimate the risks associated with HLA mismatching in HCT. Information on haplotype content and expression in ethnically- diverse transplant populations will significantly advance understanding of outcomes disparities in US transplants.