Isabel Germano1, Brígida Santos2,3, Mariana Delgadinho4, Catarina Ginete4, Pedro Lopes1, Ana Paula Arez5, Miguel Brito3,4, Paula Faustino6,7,8. 1. Instituto Nacional de Saúde Doutor Ricardo Jorge (INSA), Lisbon, Portugal. 2. Hospital Pediátrico David Bernardino (HPDB), Luanda, Angola. 3. Centro de Investigação em Saúde de Angola (CISA), Caxito, Angola. 4. Health and Technology Research Center (H&TRC), Escola Superior de Tecnologia da Saúde de Lisboa, Instituto Politécnico de Lisboa (ESTeSL/IPL), Lisbon, Portugal. 5. Global Health and Tropical Medicine (GHTM), Instituto de Higiene e Medicina Tropical (IHMT), Universidade NOVA de Lisboa (UNL), Lisbon, Portugal. 6. Instituto Nacional de Saúde Doutor Ricardo Jorge (INSA), Lisbon, Portugal. paula.faustino@insa.min-saude.pt. 7. Instituto de Saúde Ambiental (ISAMB), Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal. paula.faustino@insa.min-saude.pt. 8. Laboratório Associado TERRA, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal. paula.faustino@insa.min-saude.pt.
Abstract
BACKGROUND: Sickle Cell Anemia (SCA) is a genetic disease caused by the c.20 A > T mutation in HBB gene, generally characterized by sickle erythrocytes, chronic hemolytic anemia, and vaso-occlusive events. This study aimed to investigate genetic modulators of anemia severity, chronic hemolytic rate, and clinical manifestations in pediatric SCA patients from Angola, where the disease is a severe public health problem. METHODS AND RESULTS: The study was conducted on 200 SCA children living in Luanda or Caxito province. Their clinical phenotype was collected from patients' hospital records. Hematological and biochemical phenotypes were characterized in steady state condition. Twelve polymorphic regions in VCAM1, CD36 and NOS3 genes were genotyped using PCR, RFLP, and Sanger sequencing. CD36 gene promoter variants showed a significant impact on anemia severity. Particularly, the rs1413661_C allele was associated with lower hemoglobin levels, and increased number of hospitalizations and transfusions. This is the first report associating this SNP with SCA phenotypic heterogeneity. Moreover, the rs1041163_C allele in VCAM1 was associated with lower LDH levels; inversely the rs2070744_C allele in NOS3 was related with higher LDH levels and number of hospitalizations, being a risk factor for increased hemolytic rate. CONCLUSION: This study highlights, for the first time in the Angolan population, the importance of the genetic modifiers of vascular cell adhesion and nitric oxide metabolism in SCA pediatric phenotypic variability.
BACKGROUND: Sickle Cell Anemia (SCA) is a genetic disease caused by the c.20 A > T mutation in HBB gene, generally characterized by sickle erythrocytes, chronic hemolytic anemia, and vaso-occlusive events. This study aimed to investigate genetic modulators of anemia severity, chronic hemolytic rate, and clinical manifestations in pediatric SCA patients from Angola, where the disease is a severe public health problem. METHODS AND RESULTS: The study was conducted on 200 SCA children living in Luanda or Caxito province. Their clinical phenotype was collected from patients' hospital records. Hematological and biochemical phenotypes were characterized in steady state condition. Twelve polymorphic regions in VCAM1, CD36 and NOS3 genes were genotyped using PCR, RFLP, and Sanger sequencing. CD36 gene promoter variants showed a significant impact on anemia severity. Particularly, the rs1413661_C allele was associated with lower hemoglobin levels, and increased number of hospitalizations and transfusions. This is the first report associating this SNP with SCA phenotypic heterogeneity. Moreover, the rs1041163_C allele in VCAM1 was associated with lower LDH levels; inversely the rs2070744_C allele in NOS3 was related with higher LDH levels and number of hospitalizations, being a risk factor for increased hemolytic rate. CONCLUSION: This study highlights, for the first time in the Angolan population, the importance of the genetic modifiers of vascular cell adhesion and nitric oxide metabolism in SCA pediatric phenotypic variability.
Authors: Gregory J Kato; Frédéric B Piel; Clarice D Reid; Marilyn H Gaston; Kwaku Ohene-Frempong; Lakshmanan Krishnamurti; Wally R Smith; Julie A Panepinto; David J Weatherall; Fernando F Costa; Elliott P Vichinsky Journal: Nat Rev Dis Primers Date: 2018-03-15 Impact factor: 52.329
Authors: Scott D Grosse; Isaac Odame; Hani K Atrash; Djesika D Amendah; Frédéric B Piel; Thomas N Williams Journal: Am J Prev Med Date: 2011-12 Impact factor: 5.043