Immunogenetics of Outcomes Disparities after Allogeneic HCT

同种异体 HCT 后结果差异的免疫遗传学

• 批准号: 10177961
• 负责人: Effie W Petersdorf
• 金额: $ 29.35万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10177961
• 关键词: Acute Graft Versus Host Disease; Affect; African; Allogenic; American; Asians; Caring; Caucasians; Chromosome Mapping; Clinical; Code; Complex; Data; Donor Selection; Evaluation; Future; Gene Expression; Genes; Genetic; Genetic Determinism; Genetic Variation; HLA-A gene; Haplotypes; Hematological Disease; Hispanics; IL6 gene; IL6ST gene; Immune Response Genes; Immunogenetics; Laboratories; Ligands; Maps; Methods; Modeling; Outcome; Pathway interactions; Patients; Pharmacology; Phase; Play; Population; Prophylactic treatment; Proteins; Regimen; Risk; Risk Estimate; Role; Signal Transduction; System; Testing; Transplant Recipients; Transplantation; Variant; causal variant; conditioning; curative treatments; design; disorder risk; ethnic diversity; genetic variant; graft vs host disease; graft vs leukemia effect; hematopoietic cell transplantation; high risk; improved; individualized medicine; innovation; mortality; mortality risk; novel; personalized approach; receptor; success; tool

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.

摘要 我们已经确定了IL 6和NKG 2通路中的遗传变异，这些变异影响了治疗后的结果差异。 非亲缘供者造血细胞移植（HCT）。IL 6 ST亚基的患者和供体变体是 与GVHD风险和死亡率增加相关，特别是在非洲和西班牙裔患者中， 与亚洲和高加索血统的患者相比。关于IL 6ST和IL 6 R的信息 证明风险是由祖先特异性编码和调节变异引起的，这些变异影响了类型和 生产的蛋白质数量。第二个遗传系统，NKG 2，也在同种异体识别中起着关键作用。 HCT。HLA-E和云母配体与供体NKG 2A、NKG 2C、NKG 2D受体一起高度表达。 多态性和不同的祖先。这两个模型共同展示了理解 配体及其受体，以充分阐明其临床意义。关于IL 6和NKG 2的贡献的信息 系统的临床结果将阐明传统上与供体-受体HLA配型相关的风险。 我们将在三个目标中检验新的假设：1）确定IL 6ST和IL 6 R变异对表达的影响， 和HCT结果; 2）定义影响HCT结果的NKG 2配体-受体特征，3）估计 与HCT中HLA错配相关的风险。关于种族- 不同的移植人群将显著促进对美国结果差异的理解 移植