ANTXR1 Intronic Variants Are Associated with Fetal Hemoglobin in the Arab-Indian Haplotype of Sickle Cell Disease

2018 ◽  
Vol 140 (1) ◽  
pp. 55-59 ◽  
Author(s):  
Zhara A. Al-Ali ◽  
Rana K. Fallatah ◽  
Esra A. Aljaffer ◽  
Eman R. Albukhari ◽  
Neriman Sadek Al-Ali ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Real Time Pcr ◽  
Genetic Variants ◽  
Fetal Hemoglobin ◽  
Genetic Mutations ◽  
Cell Disease ◽  
Hbf Level ◽  
Intronic Variants

Disease severity of sickle cell anemia is highly variable, and it is commonly accepted that fetal hemoglobin (HbF) levels play a major role as an ameliorating factor. Investigation of genetic variants have identified several genes to be the principal influencers of HbF regulation. Here, we further elucidated the association of rs4527238 and rs35685045 of ANTXR1 genes in the context of HbF level variance in sickle cell anemia patients of the Arab-Indian haplotype. Samples from 630 sickle cell anemia patients were analyzed for the mutations at 2 specific locations of the ANTXR1 gene by TaqMan®-based real-time PCR. The CC genotype (p = 0.018) of rs4527238 and the TT genotype (p = 0.048) of rs35685045 of ANTXR1 were found to be significantly associated with low HbF expression. The frequency of the CC genotype of rs4527238 was observed to be high in the low HbF patient group compared to the high HbF group (p = 0.009). Likewise, the frequency of the TT genotype of rs35685045 was also high among the low HbF group (p = 0.017). The ANTXR1 genetic mutations and the association with HbF expression in the Arab-Indian haplotype sickle cell patients revealed that the ANTXR1 gene may be a major HbF modulator leading to potential therapeutic options that should be further explored.

scholarly journals High fetal hemoglobin production in sickle cell anemia in the eastern province of Saudi Arabia is genetically determined

Blood ◽  
1986 ◽  
Vol 67 (5) ◽  
pp. 1404-1410 ◽  
Author(s):  
BA Miller ◽  
M Salameh ◽  
M Ahmed ◽  
J Wainscoat ◽  
G Antognetti ◽  
...  
Keyword(s):  
Saudi Arabia ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Fetal Hemoglobin ◽  
Cell Disease ◽  
Chromosome 11 ◽  
Eastern Province ◽  
Genetically Determined ◽  
Hemoglobin Production

Abstract Homozygous sickle cell disease in the eastern province of Saudi Arabia is clinically mild. Circulating fetal hemoglobin levels of 16.0 +/- 7.4% were found in these anemic patients, but only 1.09 +/- 0.97% in their sickle trait parents. To determine whether these sickle cell anemia patients inherit an increased capacity to synthesize fetal hemoglobin, a radioimmunoassay of fetal and adult hemoglobin was performed on erythroid progenitor (BFU-E)-derived erythroblasts from Saudi Arabian sickle cell patients and their parents. Mean fetal hemoglobin content per BFU-E-derived erythroblast from Saudi Arabian sickle cell patients was 6.2 +/- 2.4 pg/cell or 30.4 +/- 8.6% fetal hemoglobin (normal 1.1 +/- 0.7 pg/cell and 5.1 +/- 1.8%). Linear regression analysis of % HbF in peripheral blood versus % HbF per BFU-E- derived cell showed a positive correlation with an r of 0.65. The variance of the intrinsic capacity to produce HbF may account for almost 40% (r2) of the variance of circulating fetal hemoglobin but other factors, particularly selective survival of F cells, must also contribute significantly. Despite virtually normal HbF levels in sickle trait parents of these Saudi patients, mean fetal hemoglobin production per BFU-E-derived erythroblast in these individuals was elevated to 3.42 +/- 1.79 pg/cell or 16.1 +/- 6.4% fetal hemoglobin, and the magnitude of fetal hemoglobin production found in parents correlated with that of the patients. These data indicate that the high fetal hemoglobin in Saudi sickle cell disease is genetically determined but expressed only during accelerated erythropoiesis. Further evidence of such genetic determination was provided by analysis of DNA polymorphisms within the beta-globin gene cluster on chromosome 11. This revealed a distinctive 5′ globin haplotype (+ + - + +) on at least one chromosome 11 in all high F SS and AS tested. The precise relationship of this haplotype to HbF production in this population remains to be defined.

Early Predictors of Fetal Hemoglobin Response to Hydroxyurea in Sickle Cell Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2344-2344
Author(s):  
Kristine Partovi ◽  
Sabrina Martyr ◽  
Vicki McGowan ◽  
Roberto Machado ◽  
James Taylor ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Fetal Hemoglobin ◽  
Maximal Response ◽  
Cell Disease ◽  
Mean Values ◽  
Total Hemoglobin ◽  
Early Predictors ◽  
Family Conference ◽  
Hbf Level

