Toward prevention of Hemoglobinopathies in Oman (original) (raw)
Related papers
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.
Haplotypes, sub-haplotypes and geographical distribution in Omani patients with sickle cell disease
Thalassemia Reports, 2015
Despite the fact that patients homozygous for the sickle cell disease (SCD) mutation have an identical genotype, the severity of the disease can be extremely variable. The hemoglobin (Hb) S mutation has been described on five different haplotypes with different clinical expression. Identifying the genotypes, haplotypes and sub-haplotypes of the β gene cluster in Oman needs to be studied in more details to establish a correlation between the genotype/ haplotype and phenotype diversity observed in SCD patients for prognostic purposes, accurate diagnosis and thus planning for the best tailored treatment. We have investigated 125 HbS homozygotes from different parts of Oman and determined their haplotypes and sub-haplotypes and correlated this to the hematological and clinical expression. We have found 11 haplotype combinations differently distributed in the country, with the Asian/Asian HbS haplotype being the most predominant. Sub-haplotypes was only found among patients with CAR/OmanI haplotype. As expected, the correlation between haplotypes, sub-haplotypes and disease severity was mainly associated with HbF expression. Our study on haplotype/phenotype correlation has shown which major haplotypes occur in the different regions of Oman. Furthermore, neither the haplotype or sub-haplotype nor the HbF alone appeared to be fully associable with the variable clinical phenotypes. External factors do occur and are associated with the expression of the disease.
Indian Journal of Hematology and Blood Transfusion, 2015
Fetal hemoglobin (HbF) plays a dominant role in ameliorating morbidity and mortality of hemoglobinopathies. We evaluated the effects of polymorphic markers within the b-globin gene cluster to identify the genetic mechanics that influence HbF on Tunisian sickling patients (n = 242). Haplotype analysis was carried out by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and the framework polymorphism was established by PCR-sequencing, four independent regions of interest were identified: the 5 0 region of b-LCR-HS2 site, the intervening sequence II (IVSII) region of two fetal (Gc and Ac) genes and the 5 0 region of b-globin gene. The correlation of these various Haplotypes and SNPs with HbF expression and clinical data was studied. Our data showed that among the various polymorphic markers analyzed, only the sequence (AT)xN12(AT)y in LCR HS2 region was significantly associated (p \ 0.05) with increased HbF levels, suggesting that the b-globin gene cluster exerts a significant effect on HbF in sickle cell patients. This study can improve understanding of the physiopathology of the disease and aid to increase our ability to predict clinical severity.
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.
Fetal hemoglobin in sickle cell anemia: The Arab-Indian haplotype and new therapeutic agents
American Journal of Hematology, 2017
Fetal hemoglobin (HbF) has well-known tempering effects on the symptoms of sickle cell disease and its levels vary among patients with different haplotypes of the sickle hemoglobin gene. Compared with sickle cell anemia haplotypes found in patients of African descent, HbF levels in Saudi and Indian patients with the Arab-Indian (AI) haplotype exceed that in any other haplotype by nearly twofold. Genetic association studies have identified some loci associated with high HbF in the AI haplotype but these observations require functional confirmation. Saudi patients with the Benin haplotype have HbF levels almost twice as high as African patients with this haplotype but this difference is unexplained. Hydroxyurea is still the only FDA approved drug for HbF induction in sickle cell disease. While most patients treated with hydroxyurea have an increase in HbF and some clinical improvement, 10 to 20% of adults show little response to this agent. We review the genetic basis of HbF regulation focusing on sickle cell anemia in Saudi Arabia and discuss new drugs that can induce increased levels of HbF.
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).
International Journal of Contemporary Medicine, 2021
Background: Sickle cell disease (SCD) is an inherited blood disorder that affects red blood cells. The study of various modulating factors, and genetic factors affecting the clinical severity of the SCD is an interesting research focus especially in communities with a distinct genetic background. The XmnI polymorphism is a common genetic variation that was reported in previous studies to increase fetal hemoglobin (HbF) level. This was a descriptive cross-sectional study, conducted in El-Obeid city in Northern Kordofan state, western Sudan, during the period from August to November 2016. The Xmn1 polymorphic site was determined by polymerase chain reaction. Data was analyzed using SPSS software program version 20. P-value of 0.05 and below was considered of significance. In present study HbF level among normal individuals AA , shown significant difference (p<0.05) between presence of Xmnl +/+ and absence of Xmnl-/-site. in patients with SS , the HbF level was higher in those who had one or two Xmnl sites as compared to those with the site absent. In patients with sickle cell trait AS and AA, only the presence of the one and two Xmnl site (+/+) compared to the absence of the site (-/-) was associated with significant increase in the HbF level. There is a close link between the Xmn1 polymorphism site and HbF level. A wide range of HbF level was obtained both in the present and absence of this site. Further studies with a large sample size as well as analysis BS haplotypes among the patient with sickle cell anemia population are needed for better understand of possible association .
Hemoglobinopathies in North Africa: A Review
Hemoglobin, 2010
Hemolytic anemias are very common diseases. Among these diseases, hemoglobinopathies are widely spread throughout the Mediterranean Basin, including North Africa (Tunisia, Algeria and Morocco). Their severity and disabling nature make them a major public health problem. This study includes our data on the Tunisian hemoglobinopathies together with all the reports concerning epidemiological, clinical and molecular aspects in Algerian and Moroccan populations. Investigation methods begin with the application of several techniques for hemoglobin (Hb) analyses [electrophoresis and isoelectric focusing (IEF), micro-chromatography assay] of anemic patients in various hospital departments. Molecular investigation by DNA analyses completes the hematological and biochemical studies using polymerase chain reaction (PCR) followed by enzymatic digestion and/or denaturing gradient gel electrophoresis (DGGE), single strand conformation polymorphism (SSCP) and sequencing. These methods offer screening for a large number of families affected by sickle cell disease and thalassemia. In Tunisia, Algeria, and Morocco, more than 45 mutations have been identified on the b-globin gene. The most common in Tunisia and in Algeria are codon 39 (C>T) and IVS-I-110 (G>A), which together account for more than 50% of all mutations. In Morocco, the predominant mutations are codon 39 and frameshift codon (FSC) 8 (-AA). The identification of molecular defects in the bgene contributes to the development of diagnostic tests (prenatal diagnosis), and gives us the opportunity to help many couples. Our studies of the haplotypes of the b S , codon 39 and IVS-I-110 origins allowed the hypothesis of a Benin origin for b S , a local North African origin for codon 39 and an Eastern Mediterranean origin for IVS-I-110. The analysis of polymorphisms associated with a moderate phenotype of b-thalassemia (b-thal) and sickle cell disease in North Africa has shown, in several cases, a strong association with some mutations and restriction fragment length polymorphisms (RFLP) haplotype IX on the b-globin locus and the-158 (C>T) polymorphism in 5¢