Prevalence of PAH in SCD Patients in Nigeria

尼日利亚 SCD 患者中 PAH 的患病率

基本信息

批准号：
8557943
负责人：
Gregory Kato
金额：
$ 2.78万
依托单位：
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8557943
关键词：
Adhesions Adult Affect Africa African American Anemia due to Chronic Disorder Apolipoproteins Biological Markers Blood Blood Urea Nitrogen Blood specimen Brain natriuretic peptide CD36 gene Candidate Disease Gene Cardiac Cause of Death Chemistry Chronic Hepatitis B Cleaved cell Clinical Clinical Trials Collaborations Communicable Diseases Comorbidity Complete Blood Count Complication Confidence Intervals Contracts Country Cross-Sectional Studies DNA DNA Markers Data Data Analyses Development Diagnosis Disease Echocardiography Enrollment Enzymes Epidemiology Female Ferritin Forensic Medicine Genes Genetic Genetic Polymorphism Globulins HIV Heart Hematological Disease Hemoglobin Hemolysis Hepatitis C Hereditary Disease High Prevalence Hookworms Human ICAM1 gene Individual Informed Consent Inherited Institution International Iron Knowledge Lactate Dehydrogenase Lead Logistic Regressions Malaria Measurement Measures Molecular N-terminal Natriuretic Peptides Nigeria Outcome Paper Participant Patients Pattern Phenotype Physical Examination Plasma Plasma Proteins Predictive Value Prevalence Preventive Proteins Public Health Publishing Pulmonary Hypertension Pulmonary artery structure Quality of Care Recording of previous events Risk Risk Factors SELE gene Sampling Schistosomiasis Screening procedure Serine Protease Serum Serum Globulins Sickle Cell Sickle Cell Anemia Single Nucleotide Polymorphism Site Spottings System Teaching Hospitals Technology Testing Transforming Growth Factor beta Tricuspid Valve Insufficiency United States United States National Institutes of Health Universities Vascular Cell Adhesion Molecule-1 Walking Writing aged arginase bone morphogenic protein burden of illness cohort design functional disability gel electrophoresis genome wide association study hydroxyurea male mortality prospective protein expression pulmonary arterial hypertension receptor systolic hypertension therapeutic target vascular inflammation

