Fetal Hemoglobin in Tunisian Sickle Cell Disease Patient: Relationship with Polymorphic Sequences Cis to the β-Globin Gene (original) (raw)
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Fetal hemoglobin in sickle cell anemia: Genetic studies of the Arab-Indian haplotype
Blood Cells, Molecules, and Diseases, 2013
Most sickle cell anemia (SCA) patients indigenous to the Eastern Province of Saudi Arabia have their HbS gene on the Arab-Indian (AI) HBB gene cluster haplotype. Their fetal hemoglobin (HbF) levels are near 20% and they have milder disease compared with SCA where the HbS gene is on African origin HBB haplotypes . The AI haplotype is characterized by an Xmn1 restriction site at position 2158 5 0 to HBG2 (rs7482144), a Hinc2 site 5 0 to HBE (rs3834466) and other polymorphisms . The causal elements that modify HbF might be in linkage disequilibrium with the b S globin gene in this Saudi population. We first performed homozygosity mapping using genome-wide single nucleotide polymorphisms (SNPs) in AI HbS homozygotes and identified a single large autozygous region including the HBB cluster and surrounding genes. By next generation sequencing, we examined this region in these same individuals and identified several variants that included a SNP in the HBD promoter region at position 268 bp 5 0 to HBD (CCAAC > TCAAC). We found this SNP only when the HbS gene was on an AI haplotype and not in SCA with other haplotypes. This SNP was functional in reporter assays in K562 cells and is an AI haplotype-specific marker. summarizes the patient characteristics. Using genome-wide SNP data from a limited number of cases, a region of autozygosity was found only in AI HbS homozygotes on chromosome 11 (coordinates 5,196,450-5,323,071). The region contains HBD, HBG1, HBG2, HBE1, and the Xmn1 5 0 HBG2 restriction site (rs7482144). By targeted deep sequencing of 400 kb of chromosome 11 (coordinates 5,143,424-5,543,424; average coverage 42x) in 4 AI patients 1,195 variants were found. A homozygous C-T variant 268 bp 5 0 HBD with high genotyping and mapping quality that was not in dbSNP build 135 or 1,000 Genomes, was present. Resequencing of 15.9 kb of chr11 (coordinates 5,253,531-5,269,435) by Sanger sequencing detected three new SNPs of which one was the 268 C > T SNP. We focused on this SNP because of its location within the Corfu deletion region and its location in the HBD promoter.
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...
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 ...
International Journal of Laboratory Hematology, 2012
Single-nucleotide changes are the most common type of genetic difference among people. They may create a new restriction enzyme recognition site or destroy a naturally occurring one. Although many restriction enzyme sites have been reported in the human b-glo-bin gene cluster, seven are nonrandomly associated with each other and form the basis of the b-globin gene cluster haplotype. Five sites make up a 5 0 subhaplotype (from the e-globin gene to the d-globin gene) and two sites a 3 0 subhaplotype (containing the b-globin gene) (Antonarakis, Kazazian & Orkin, 1985).
Medical Principles and Practice, 2010
Objective: To investigate the prevalence of haptoglobin (Hp) gene alleles in Kuwaiti sickle cell disease (SCD) patients, who generally have a mild phenotype, and compare the pattern to Nigerian SCD patients whose SCD phenotype is more severe. Subjects and Methods: Hp genotyping was carried out in a group of 82 and 54 SCD patients from Kuwait and Nigeria, respectively, and appropriate Hb AA controls. The Hp genotyping was done using a PCR technique followed by agarose gel electrophoresis. Results: The frequency of the Hp-2 allele was 73.8% among Kuwaiti SCD patients, while the Hp-1 allele predominated among Nigerian patients (60.7%). However, the differences were not significant (p > 0.05) when the allele distributions were compared between Kuwaiti SCD and their AA counterparts or between Nigerian SCD and their AA controls. There was no association of Hp-2 allele with frequent vaso-occlusive crisis among the Kuwaiti SCD patients. Conclusion: The distribution of Hp alleles appears ...
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
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
Beta globin gene haplotypes in Bahraini patients with sickle cell anaemia
Bahrain Medical …, 1995
Molecular genetic studies were undertaken to determine the haplotype of chromosomes carrying the sickle cell allele in Bahraini patients, and hence allow consideration of the possible source of these alleles. A total of 59 individuals from 19 families were studied. Of these, 35 were affected with sickle cell anaemia, and 24 were carriers.