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 =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. No results are available.

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National Heart, Lung, and Blood Institute
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Aliyu, Zakari Y; Kato, Gregory J; Taylor 6th, James et al. (2008) Sickle cell disease and pulmonary hypertension in Africa: a global perspective and review of epidemiology, pathophysiology, and management. Am J Hematol 83:63-70
Aliyu, Zakari Y; Gordeuk, Victor; Sachdev, Vandana et al. (2008) Prevalence and risk factors for pulmonary artery systolic hypertension among sickle cell disease patients in Nigeria. Am J Hematol 83:485-90