项目摘要

Sickle cell disease (SCD) is an autosomal recessive disorder and the most common genetic disease in the world. SCD is the most common inherited blood disorder in the United States, affecting 70,000 to 80,000 Americans. Secondary pulmonary arterial hypertension (PAH) has been shown to have a prevalence of 30% in patients with SCD with mortality rates of 40% at 40 months after diagnosis in the United States. The burden of disease of SCD is highest in Nigeria (West Africa) where approximately 4% of the 140 million people in that country are homozygous for SCD, but the prevalence and outcomes of pulmonary hypertension in Africa have not been investigated. Many known infectious risk factors for PAH are also highly prevalent in Nigeria, including Human Immuno Deficiency Virus/Acquired Immune Deficiency Syndrome (HIV/AIDS), malaria, chronic hepatitis B and C, schistosomiasis and hookworm. Our first clinical hypothesis is that interactions between these infectious complications and sickle cell related hemolysis would lead to an even higher prevalence of PAH in Nigeria. Our study is therefore designed to determine the prevalence of PAH in Nigerian patients with SCD using echocardiographic measurements of the tricuspid regurgitant jet velocity. We aim to determine the associations and epidemiological interactions that might lead to PAH, of endemic infectious disease co-morbidities, especially HIV/AIDS, with SCD by screening for these infectious diseases in control subjects and in SCD patients with and without PAH. Our second translational hypothesis is that genetic polymorphisms in candidate genes that regulate endothelial function and adhesion contribute to the development of PAH phenotype in African SCD patients. Using both candidate gene and genome wide association approaches, we will identify and selectively characterize single nucleotide polymorphisms (SNPs) in genes important for endothelial function, vascular inflammation and cardiac function (functional VCAM1 SNPs and steady state soluble VCAM-1 levels, SELP, SELE, SELL, ICAM1, ITGA4, and CD36, TGF-beta superfamily gene polymorphisms - specifically bone morphogenic protein receptor II, and CORIN, the serine protease which, cleaves the natriuretic peptide precursors secreted by the heart, proANP and proBNP, to the physiologically active ANP and BNP). Finally, our study using the SELDI-TOF-MS system and 2D differential gel electrophoresis (DIGE), will examine differential patterns of plasma protein expression, in particular the apolipoproteins and arginase I and II enzymes, as potential biomarkers or therapeutic targets in sickle cell patients with pulmonary hypertension. Our proposal uniquely integrates international clinical, epidemiologic and molecular studies to determine the burden of SCD related PAH, decipher the mechanism of interactions of PAH and infectious diseases and identify genetic and protein markers and potential therapeutic targets for PAH. Our collaboration will provide an opportunity for the rapid transfer of appropriate technology and knowledge relevant to the provision of the highest quality care to sickle cell patients in Nigeria and the world. As of December 2006, 308 (178 males, 130 females) participants in Nigeria had been enrolled into the NIH-Nigeria Sickle Cell PAH screening study- 210 patients with SCD and 98 healthy controls. Each participant was informed of the study and gave written informed consent. A standardized history and physical examination was then performed. Obtaining a blood sample for complete blood count and routine chemistries as well as DNA isolation and plasma storage followed this. Each participant also underwent echocardiography and a six-minute walk test (308 completed echocardiograms). Pulmonary artery systolic hypertension was defined prospectively as tricuspid regurgitant jet velocity > or =2.5 m/sec. Results were compared with a previously published US prospective SCD cohort. Only 7% of Nigerians compared with 46% of US adults with SCD were >35 years. Tricuspid regurgitant jet velocity was > or =2.5 m/sec in 25% of Nigerian SCD patients. Higher jet velocity was associated with greater serum globulin (P = 0.002), blood urea nitrogen (P = 0.019) and lactate dehydrogenase concentrations (P = 0.026) and with inability to walk >300 m in 6 min (P = 0.042). Compared with the US cohort, Nigerian patients had more hemolysis as indicated by lower hemoglobin and higher lactate dehydrogenase concentrations (P < or = 0.003). Pulmonary hypertension is common among Nigerian SCD patients. The public health implication of this finding is significant considering the potential number of individuals at risk for this complication. Better understanding of the long-term outcome of pulmonary hypertension and causes of death in SCD and the institution of preventive measures are major public health challenges for Africa. The inclusion of African sites in sickle cell pulmonary hypertension clinical trials should be encouraged. N-terminal (NT) pro-brain natriuretic peptide (proBNP) > or =160 ng/l has a 78% positive predictive value for pulmonary hypertension and is associated with increased mortality in US sickle cell disease patients, but the importance in sickle cell disease patients in Africa is not known. In a cross-sectional study at Ahmadu Bello University Teaching Hospital, Shika-Zaria, Nigeria, we studied 133 hydroxycarbamide-nave Nigerian sickle cell anaemia patients aged 18-52 years at steady-state and 65 healthy controls. Twenty-six percent of patients versus 5% of controls had NT-proBNP> or =160 ng/l (P = 0.0006). By logistic regression among the patients, human immunodeficiency virus seropositivity, higher serum ferritin and lower haemoglobin or higher lactate dehydrogenase independently predicted elevated NT-proBNP. After adjustment for haemoglobin concentration, elevated NT-proBNP concentration was associated with an estimated 7.8-fold increase in the odds of severe functional impairment, defined as an inability to walk more than 300 m in 6 min (95% confidence interval 1.5-32.6; P = 0.005). Similarly, elevated tricuspid regurgitation velocity was associated with an estimated 5.6-fold increase in the odds of functional impairment (95% confidence interval 1.5-21.0; P = 0.011). In conclusion, NT-proBNP elevation is common and is associated with markers of anaemia, inflammation and iron status and with severe functional impairment among sickle cell anaemia patients in Nigeria. The study is no longer open for accrual but data analysis and sample management continues. This year DNA was extracted on contract with SeraCare from the Nigerian Watman papers. The DNA was quantified and profiled with forensic DNA markers. We have just received the data and have closed out the contract. We have not analyzed these data yet. Blood spotted onto special paper to preserve DNA. We have finally had this extracted for use in the lab. The quality of the DNA was assessed by the forensic DNA markers and we will be able to determine relatedness of subjects enrolled on the study.

