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• W2077971504 abstract "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 [1–9]. The AI haplotype is characterized by an Xmn1 restriction site at position 2158 50 to HBG2 (rs7482144), a Hinc2 site 50 to HBE (rs3834466) and other polymorphisms [10]. The causal elements that modify HbF might be in linkage disequilibrium with the b globin gene in this Saudi population. We first performed homozygosity mapping using genome-wide single nucleotide polymorphisms (SNPs) in AI HbS homozygotes [11,12] 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 50 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. Table I 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 50 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 50 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. The C > T SNP in the HBD promoter was found only in individuals with the AI haplotype. Saudi sickle cell trait carriers with the AI haplotype were heterozygous for this SNP; while siblings without HbS did not carry this mutation. Among 25 AI HbS-b thalassemia patients, 16 were heterozygous at this site (C/T) and 9 were homozygous (T/T). All AI HbS-b thalassemia patients who were homozygous T/T were also homozygous for the AI haplotype (Table I). Fifteen African American SCA patients with unusually high HbF, 54 Saudi SCA patients from the Southwestern Province (SW)—mainly Benin but including subjects with the Senegal haplotype—19 SW HbS-b thalassemia patients, 16 SW sickle cell trait cases, and 25 normal Saudi controls did not carry the 268 HBD SNP. This SNP was not found in 1,094 individuals in 1,000 Genomes May 2011 release. It is important to note that hemoglobin electrophoresis results in Table I were performed using different methods, so direct comparison of HbF and HbA2 between different groups will not be accurate. In addition, the effect of coinheritance of a-thalassemia, or presence of iron deficiency anemia on Hb A2 level was not assessed. Finally, HbA2 levels are artifactually high when HbS is present because of the co-elution of minor HbS species. For these reasons, it is not possible to estimate the effects of the 268 C-T SNP on these subjects HbA2 levels. Reduced expression of HBD relative to HBB in normal individuals is partly a result of a degenerate CCAAT box in the HBD promoter (CCAAC). The CCAAC motif is the site of the 268 C > T SNP (TCAAC) [13–15]. When we compared the activity of the wild-type HBD promoter with the promoter containing the 268 C > T SNP the variant promoter was associated with a significant decrease in the expression of a reporter construct suggesting that it could further impair already enfeebled HBD expression (Fig. 1). Although HBG is expressed at high levels in K562 cells, endogenous HBD is also expressed [16]. The expression studies were designed solely to test the hypothesis that the 268 C > T SNP downregulates the expression of the HBD promoter. The literature provides further evidence for a functional role of the 268 C > T SNP. Its presence was associated with d thalassemia in one individual with reduced HbA2 of 2% and a slightly increased HbF of 1.3% [13]. Moreover, mutations at positions 230, 231, 236, 255, 265, 276, and 277 in the HBD promoter were reported in HbVar database (http://globin.cse.psu.edu/) to cause d thalassemia [14,17–19], and HbF levels of 3.3–4.7% have been noted in some hematologically normal individuals with homozygous d thalassemia [19,20]. A mechanism for increased HbF in the presence of less common HBD promoter mutations is unknown. Any role for the 268 C-T SNP as a modifier of HbF in AI haplotype HbS sickle cell disease is unknown. Perhaps HBD promoter SNPs reduce the interaction of the locus control region and the transcription apparatus with this promoter permitting enhanced interactions with HBG promoters [21]. The paradox of the Corfu deletion first suggested the potential of the HBD-HBG1 intergenic area, the site of the 268 C-T SNP, as a silencer of HBG expression [22]. One potential functional area is the polypyrimidine (PYR) binding site about 960 bp upstream of HBD; however, polymorphisms" @default.
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• W2077971504 date "2012-05-28" @default.
• W2077971504 modified "2023-09-26" @default.
• W2077971504 title "A functional promoter polymorphism of the δ-globin gene is a specific marker of the Arab-Indian haplotype" @default.
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• W2077971504 doi "https://doi.org/10.1002/ajh.23239" @default.
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