Reduced rate of sickle-related complications in Brazilian patients carrying HbF-promoting alleles at the BCL11A and HMIP-2 loci (original) (raw)
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Blood cells, molecules & diseases, 2014
Increased levels of fetal hemoglobin (HbF, α2γ2) may reduce sickle cell anemia severity due to its ability to inhibit HbS polymerization and also reduce the mean corpuscular HbS concentration. We have investigated the influence of three known major loci on the HbF trait (HBG2, rs748214; BCL11A, rs4671393; and HBS1L-MYB, rs28384513, rs489544 and rs9399137) and HbF levels in SCA patients from the State of Pará, Northern Brazil. Our results showed that high levels of HbF were primarily influenced by alleles of BCL11A (rs4671393) and HMIP (rs4895441) loci, and to a lesser extent by rs748214 Gγ-globin (HBG2) gene promoter. The SNPs rs4671393 and rs4895441 explained 10% and 9.2%, respectively, of the variation in HbF levels, while 4.1% of trait variation was explained by rs748214. The results can be considered as in accordance with the pattern of ancestry displayed by the SCA patients: 39.6% European, 29.6% African and 30.8% Native American, and reinforce the suggestion that studies of as...
eJHaem, 2021
Understanding the interplay of genetic factors with haemoglobin expression and pathological processes in sickle cell disease is important for pharmacological and gene-therapeutic interventions. In our nascent study cohort of Nigerian patients, we found that three major disease-modifying factors, HbF levels, α-thalassaemia deletion and BCL11A genotype, had expected beneficial haematological effects. A key BCL11A variant, while improving HbF levels (5.7%-9.0%), also led to a small, but significant decrease in HbA 2. We conclude that in general, interventions boosting HbF are likely to reduce HbA 2 in patients' erythroid cells and that such therapeutic strategies might benefit from a parallel stimulation of HbA 2 through independent mechanisms.
American Journal of Hematology, 2012
Fetal hemoglobin (HbF) is a major modifier of disease severity in sickle cell anemia (SCA). Three major HbF quantitative trait loci (QTL) are known: the Xmn I site upstream of G γ-globin gene (HBG2) on chromosome 11p15, BCL11A on chromosome 2p16, and HBS1L-MYB intergenic polymorphism (HMIP) on chromosome 6q23. However, the roles of these QTLs in SCA patients with uncharacteristically high HbF are not known. We studied 20 African American SCA patients with markedly elevated HbF (mean 17.2%). They had significantly higher minor allele frequencies (MAF) in two HbF QTLs, BCL11A and HMIP, compared with those with low HbF. A 3-bp (TAC) deletion in complete linkage disequilibrium (LD) with the minor allele of rs9399137 in HMIP was also present significantly more often in these patients. To further explore other genetic loci that might be responsible for this high HbF, we sequenced a 14.1 kb DNA fragment between the A γ(HBG1) and δ-globin genes (HBD). Thirty-eight SNPs were found. Four SNPs had significantly higher major allele frequencies in the unusually high HbF group. In silico analyses of these 4 polymorphisms predicted alteration in transcription factor binding sites in 3. Keywords Sickle cell anemia; Fetal hemoglobin; HbF quantitative trait loci HbF inhibits deoxy-HbS polymerization. Patients with elevated HbF have fewer vasoocclusive complications and prolonged survival [1]. Three major HbF QTL are known. The C>T polymorphism (rs7482144) at nucleotide-158 upstream of HBG2 is associated with increased HbF in some SCA patients [2]. Polymorphisms in intron 2 of BCL11A represented by rs766432 was associated with HbF in healthy Northern Europeans [3], African Americans with SCA [4, 5], Chinese with β-thalassemia trait and Thai's with HbE-β thalassemia [5]. BCL11A polymorphisms correlate highly with HbF levels in SCA, accounting for 7-12% of the HbF variance [6]. The HMIP polymorphisms are distributed in three LD blocks [7]. HMIP block 2 represented by rs9399137 is most significantly associated with HbF expression and might function as a distal regulatory element [8,9]. We studied a selected group of 20 African American SCA patients with exceptionally high HbF (mean 17.2%) which differed by more than 4 times the standard deviation of 30 other