镰状细胞病（SCD）是一种常染色体隐性疾病，是世界上最常见的遗传疾病。 SCD是美国最常见的血液疾病，影响了70,000至80,000名美国人。在美国诊断后40个月时，SCD患者的死亡率为40％的患者，次级肺动脉高压（PAH）的患病率为30％。 SCD疾病的负担在尼日利亚（西非）最高，在该国1.4亿人中，大约有4％的SCD是纯合的，但尚未调查非洲肺动脉高压的患病率和结果。 PAH的许多已知感染危险因素在尼日利亚也很普遍，包括人免疫缺陷病毒/获得性免疫缺乏综合征（HIV/AIDS），疟疾，慢性乙型肝炎和C，血吸虫病和钩虫病。我们的第一个临床假设是，这些感染性并发症与镰状细胞相关溶血之间的相互作用将导致尼日利亚PAH的患病率更高。因此，我们的研究旨在通过使用三尖瓣反流式喷射速度的超声心动图测量来确定尼日利亚SCD患者的PAH患病率。我们旨在确定可能导致PAH的相关性和流行病学相互作用，这些相互作用，尤其是艾滋病毒/艾滋病的地方性传染病，尤其是艾滋病毒/艾滋病，通过筛查在对照组和有PAH和没有PAH的SCD患者中的这些传染病。我们的第二个翻译假设是，调节内皮功能和粘附的候选基因中的遗传多态性有助于非洲SCD患者的PAH表型的发展。使用候选基因和基因组广泛的关联方法，我们将确定并选择性地表征对内皮功能，血管炎症和心脏功能重要的基因中的单核苷酸多态性（SNP）（功能性VCAM1 SNP和稳态态溶剂溶液vcam-1水平 - 特别是骨形态发生蛋白受体II和Corin，丝氨酸蛋白酶，它裂解了由心脏，proanp和probnp分泌到生理上活性的ANP和BNP的那二钠肽前体。最后，我们使用SELDI-TOF-MS系统和2D差异凝胶电泳（DIGE）的研究将检查血浆蛋白表达的差异模式，特别是载脂蛋白蛋白和精氨酸酶I和II酶，作为潜在的生物标志物或肺部高血压患者的潜在生物标志物或治疗靶标。我们的建议独特地整合了国际临床，流行病学和分子研究，以确定与SCD相关的PAH的负担，破译PAH和传染病的相互作用机制，并鉴定PAH的遗传和蛋白质标记以及潜在的治疗靶标。我们的合作将为快速转移适当的技术和知识提供与将最高质量护理提供给尼日利亚和世界上的镰状细胞患者相关的知识的机会。截至2006年12月，尼日利亚的308名（178名男性，130名女性）参加了NIH尼日利亚镰状细胞PAH筛查研究-210例SCD患者和98位健康对照组。每个参与者都被告知研究，并给予书面知情同意。然后进行标准化病史和体格检查。此后，获得血液样本以进行全血数和常规化学分配以及DNA分离和血浆储存。每个参与者还进行了超声心动图和六分钟的步行测试（308个完成的超声心动图）。肺动脉收缩期高血压被前瞻性地定义为三尖端反流射流速度>或= 2.5 m/sec。将结果与先前发表的美国前瞻性SCD队列进行了比较。尼日利亚人中只有7％，而46％的SCD成年人> 35年。在25％的尼日利亚SCD患者中，三尖型弹性喷射速度>或= 2.5 m/sec。较高的射流速度与较高的血清球蛋白（P = 0.002），血尿素氮（P = 0.019）和乳酸脱氢酶浓度（P = 0.026）有关，并且无法在6分钟内行走> 300 m（P = 0.042）。与美国队列相比，尼日利亚患者的溶血更多，如较低的血红蛋白和较高的乳酸脱氢酶浓度所示（P <OR = 0.003）。肺动脉高压在尼日利亚SCD患者中很常见。考虑到有可能有这种并发症风险的个体的潜在人数，这一发现的公共卫生影响很大。更好地理解SCD肺高血压和死亡原因的长期结局和预防措施的制度是非洲的主要公共卫生挑战。应该鼓励将非洲部位纳入镰状细胞肺动脉高压临床试验。 N末端（NT）核核苷酸肽（prognp）>或= 160 ng/L的肺高血压为78％的阳性预测价值，并且与美国镰状细胞疾病患者的死亡率增加有关，但尚不清楚非洲镰状细胞疾病患者的重要性。在尼日利亚Shika-Zaria的艾哈迈杜贝洛大学教学医院的一项横断面研究中，我们研究了133个羟基甲酰胺 - 尼日利亚尼日利亚镰状细胞贫血患者，在稳态和65个健康对照组中年龄18-52岁。 26％的患者与5％的对照组具有NT-PROBNP>或= 160 ng/L（p = 0.0006）。通过患者的逻辑回归，人类免疫缺陷病毒血清阳性，较高的血清铁蛋白和较低的血红蛋白或更高的乳酸脱氢酶独立预测的NT-促螺旋体升高。调整血红蛋白浓度后，NT-proBNP浓度升高与严重功能障碍的几率估计增加了7.8倍，这定义为无法在6分钟内行走超过300 m（95％置信区间1.5-32.6; p = 0.005）。类似地，升高的三尖端反流速度升高与功能障碍几率估计增加5.6倍（95％置信区间1.5-21.0； p = 0.011）。总之，NT-ProBNP升高很常见，与贫血，炎症和铁状态的标记以及尼日利亚镰状细胞贫血患者的严重功能障碍有关。这项研究不再开放以进行应计，但数据分析和样本管理仍在继续。今年，DNA与尼日利亚沃特曼论文的Seracare合同提取。量化DNA并用法医DNA标记进行了分析。我们刚刚收到数据并关闭了合同。我们尚未分析这些数据。血液被发现在特殊纸上以保存DNA。我们终于将其提取到实验室中。 DNA的质量通过法医DNA标记进行评估，我们将能够确定研究参与研究的受试者的相关性。