ABSTRACT
BACKGROUND: Understanding the genetics underlying the heritable subphenotypes of sickle cell anemia, specific to each population, would be prognostically useful and could inform personalized therapeutics.The objective of this study was to describe the genetic modulators of sickle cell disease in a cohort of pediatric patients followed up in Mayotte. METHODS: This retrospective cohort study analyzed clinical and biological data, collected between January1st2007 and December 31st2017, in children younger than 18 years. RESULTS: We included 185 children with 72% SS, 16% Sß0-thalassemia and 12% Sß + thalassemia. The average age was 9.5 years; 10% of patients were lost to follow up. The Bantu haplotype was associated with an increase in hospitalizations and transfusions. The alpha-thalassemic mutation was associated with a decrease of hemolysis biological parameters (anemia, reticulocytes), and a decrease of cerebral vasculopathy. The Single Nucleotide Polymorphisms BCL11A rs4671393, BCL11A rs11886868, BCL11A rs1427407 and HMIP rs9399137 were associated with the group of children with HbF > 10%. Patients with HbF > 10% presented a significant risk of early onset of cerebral vasculopathy. CONCLUSIONS: The most remarkable result of our study was the association of SNPs with clinically relevant phenotypic groups. BCL11A rs4671393, BCL11A rs11886868, BCL11A rs1427407 and HMIP rs9399137 were correlated with HbF > 10%, a group that has a higher risk of cerebral vasculopathy and should be oriented towards the hemolytic sub-phenotype.
Subject(s)
Anemia, Sickle Cell , Fetal Hemoglobin , Anemia, Sickle Cell/complications , Anemia, Sickle Cell/genetics , Child , Comoros , Fetal Hemoglobin/genetics , Humans , Polymorphism, Single Nucleotide , Repressor Proteins , Retrospective StudiesABSTRACT
Sickle cell disease presents a great clinical variability that remains largely misunderstood. New disease protective genetic modifiers acting mainly through an increased Hb F level have recently been described. We studied relations between clinical and hematological phenotypes and known sickle cell disease genetic modifiers in patients from Mayotte Island, a remote French territory located in the Indian Ocean. Eighty-two children with sickle cell disease were enrolled; their median age was 5.9 years (range 1-18). Clinical and hematological features of sickle cell disease were retrospectively collected. Genetic studies included determination of ß-globin genotypes [Hb SS, Hb S-ß(0)-thalassemia (Hb S-ß(0)-thal), Hb S-ß(+)-thal], ß(S)-globin locus haplotype, α-thalassemia (α-thal), and single nucleotide polymorphisms (SNPs) located in quantitative trait loci for Hb F expression (XmnI polymorphism, BCL11A rs4671393 and rs11886868, intergenic region of HBS1L-MYB rs28384513, rs4895441 and rs9399137). Univariate and multivariate analyses were conducted. Twenty-eight percent of the patients had Hb S-ß-thal (eight different mutations in 21 patients), 55.0% had the -α(3.7) (rightward) deletion and 88.0% of the homozygous Hb SS patients were carrying a homozygous Bantu haplotype. In the multivariate model, the prognosis role of the SNP BCL11A rs4671393 was confirmed in the studied population showing a significant association with an elevated Hb F level and with a low hospitalization rate. The -α(3.7) deletion, XmnI polymorphism and intergenic region HBS1L-MYB SNPs were not significantly linked to any clinical criteria of severity. This report, the first to describe the main features of children with sickle cell disease on Mayotte Island, highlights the protective effect of the BCL11A polymorphism in this population.
Subject(s)
Anemia, Sickle Cell/genetics , Genes, Modifier , Adolescent , Anemia, Sickle Cell/diagnosis , Anemia, Sickle Cell/therapy , Child , Child, Preschool , Cohort Studies , Erythrocyte Indices , Female , Gene Expression Regulation , Genetic Association Studies , Genotype , Hemoglobin, Sickle/genetics , Humans , Infant , Male , Phenotype , Polymorphism, Single Nucleotide , Quantitative Trait Loci , alpha-Thalassemia/diagnosis , alpha-Thalassemia/genetics , beta-Thalassemia/diagnosis , beta-Thalassemia/geneticsABSTRACT
From 2001 to 2008, 119 pediatric cases of meningococcal disease caused by serogroup W were reported in France. They cases represented 4% of all meningococcal disease cases in children and were mostly in infants (54%). Meningitis occurred in 78 (66%) patients but differed by isolate. Isolates of the clonal complex sequence type-22 were associated with nonmeningeal presentation. Further investigations of clinical tropism of meningococcal W isolates are warranted.