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WHOLE-EXOME SEQUENCING INDICATES FLG2 VARIANT ASSOCIATED WITH LEG ULCERS IN BRAZILIAN SICKLE CELL ANEMIA PATIENTS
Sequenciamento de todo-exoma
Úlcera de perna
Estudo de associação
Doença complexa
Variantes
Whole-exome sequencing
Leg ulcer
Association study
Complex disease
Variants
Author
Siqueira, Gabriela Queila de Carvalho
Ananina, Galina
Souza, Bruno Batista de
Borges, Murilo Guimarães
Ito, Mirta Tomie
Costa, Sueli Matilde da Silva
Domingos, Igor de Farias
Falcão, Diego Arruda
Cendes, Iscia Lopes
Bezerra, Marcos André Cavalcanti
Araújo, Aderson da Silva
Araújo, Antônio Roberto Lucena
Gonçalves, Marilda de Souza
Saad, Sara Teresinha Olalla
Costa, Fernando Ferreira
Melo, Mônica Barbosa de
Ananina, Galina
Souza, Bruno Batista de
Borges, Murilo Guimarães
Ito, Mirta Tomie
Costa, Sueli Matilde da Silva
Domingos, Igor de Farias
Falcão, Diego Arruda
Cendes, Iscia Lopes
Bezerra, Marcos André Cavalcanti
Araújo, Aderson da Silva
Araújo, Antônio Roberto Lucena
Gonçalves, Marilda de Souza
Saad, Sara Teresinha Olalla
Costa, Fernando Ferreira
Melo, Mônica Barbosa de
Affilliation
University of Campinas. Center for Molecular Biology and Genetic Engineering. Campinas, SP, Brazil.
University of Campinas. Center for Molecular Biology and Genetic Engineering. Campinas, SP, Brazil.
University of Campinas. Center for Molecular Biology and Genetic Engineering. Campinas, SP, Brazil.
University of Campinas. Faculty of Medical Sciences. Department of Medical Genetics and Genome Medicine. Campinas, SP, Brazil.
University of Campinas. Center for Molecular Biology and Genetic Engineering. Campinas, SP, Brazil.
University of Campinas. Center for Molecular Biology and Genetic Engineering. Campinas, SP, Brazil.
Federal University of Pernambuco. Genetics Postgraduate Program. Recife, PE, Brazil.
Federal University of Pernambuco. Genetics Postgraduate Program. Recife, PE, Brazil.
University of Campinas. Faculty of Medical Sciences. Department of Medical Genetics and Genome Medicine. Campinas, SP, Brazil.
Federal University of Pernambuco. Genetics Postgraduate Program. Recife, PE, Brazil.
Hematology and Hemotherapy Foundation of Pernambuco, Recife, PE, Brazil.
Federal University of Pernambuco. Genetics Postgraduate Program. Recife, PE, Brazil.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.
University of Campinas. Hematology and Hemotherapy Center. Campinas, SP, Brazil.
University of Campinas. Hematology and Hemotherapy Center. Campinas, SP, Brazil.
University of Campinas. Center for Molecular Biology and Genetic Engineering. Campinas, SP, Brazil.
University of Campinas. Center for Molecular Biology and Genetic Engineering. Campinas, SP, Brazil.
University of Campinas. Center for Molecular Biology and Genetic Engineering. Campinas, SP, Brazil.
University of Campinas. Faculty of Medical Sciences. Department of Medical Genetics and Genome Medicine. Campinas, SP, Brazil.
University of Campinas. Center for Molecular Biology and Genetic Engineering. Campinas, SP, Brazil.
University of Campinas. Center for Molecular Biology and Genetic Engineering. Campinas, SP, Brazil.
Federal University of Pernambuco. Genetics Postgraduate Program. Recife, PE, Brazil.
Federal University of Pernambuco. Genetics Postgraduate Program. Recife, PE, Brazil.
University of Campinas. Faculty of Medical Sciences. Department of Medical Genetics and Genome Medicine. Campinas, SP, Brazil.
Federal University of Pernambuco. Genetics Postgraduate Program. Recife, PE, Brazil.
Hematology and Hemotherapy Foundation of Pernambuco, Recife, PE, Brazil.
Federal University of Pernambuco. Genetics Postgraduate Program. Recife, PE, Brazil.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.
University of Campinas. Hematology and Hemotherapy Center. Campinas, SP, Brazil.
University of Campinas. Hematology and Hemotherapy Center. Campinas, SP, Brazil.
University of Campinas. Center for Molecular Biology and Genetic Engineering. Campinas, SP, Brazil.
Abstract
Although sickle cell anemia results from homozygosity for a single mutation at position 7 of the b-globin chain, the clinical aspects of this condition are very heterogeneous. Complications include leg ulcers, which have a negative impact on patients’ quality of life and are related to the severity of the disease. Nevertheless, the complex pathogenesis of this complication has yet to be elucidated. To identify novel genes associated with leg ulcers in sickle cell anemia, we performed whole-exome sequencing of extreme phenotypes in a sample of Brazilian sickle cell anemia patients and validated our findings in another sample. Our discovery cohort consisted of 40 unrelated sickle cell anemia patients selected based on extreme phenotypes: 20 patients without leg ulcers, aged from 40 to 61 years, and 20 with chronic leg ulcers. DNA was extracted from peripheral blood leukocytes and used for whole-exome sequencing. After the bioinformatics analysis, eight variants were selected for validation by Sanger sequencing and TaqManVR genotyping in 293 sickle cell anemia patients (153 without leg ulcers) from two different locations in Brazil. After the validation, Fisher’s
exact test revealed a statistically significant difference in a stop codon variant (rs12568784 G/T) in the FLG2 gene between the GT and GG genotypes (P¼0.035).We highlight the importance of rs12568784 in leg ulcer development as this variant of the FLG2 gene results in impairment of the skin barrier, predisposing the individual to inflammation and infection. Additionally, we suggest that the remaining seven variants and the genes in which they occur could be strong candidates for leg ulcers in sickle cell anemia.
Keywords in Portuguese
Anemia falciformeSequenciamento de todo-exoma
Úlcera de perna
Estudo de associação
Doença complexa
Variantes
Keywords
Sickle cell anemiaWhole-exome sequencing
Leg ulcer
Association study
Complex disease
Variants
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