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-? 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. ? ? Preliminary data of 188 SCD patients with a mean age of 21 years (88 males, 60 females, mean hemoglobin level of 8.3 g/dl) indicates a prevalence of PAH of 23% (based on a tricuspid jet velocity of equal to or greater than 2.5 m/sec). In comparison, the prevalence of PAH is 4% among 45 apparently healthy Nigerian controls (p=0.001). Of the sickle cell patients affected with PAH in Nigeria, 94% had less than five units of life-time red blood transfusions and 92% had less than three hospitalizations for vaso-occlusive crisis or other hospitalizations in the preceding five years. Since the hemoglobin level of the African patients is similar to that in American patients, the low vaso-occlusive severity of Nigerian patients suggests that their SCD phenotype is almost exclusively hemolytic.
