Genetic Mechanisms of Survivorship Disparities after Unrelated HCT

描述（申请人提供）：白血病患者可以通过非相关造血细胞移植（HCT）治愈。我们发现，非相关HCT后的生存率很大程度上取决于患者的种族。与高加索（CAU）患者相比，非洲裔美国人（AFA）患者的死亡风险显著增加，亚洲（API）患者的复发风险增加，移植物抗宿主病的风险降低。我们确定了1L1A、ILIB、IL6和IL15RA基因变异在预后中的作用，并假设生存差异部分是由于高危IRG等位基因和单倍型频率的遗传相关差异。目前关于IRG单倍型多样性的信息由于缺乏确定阶段分配的可靠工具而受到阻碍。研究IRG多样性影响HCT后存活的机制还需要精确定义移植患者和供体的种族。由于AFA个体和API个体都存在外源性，应用遗传信息标记（AIMs）测量外源性将极大地促进生存差异遗传机制的研究。本提案的具体目的是：1)确定由aims定义的AFA、API、CAU血统个体的ILIA、ILIB、IL1RN、IL6、IL6R、il5和1L15RA序列变异及其在单倍型上的组织；2)确定ILIA、ILIB、IL1RN、IL6、IL6R、IL15和IL15FiA单倍型在几十年内的系统发育；3)明确AFA、API和CAU移植患者GVHD、GVL和生存的SNP、单倍型和进化基机制；4)确定IRG变异对健康个体基因表达的影响。这个新的应用程序是第一个使用一种新的单倍型相位工具和目标来分配祖先，来询问移植中生存差异的遗传机制。这些信息将有助于优化AFA和API患者的移植结果，同时为继续研究疾病的遗传基础创造一个高度新颖和独特的资源。

DESCRIPTION (provided by applicant): Patients suffering from leukemia can be cured with unrelated hematopoietic cell transplantation (HCT). We discovered that survival after unrelated HCT strongly depends on the patient's ethnicity. African American (AFA) patients had significantly increased risk of mortality and Asian (API) patients had increased risk of relapse and decreased risk of graft-versus-host disease, when compared to Caucasian (CAU) patients. We identified a role for 1L1A, ILIB, IL6, and IL15RA gene variation in outcome and hypothesize that the survival disparities are in part due to ancestry-related differences in the frequencies of at-risk IRG alleles and haplotypes. Current information on IRG haplotype diversity is hampered by the lack of robust tools for definitive phase assignment. Investigation into the mechanisms through which IRG diversity impacts survival after HCT also requires precise definition of the race of the transplant patient and donor. As AFA and API individuals have known admixture, application of ancestry-informative markers (AIMs) for measuring admixture will greatly facilitate the study of genetic mechanisms of survivorship disparities. The specific aims of this proposal are to 1) Determine ILIA, ILIB, IL1RN, IL6, IL6R, ILI 5 and 1L15RA sequence variation and its organization on haplotypes in individuals of AFA, API, CAU ancestry as defined by AIMs; 2) define the phylogeny of ILIA, ILIB, IL1RN, IL6, IL6R, IL15 and IL15FiA haplotypes in cades; 3) define SNP, haplotype, and clad-based mechanisms of GVHD, GVL and survival in AFA, API and CAU transplant patients, and 4) determine the impact of IRG variation on gene expression in healthy individuals. This new application is the first of its kind to interrogate the genetic mechanisms for survivorship disparities in transplantation, using a novel haplotype phasing tool and AIMs for assignment of ancestry. The information will aid efforts to optimize transplant outcomes for AFA and API patients, while creating a highly novel and unique resource for continued investigation into the genetic basis of disease.