elsvier, 2015
India along with Nigeria and DRC contribute to 57% of the world sickle cell anemia population. The annual number of newborns in India with SCA was estimated at 44,000 in 2010. Even with this high prevalence there is minimal information about genetic factors that influence the disease course in Indian patients. The current study was conducted on 240 patients with SCD and 60 with sickle cell trait, to determine the association of genetic variants at the BCL11A (rs1427407) and HBS1-MYB (rs6934903) loci with fetal hemoglobin levels (HbF). Both these loci have been implicated with influencing HbF levels, a powerful modulator of the clinical and hematologic features of SCD. Our results indicate the BCL11A rs1427407 G N T variant to be significantly associated with HbF levels {19.12 ± 6.61 (GG), 20.27 ± 6.92 (GT) and 24.83 ± 2.92 (TT) respectively} contributing to~23% of the trait variance. Interestingly no association of the HBS1L-MYB rs6934903 with the HbF levels was seen. The present study indicates the BCL11A (rs1427407) but not HMIP (rs6934903) to be associated with elevated HbF levels in Indian patient. Further interrogation of additional variants at both the loci; as also a GWAS which may help uncover new loci controlling HbF levels.
Genetics of fetal hemoglobin in tribal Indian patients with sickle cell anemia
Translational Research, 2015
India tops the list of countries with sickle cell disease (SCD) with an estimated 44,000 live births in 2010 and a prevalence of 10%-33%. In the present study, the first from India, we have investigated the effect of genetic variants in the BCL11A, the HMIP (HBS1L-MYB intergenic polymorphism) locus, in addition to the HBB locus, which are known to be associated with fetal hemoglobin (HbF) levels, a major modulator of the disease phenotype. The present study was conducted on 240 individuals with SCD and 60 with sickle cell trait. Genotyping was performed for the BCL11A rs11886868 and rs34211119; HMIP rs9399137, rs189600565, rs7776196, rs34778774, and rs53293029; HBG2 Xmn1 polymorphism rs7482144; and 268C. T HBD promoter polymorphism. All the 3 quantitative trait loci were associated with HbF levels in Indian patients with SCD. The highest difference was seen in the Xmn1 singlenucleotide polymorphism, which accounted for 11% of the trait variance, the BCL11A rs11886868 for 3.65%, whereas the HMIP rs9399137 for 3.8%. The present study indicates the BCL11A, HMIP, and b-globin region to be associated with increased HbF levels in Indian patient. Further interrogation of these genotypes with respect to pain crisis is warranted in this population, which may help in prognostication, as also a genome-wide association study, which may help uncover new loci controlling HbF levels. (Translational Research 2015;-:1-8) Abbreviations: AI haplotype ¼ Arab-Indian haplotype; ANOVA ¼ Analysis of variance; ARMS-PCR ¼ Amplification refractory mutation system-polymerase chain reaction; BCL11A ¼ B-cell lymphoma/leukemia 11A; CSSCD ¼ Cooperative study of sickle cell disease; DNA ¼ Deoxyribonucleic acid; EDTA ¼ Ethylenediaminetetraacetic acid; GWAS ¼ Genome wide association studies; HbA2 ¼ a-globin gene; HBB ¼ b-globin gene; HBD ¼ d-globin gene; HbF ¼ Fetal hemoglobin; HbG2 ¼ g-globin gene; HBS ¼ Sickle hemoglobin; HBS1L ¼ HBS1-like translational GTPase; HMIP ¼ HBS1L-MYB intergenic region; HPLC ¼ High Performance Liquid Chromatography; HWE ¼ Hardy-Weinberg Equilibrium; LD ¼ Linkage disequilibrium; MYB ¼ oncogene; OBC ¼ Other backward class; PCR ¼ Polymerase chain reaction; QTL ¼ Quantitative trait loci; SC ¼ Scheduled caste; SCD ¼ Sickle cell disease; SNP ¼ Single nucleotide polymorphism; SS ¼ Sickle cell disease patients; ST ¼ Scheduled tribe
