Genetic epidemiology of hematopoietic cell transplant outcomes

描述(申请人提供)：异基因造血细胞移植(allo-hct)是一个代谢需求很高的时期。迫切需要恢复血液形成和对发烧和感染的反应，以及移植物抗宿主病(GVHD)和可能的移植物抗白血病效应的持续挑战。随着核DNA人类白细胞抗原(HLA)系统的匹配完善，HCT的结果显著改善，该系统包含编码主要组织相容性复合体的基因。然而，据我们所知，没有研究认为线粒体DNA和/或线粒体DNA匹配是否影响HCT结局。线粒体(MT)通过氧化磷酸化(OXPHOS)为细胞提供能量，调节细胞的存活和死亡，越来越多的人认为线粒体在功能上影响先天性和获得性免疫系统的反应。线粒体DNA的多态可以分为与人类全球迁徙相关的单倍型(Mthap)。线粒体DNA不含内含子，因此多态对编码序列有直接影响。在支持方面，Cybrid(具有相同核DNA但不同mtDNA的细胞克隆)研究表明，不同mthap之间存在OXPHOS和其他功能差异(包括免疫反应)的证据。许多关联研究已经将特定的MAPAP与疾病的发生、严重程度和/或治疗反应联系起来。我们在437名患者和327名捐赠者中探讨了患者或捐赠者mTAP(H、J、U、T、Z、K、V、X、I、W、K2)是否与allo-HCT结局相关。我们发现，特定的供受者MAP(如K、K2、V、W、J、U)可能是HCT受者死亡率、GVHD和/或复发的决定因素。在这里，我们将在一个更大、更同质的患者群体中验证我们的初步发现，以进一步研究mthap在allo-HCT中的作用。我们将从国家骨髓捐赠者计划获得4200多名无关捐赠者和4200名HCT接受者的DNA和全面的临床数据，并对mt基因组进行下一代测序，以建立mthap。我们还将在我们最近对线粒体功能的体内研究的基础上，探索线粒体HAPs在红细胞压积中的功能意义。我们的具体目标是：1)确定受者或供者MAP是否与HCT结局相关；以及2)调查供者和受者在HCT中的MAP不匹配是否与不良结局相关。第二个目的是探索与极端红细胞移植临床结局(例如，K2，V)相关的mthap表型与H相比是否在免疫缺陷小鼠(NOD-SCID IL2rγNull(“Nsg”))小鼠中人类干细胞植入百分比方面存在差异。我们的研究将为我们的初步结果提供必要的验证，调查mHAPs错配在HCT结局中的作用，并提供体内和体外数据，说明mHAPs在HCT中的功能意义。如果我们的初步结果得到证实，它们最终可能导致在全球范围内实施额外的选择标准，以确定最佳的allo-HCT捐赠者，以降低不利的HCT结局的风险。

DESCRIPTION (provided by applicant): Allogeneic hematopoietic cell transplant (allo-HCT) is a time of high metabolic demand. There are immediate needs for restoration of blood formation and response to fever and infection, as well as ongoing challenges of graft versus host disease (GVHD) and possibly graft versus leukemia effects. HCT outcomes have significantly improved with matching refinement of the nuclear DNA human leukocyte antigen (HLA) system, which contains genes encoding for the major histocompatibility complex. However, there were no studies to our knowledge that considered whether mitochondrial DNA and/or mitochondrial DNA matching affected HCT outcomes. Mitochondria (mt) provide cells energy through oxidative phosphorylation (OXPHOS), regulate cell survival and death, and are increasingly thought to functionally influence innate and adaptive immune system responses. Polymorphisms in mtDNA can be grouped into haplotypes (mthaps) that are associated with human global migration. MtDNA contains no introns and therefore polymorphisms can have a direct effect on coding sequences. In support, cybrid (cell clones that have identical nuclear DNA but different mtDNA) studies show evidence of OXPHOS and other functional differences (including immune response) among various mthaps. Numerous association studies have linked specific mthaps to disease occurrence, severity and/or therapy response. We explored whether patient or donor mthaps (H, J, U, T, Z, K, V, X, I, W, K2) were associated with allo-HCT outcomes in 437 patients and 327 donors. We found that certain donor and recipient mthaps (e.g., K, K2, V, W, J, U) may be determinants of mortality, GVHD and/or relapse in HCT recipients. Here, we will validate our initial findings in a much larger, homogenous patient population to further investigate the role of mthaps in allo-HCT. We will obtain DNA and comprehensive clinical data from the National Marrow Donor Program on over 4200 unrelated donors and 4200 HCT recipients and perform NextGen sequencing of the mt genome to establish mthaps. We also will build upon our recent in vivo studies of mt function and explore the functional significance of mthaps in HCT. Our specific aims are to 1) Determine whether recipient or donor mthaps are associated with HCT outcomes; and 2) Investigate whether mismatch between donor and recipient mthaps in HCT is associated with adverse outcomes. A secondary aim is to explore whether mthap phenotypes associated with extreme HCT clinical outcomes (e.g., K2, V) compared to H vary with regard to percent human stem cell engraftment in immunodeficient (NOD-SCID IL2rγnull ("NSG")) mice. Our study will provide necessary validation of our initial results, investigate the role of mismatching of mthaps in HCT outcomes, and provide in vivo and in vitro data of the functional significance of mthaps in the context of HCT. If our preliminary results are confirmed, they could ultimately lead to worldwide implementation of additional selection criteria to identify optimal allo-HCT donors to reduce risk of adverse HCT outcomes.