DNA polymorphisms at the BCL11A , HBS1L-MYB , and β- globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease

Abstract

Sickle cell disease (SCD) is a debilitating monogenic blood disorder with a highly variable phenotype characterized by severe pain crises, acute clinical events, and early mortality. Interindividual variation in fetal hemoglobin (HbF) expression is a known and potentially heritable modifier of SCD severity. High HbF levels are correlated with reduced morbidity and mortality. Here, we genotyped additional BCL11A SNPs, HBS1L-MYB SNPs, and an SNP upstream of G ␥-globin (HBG2; the XmnI polymorphism), in two independent SCD cohorts: the African American Cooperative Study of Sickle Cell Disease (CSSCD) and an SCD cohort from Brazil. We studied the effect of these SNPs on HbF levels and on a measure of SCD-related morbidity (pain crisis rate). We strongly replicated the association between these SNPs and HbF level variation (in the CSSCD, P values range from 0.04 to 2 ؋ 10 ؊42 ). Together, common SNPs at the BCL11A, HBS1L-MYB, and ␤-globin (HBB) loci account for >20% of the variation in HbF levels in SCD patients. We also have shown that HbF-associated SNPs associate with pain crisis rate in SCD patients. These results provide a clear example of inherited common sequence variants modifying the severity of a monogenic disease.genetic modifier ͉ single nucleotide polymorphism ͉ globin gene regulation

Standardization method for measurement of hydroxyurea by Ultra High Efficiency Liquid Chromatography in plasma of patients with sickle cell disease

“…Besides increasing the concentration of HbF, these mechanisms confer benefits such as reduced hemolysis, decreased adhesion of erythrocytes, leukocytes, and platelets to the vascular endothelium, and vasodilatation, contributing to a reduction in vaso-occlusive and inflammatory complications (Lettre et al, 2008).…”

Variantes genéticas asociadas con niveles de hemoglobina fetal muestran diversos orígenes étnicos en pacientes colombianos con anemia falciforme

“…The SNPs evaluated in this paper showed a strong association with the HbF levels in a wide spectrum of populations, including those from Europe, North America and Brazil where three joint QTLs (rs9399137, 4895441 y rs11886868) explain more than 20% of HbF variability (5,18,22). Therefore, they are suited to estimate the prevalence of HbFpromoting alleles at these loci.…”

“…These variants occur in two subloci, HMIP-A and HMIP-2B, that map to distinct enhancer elements for MYB (3,4, Menzel, et al, manuscript in preparation). HbF-increasing alleles at all three regions loci have subsequently been shown to alleviate the severity of sickle cell anemia and beta-thalassemia (5,6). Additional QTLs have been detected on chromosomes 8 and X through linkage analysis but have not been mapped in detail (7).…”

Sobre escravos e genes: “origens” e “processos” nos estudos da genética sobre a população brasileira

“…Interest in the different haplotypes is mainly to do with clinical applicability, with the central hypothesis of these studies linking the severity of clinical manifestations to the haplotype present in the patient 3 (Nagel, 1984). Although there are studies that do not corroborate this hypothesis (Fullwiley, 2011), research into the diversity of hemoglobin S haplotypes has been central in the field of genetics of hemoglobin S. There are also studies that seek to establish differentiations within haplotypes and other genetic factors in order to explain the differences in the severity of the symptoms (Lettre, 2008). As we shall see later, some of these studies have suggested that the Brazilian population could be promising for studying the genetic factors that influence the clinical manifestations of the disease due to its high degree of miscegenation (Silva et al, 2011).…”