Hb S/β-Thalassemia in the REDS-III Brazil Sickle Cell Disease Cohort: Clinical, Laboratory and Molecular Characteristics

Abstract

We described the clinical, laboratory and molecular characteristics of individuals with Hb S (HBB: c.20A>T)/β-thalassemia (Hb S/β-thal) participating in the Recipient Epidemiology and Donor Evaluation Study (REDS-III) Brazil Sickle Cell Disease cohort. HBB gene sequencing was performed to genotype each β-thal mutation. Patients were classified as Hb S/β⁰-thal, Hb S/β⁺-thal-severe or Hb S/β⁺-thal based on prior literature and databases of hemoglobin (Hb) variants. Characteristics of patients with each β-thal mutation were described and the clinical profile of patients grouped into Hb S/β⁰-thal, Hb S/β⁺-thal and Hb S/β⁺-thal-severe were compared. Of the 2793 patients enrolled, 84 (3.0%) had Hb S/β⁰-thal and 83 (3.0%) had Hb S/β⁺-thal; 40/83 (48.2%) patients with Hb S/β⁺-thal had mutations defined as severe. We identified 19 different β-thal mutations, eight Hb S/β⁰-thal, three Hb S/β⁺-thal-severe and eight Hb S/β⁺-thal. The most frequent β⁰ and β⁺ mutations were codon 39 (HBB: c.118C>T) and IVS-I-6 (T>C) (HBB: c.92+6T>C), respectively. Individuals with Hb S/β⁰-thal had a similar clinical and laboratory phenotype when compared to those with Hb S/β⁺-thal-severe. Individuals with Hb S/β⁺-thal-severe had significantly lower total Hb and Hb A levels and higher Hb S, white blood cell (WBC) count, platelets and hemolysis markers when compared to those with Hb S/β⁺-thal. Likewise, individuals with Hb S/β⁺-thal-severe showed a significantly higher occurrence of hospitalizations, vaso-occlusive events (VOE), acute chest syndrome (ACS), splenic sequestration, blood utilization, and hydroxyurea (HU) therapy.

Keywords:

• Clinical events
• Hb S/β⁺-thalassemia (Hb S/β⁺-thal)
• Hb S/β⁰-thalassemia (Hb S/β⁰-thal)
• sickle cell disease
• thalassemia mutation

Acknowledgments

First, the authors acknowledge all participants and parents of pediatric participants for their cooperation in being part of this the study. The authors also thank the staff at all participating Brazilian and American research sites. Without all of these contributions, this study would not have been possible. This study was supported by the National Heart, Lung, and Blood Institute (NHLBI) Recipient Epidemiology and Donor Evaluation Study-III: International Component (Brazil), with the participation of the following centers and investigators. Brazilian participants: Instituto de Medicina Tropical de São Paulo (USP), Ester C. Sabino, Cecilia Alencar; Fundação Pró-Sangue (São Paulo), Alfredo Mendrone Jr., Cesar de Almeida Neto, Ligia Capuani; Instituto de Tratamento do Câncer Infantil (São Paulo), Miriam V. Flor-Park; Faculdade de Medicina da Universidade de São Paulo (São Paulo), Paula Blatyta; Hemominas, Belo Horizonte (Minas Gerais), Anna Bárbara de Freitas Carneiro-Proietti, Carolina Miranda Teixeira, Tassila Salomon, Franciane Mendes de Oliveira, Valquíria Reis. Hemominas; Montes Claros (Minas Gerais), Rosemere Afonso Mota, José Wilson Sales; Hemominas, Juiz de Fora (Minas Gerais), Daniella de Oliveira Werneck Rodrigues; Fundação Hemope, Recife (Pernambuco), Paula Loureiro, Aderson Araújo, Maria do Carmo Valgueir; Hemorio, (Rio de Janeiro), Clarisse Lobo, Claudia Maximo, Luiz Amorim; Instituto de Matemática e Estatística da Universidade de São Paulo, USP (São Paulo), João Eduardo Ferreira, Márcio Katsumi Oikawa, Pedro Losco Takecian, Mina Cintho Ozahata, Rodrigo Muller de Carvalho. US Investigators: Vitlant Research Institute and University of California San Francisco (UCSF), San Francisco, CA, Brian Custer, Michael P. Busch, Shannon Kelly and Thelma Therezinha Gonçalez; Research Triangle Instiute (RTI), Rockville, MD; Donald Brambilla, Liliana R. Preiss, Christopher McClure; UCSF Benioff Children’s Hospital Oakland, Oakland, CA, Carolyn Hoppe; NHLBI, National Institutes of Health (NIH), Bethesda, MD, Simone A. Glynn.

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Additional information

Funding

This study was supported by the National Institutes of Health, National Heart, Lung, and Blood Institute by [Grant HHSN268201100007I]. André R. Belisário received a scholarship from the International Traineeships in AIDS Prevention Studies program (ITAPS) to participate in a scientific manuscript writing program at the University of California, San Francisco, CA, USA. This work was also supported by the “Fundação de Amparo à Pesquisa de Minas Gerais”, Brazil (FAPEMIG; grant # APQ-01764-16).