Annals of Hematology, 2019
Sickle cell anemia (SCA) is an autosomal recessive monogenic disease with significant clinical variability. Cerebrovascular disease, particularly ischemic stroke, is one of the most severe complications of SCA in children. This study aimed to investigate the influence of genetic variants on the levels of fetal hemoglobin (Hb F) and biochemical parameters related with chronic hemolysis, as well as on ischemic stroke risk, in ninety-one unrelated SCA patients, children of sub-Saharan progenitors. Our results show that a higher Hb F level has an inverse relationship with the occurrence of stroke, since the group of patients who suffered stroke presents a significantly lower mean Hb F level (5.34 ± 4.57% versus 9.36 ± 6.48%; p = 0.024). Furthermore, the co-inheritance of alpha-thalassemia improves the chronic hemolytic pattern, evidenced by a decreased reticulocyte count (8.61 ± 3.58% versus 12.85 ± 4.71%; p < 0.001). In addition, our findings have confirmed the importance of HBG2 and BCL11A loci in the regulation of Hb F expression in sub-Saharan African SCA patients, as rs7482144_A, rs11886868_C, and rs4671393_A alleles are significantly associated with a considerable increase in Hb F levels (p = 0.019, p = 0.026, and p = 0.028, respectively). Concerning KLF1, twelve different variants were identified, two of them novel. Seventy-three patients (80.2%) presented at least one variant in this gene. However, no correlation was observed between the presence of these variants and Hb F level, severity of hemolysis, or stroke occurrence, which is consistent with their in silico-predicted minor functional consequences. Thus, we conclude that the prevalence of functional KLF1 variants in a sub-Saharan African background does not seem to be relevant to SCA clinical modulation.
The genetic dissection of fetal haemoglobin persistence in sickle cell disease in Nigeria
BackgroundThe clinical severity of sickle cell disease (SCD) is strongly influenced by the level of fetal haemoglobin (HbF) persistent in each patient. Three major HbF loci (BCL11A,HBS1L-MYB, andXmn1-HBG2) have been reported, but a considerable hidden heritability remains.AimBuilding on the power of a large and genetically diverse patient pool present in Nigeria, we conducted a genome-wide association study for HbF levels in patients from three regions of the country with a diverse ethnic make-up.MethodsWe analysed genome-wide trait association in 1006 Nigerian patients with SCD (HbSS/HbSβ0), followed by a replication and meta-analysis exercise in four independent SCD cohorts (3,582 patients). To dissect association signals at the major loci, we performed stepwise conditional analysis, haplotype association analysis and included public functional annotation data (fGCTA).ResultsAssociation signals were detected forBCL11A(lead SNP rs6706648, β=- 0.39,P=4.96 x 10-34) andHBS1L-MYB(lead ...
2012
Fetal hemoglobin (HbF) protects against many but not all of the hematologic and clinical complications of sickle cell anemia. This protection is dependent on the ability of HbF to hinder deoxyHbS polymerization. HbF level is variable and highly heritable. Previous genetic association studies found single nucleotide polymorphisms (SNPs) in regions of BCL11A (chromosome 2p), in the HBS1L-MYB intergenic polymorphism (HMIP; chromosome 6q), and linked to HBB (chromosome 11p) that were associated with HbF (reviewed in Akinsheye et al). Our aim was to perform a meta-analysis of genome-wide association studies (GWAS) to find genetic loci with modest effect sizes that were associated with HbF when a larger sample size was examined. Common SNPs (585, 563 total) from 7 cohorts totaling 2040 patients were meta-analyzed using the 1,2 1 Meta-analysis of 2040 sickle cell anemia patients: BCL11A and HBS1...