Genetic vs environment in scleroderma outcomes study

硬皮病结果研究中的遗传与环境

• 批准号: 6660902
• 负责人: JOHN Duffin REVEILLE
• 金额: $ 18.37万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6660902
• 关键词: African American; Hispanic Americans; MHC class II antigen; caucasian American; gene environment interaction; genetic susceptibility; health behavior; human population genetics; human subject; medical complication; pathologic process; patient oriented research; prognosis; racial /ethnic difference; socioenvironment; systemic scleroderma

The hypothesis to be tested in this proposal is that systemic sclerosis (SSC) is a more aggressive disease in non-Caucasians who manifest a higher occurrence of critical organ involvement and a worse prognosis, and that reasons for this may include both genetic factor factors as well as sociodemographic or behavioral determinants. To ascertain this we have established a multi-ethic cohort of 175 patients with SSC of relatively recent onset (<five years) deemed the GENISOS cohort (Genetics versus Environment In Scleroderma Outcome Study) which are following at regular intervals. Our specific aims are: 1) To continue followup of the GENISOS cohort of Caucasians, Hispanics and African Americans with SSc of five years of less duration at the University of Texas Health Science Center at Houston, the University of Texas Medical Branch at Galveston and the University of Texas Health Science Center at San Antonio in order to follow their course and outcome at regular intervals for a period of five to seven years and to enroll 80 new cases at the three centers, focusing especially on African American patients. 2) To determine the HLA class II genotypes (HLA-DRB1, DQA1, DQB1 and DPB1 alleles) as well as disease-associated alleles of other candidate genes found to be associated with SSc in ongoing studies in our Division and elsewhere (e.g. fibrillin, SPARC, and others). 3) To determine the sociodemographic parameters (income, education, insurance status) and behavioral features (illness behavior, health care utilization and attitudes, compliance) of these patients. 4) To determine pertinent clinical and laboratory parameters, including disease manifestations (e.g. extent of organ system involvement and co- morbidities), laboratory features (CBC, urinalysis, serum creatinine, serial pulmonary function tests, high resolution CT(HRCT), chest Xray and selected SSc-associated autoantibodies (anti-centromere antibodies (ACA), anti-topoisomerase I (anti-topo I), anti-fibrillin (anti-fib, etc) whose expression has been shown to e associated with specific clinical features of SSc as well as with certain HLA class II alleles. 5) To follow disease progression to outcomes manifested by: a) the development of end-stage pulmonary fibrosis (manifested by a forced vital capacity of < 50% predicted, resting arterial PO2 of < 65n mm Hg of pulmonary hypertension, or lung transplant; b) end-stage scleroderma- related renal disease (defined as "scleroderma renal cris" or serum creatinine > 3.0 mg/dl not transplant; b) end-stage scleroderma-related renal disease (defined as "scleroderma renal crisis" or a serum creatinine>3.0 mg/dl not drug related; c) scleroderma heart disease, defined as either congestive heart failure (defined as a left ventricular ejection fraction of <40%) or malignant arrhythmias requiring therapy; d) functional disability (determined by the SF36 and the mHAQ); e) skin score; f) cumulative disease damage (as measured by the Disease Severity Scale proposed by Medsger et al (1) or death. 6) To examine how gene expression (of fibroblasts from involved and uninvolved skin and from peripheral blood leukocytes) at one point early in disease course predict disease progression (using the outcomes stated above). 7) To examine the relative contributions and interactions of genetic, demographic, socioeconomic, cultural, family history and initial and followup clinical and laboratory features on the course and outcome of early SSc through time dependent statistical analytic approaches including proportional hazard Cox-regression models and longitudinal analysis methods. By elucidating the sociodemographic, behavioral and genetic contributions to morbidity and mortality in SSC, interventions would be possible that could improve the course and outcome of this disease.

在该提案中要检验的假设是，在非高加索人中，系统性硬化症（SSC）是一种更具侵略性的疾病，他们表现出更高的关键器官受累和较差的预后发生，并且这样做的原因可能包括遗传因素因素以及社会人口学或行为确定性。为了确定这一点，我们已经建立了175例SSC患者相对较新的（<五年）的多伦理队列，认为Genisos队列（在硬皮病结局研究中的遗传学与环境研究）是定期遵循的。我们的具体目的是：1）继续跟进高加索人，西班牙裔和非洲裔美国人的同伙，持续时间较小五年，在德克萨斯大学健康科学中心，德克萨斯大学的德克萨斯大学医学分支机构，加尔维斯顿大学的德克萨斯大学医学分支机构和德克萨斯大学健康科学中心，以便在圣安东尼奥大学进行了五年的新赛事，以期为五个年度的赛事，以纪念五年的新赛事，并在五年中以五年的时间进行五十份新的赛事。特别关注非裔美国人患者。 2）确定HLA II类基因型（HLA-DRB1，DQA1，DQB1和DPB1等位基因）以及其他候选基因的疾病相关等位基因在我们的部门以及其他地方正在进行的研究中与SSC相关的疾病相关等位基因（例如Fibrillilin，sparc等）。 3）确定这些患者的社会人口统计学参数（收入，教育，保险状况）和行为特征（疾病行为，卫生保健利用和态度，遵守情况）。 4）确定相关的临床和实验室参数，包括疾病表现（例如器官系统的参与度和共同病毒的程度），实验室特征（CBC，尿液分析，血清肌酐，串行肺功能测试，高分辨率CT（HRCT），胸部XRARE和SSC-SSC-CASIPIAD AUTOPIASIED AUTOCAILIAD AUTIPIED AUTIBERIADERISE（ACA）（ACA），抗昆虫异构酶I（抗topo I），抗原纤维蛋白（抗FIB等）的表达与SSC的特定临床特征以及某些HLA II类等位基因相关，以遵循以下疾病的进展。肺高血压或肺移植的65n mm汞与药物无关； c）硬皮病心脏病，被定义为充血性心力衰竭（定义为<40％的左心室射血分数）或需要治疗的恶性心律失常； d）功能障碍（由SF36和MHAQ确定）； e）皮肤评分； f）累积性疾病损害（如Medsger等人（1）或死亡所提出的疾病严重程度量表。6），以研究如何在疾病过程中早期的早期（使用上述疾病进展）来研究一度涉及皮肤和无侵入性皮肤的基因表达（成纤维细胞的基因表达（来自涉及的皮肤和未涉及的皮肤）。 7）检查遗传，人口统计学，社会经济，文化，家族史以及初始和后续实验室特征在SSC早期通过时间依赖统计统计分析方法（包括比例危害COX COX-COX-COX-COX-RESISTRY模型和纵向分析方法）的相对贡献和相互作用。通过阐明SSC中发病和死亡率的社会人口统计学，行为和遗传贡献，可以改善这种疾病的过程和结果。