Genetic Mechanisms of Survivorship Disparities after Unrelated HCT

无关 HCT 后生存差异的遗传机制

• 批准号: 8521195
• 负责人: Effie W Petersdorf
• 金额: $ 30.07万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-12 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8521195
• 关键词: Acute Graft Versus Host Disease; Admixture; African American; Alleles; Allogenic; Asians; Behavior Therapy; Blood; Candidate Disease Gene; Caucasians; Caucasoid Race; Cessation of life; Clinical; Data; Development; Disease; Donor Selection; Donor person; Employee Strikes; Equilibrium; Ethnic Origin; Evaluation; Frequencies; Future; Gene Expression; Genes; Genetic; Genetic Code; Genetic Variation; Genotype; Goals; Haplotypes; Healthcare; Hematologic Neoplasms; Hematopoietic Neoplasms; IL6 gene; Immune Response Genes; Immune system; Immunotherapy; Individual; Interleukin-15; Investigation; Measures; Methods; Morbidity - disease rate; National Cancer Institute; Outcome; Patients; Phase; Phylogenetic Analysis; Phylogeny; Physicians; Play; Principal Investigator; Race; Radiation; Recurrence; Regimen; Relapse; Resources; Risk; Risk Assessment; Risk Estimate; Role; Stem cells; Structure; Testing; The Sun; Therapeutic immunosuppression; Toxic effect; Transplant Recipients; Transplantation; Trees; United States; Variant; anakinra; base; experience; graft vs host disease; hematopoietic cell transplantation; ilium; improved; innovation; interest; leukemia; meetings; microbial alkaline proteinase inhibitor; mortality; novel; survivorship; tool

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.

描述(申请人提供)：白血病患者可以通过非亲缘关系的造血细胞移植(HCT)治愈。我们发现，无血缘关系的HCT后的存活率强烈依赖于患者的种族。与高加索人(CAU)患者相比，非裔美国人(AFA)患者的死亡风险显著增加，而亚洲(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，并假设生存差异的部分原因是与祖先相关的高危IRG等位基因和单倍型频率的差异。目前关于IRG单倍型多样性的信息受到缺乏确定阶段分配的可靠工具的阻碍。对IRG多样性影响HCT后存活率的机制的研究也需要对移植患者和供者的种族进行准确的定义。正如AFA和API个体已经知道的混杂，应用祖先信息标记(AIMS)来测量混杂将极大地促进生存差异的遗传机制的研究。这项建议的具体目的是：1)根据AIMS的定义，确定ILIA、ILIB、IL1RN、IL6、IL6R、ILI5和1L15RA序列的变异及其对AFA、API和CAU血统个体单倍型的影响；2)确定CADES中ILIA、ILIB、IL1RN、IL6、IL6R、IL15和IL15FiA单倍型的系统发育；3)确定GVHD、GVL和AFA、API和CAU移植患者的SNP、单倍型和基于包膜的机制，以及4)确定IRG变异对健康个体基因表达的影响。这一新的应用是第一次使用一种新的单倍型分期工具来询问移植中存活率差异的遗传机制，目的是分配祖先。这些信息将有助于努力优化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非常新颖和独特的资源。