Abstract We investigated the kinetics of hematologic change in patients with sickle cell disease (SCD, HbSS, n=6) or SC disease (HbSC, n=1) who had been newly started on hydroxyurea (HU), with the intention of identifying early correlates to fetal hemoglobin (HbF) responsiveness. We found that HbF increased in all patients on HU, and that the half-maximal degree of HbF response could be estimated by 2 months, in patients’ whose MCVs had risen ≥ 10% above baseline. All 7 patients were treated with HU and followed closely for 6 months or more, until hematologic stability. Hematologic stability was apparent by ≥ 5 months. White blood cell count (WBC), absolute neutrophil count (ANC), reticulocyte (retic) count, % HbF, and mean corpuscular volume (MCV) were examined at bi-weekly intervals. Baseline values (1 or 2 values averaged) were compared with mean values obtained during weeks 2 to 8 (3 or 4 values averaged). As expected, by 2 months WBC and ANC had fallen 30 +/− 8% and 26 +/− 8%, respectively. Change in total hemoglobin (5.8 +/−6.7%), total platelet count (less 11 +/− 10.8%), and LDH (5.3 +/− 8.7%) was not consistent during this two month interval. By eight weeks after initiation of HU, retic counts had dropped in all six SS patients, from 15 to 52% less than baseline while MCV rose 9–21% above baseline; in general, rise in MCV preceded the rise in HbF. Overall, by the time of hematologic stability, all patients had increased their percent HbF, at between 3–8.5-fold relative to baseline; baseline percent HbF of total hemoglobin (Hgb) ranged from 0.7 to 8.3% and, after stabilization, from 5.2% to 24.9%. Maximal percentage of Hgb that was accounted for by HbF at stabilization was arbitrarily set at 100; at 8 weeks, all patients had achieved ≥ 42% of their maximal HbF level, mean 55 +/− 9.4% of maximum HbF. Two additional patients in whom extensive lab data were available, but who were suspected to be non-compliant or sub-therapeutically treated, had a >10% rise in MCV that was temporally associated with an inflection upward for HbF. Patient 8 had mean bi-weekly MCVs of 94, 91, 93, and, after a family conference, 102 (p=.003); Concurrent HbF was 7, 6, 6 and then 10 (p=.046). Patient 9 had mean bi-weekly MCVs on low-dose HU of 97, 96, and, after dose adjustment, 109(p=.003); HbF was 2%, 3%, and then 5 (p=.0094). We speculate that, in many patients, an increase in MCV above baseline of ≥ 10% is a marker of adequate HU dosing, and that HbF levels at that time approximate half-maximal response. A larger series will be necessary to confirm this relationship; a predictive model, correlating MCV and HbF responsiveness, could be used to determine sufficiency of, and compliance to, HU therapy, and to early identify patients who are at high-risk from SCD (e.g. with pulmonary hypertension) whose HbF responsiveness may not be adequate from HU alone. Figure Figure

scholarly journals Effects of hydroxyurea on hemoglobin F and water content in the red blood cells of dogs and of patients with sickle cell anemia

Blood ◽  
1991 ◽  
Vol 78 (1) ◽  
pp. 212-216 ◽  
Author(s):  
EP Orringer ◽  
DS Blythe ◽  
AE Johnson ◽  
G Jr Phillips ◽  
GJ Dover ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Water Content ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Fetal Hemoglobin ◽  
Hemoglobin Concentration ◽  
Mean Corpuscular Hemoglobin ◽  
Cell Disease ◽  
Hemoglobin F ◽  
The Mean

A rationale for clinical trials of hydroxyurea (HU) treatment in sickle cell disease is that the agent increases red blood cell (RBC) fetal hemoglobin content. However, an additional effect of HU is to raise the mean corpuscular volume (MCV). To investigate the action of HU in a species that makes no electrophoretically distinguishable fetal hemoglobin, we treated dogs with the drug and compared their response to that of five patients with sickle cell anemia. Both dogs and patients had an increase in MCV, but the effect of HU treatment on the mean corpuscular hemoglobin concentration (MCHC), density, and water content of the RBCs differed in the two species. The dog RBCs became low in MCHC, high in ion and water content, and low in mean density. Thus, HU can raise MCV and lower MCHC without influencing fetal hemoglobin synthesis. A different pattern was seen in the sickle cell patients during HU treatment. Although the MCV of their RBCs increased, there was no change in MCHC, ion content, or mean density. A notable change in the sickle cell patients' blood was that two subpopulations of cells were nearly eliminated during HU treatment; the hypodense reticulocyte fraction and the hyperdense fraction that contains irreversibly sickled cells. These findings lead us to suggest that trials of HU in sickle cell disease must recognize the possibility that any beneficial effect of this agent might be due not only to an increase in hemoglobin F alone, but perhaps also to the associated increase in MCV or the altered RBC density profile.

scholarly journals Identifying genetic variants and pathways associated with extreme levels of fetal hemoglobin in Sickle Cell Disease in Tanzania.

2020 ◽  
Author(s):  
Siana Nkya ◽  
Liberata Mwita ◽  
Josephine Mgaya ◽  
Happiness Kumburu ◽  
Marco van Zwetselaar ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Genetic Variants ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Cell Disease ◽  
Synonymous Mutations ◽  
Targeted Next Generation Sequencing ◽  
Blood Disorder ◽  
Common Genetic Variants

Abstract Background: Sickle cell disease (SCD) is a blood disorder caused by a point mutation on the beta globin gene resulting in the synthesis of abnormal hemoglobin. Fetal hemoglobin (HbF) reduces disease severity, but the levels vary from one individual to another. Most research has focused on common variants which differ across populations and hence do not fully account for HbF variation. Methods: We investigated rare and common genetic variants that influence HbF levels in 14 SCD patients to elucidate variants and pathways in SCD patients with extreme HbF levels (≥7.7% for high HbF) and (≤2.5% for low HbF) in Tanzania. We performed targeted next generation sequencing (Illumina_Miseq) covering exonic and other significant fetal hemoglobin-associated loci, including BCL11A, MYB, HOXA9, HBB, HBG1, HBG2, CHD4, KLF1, MBD3, ZBTB7A and PGLYRP1.Results: Results revealed a range of genetic variants, including bi-allelic and multi-allelic SNPs, frameshift insertions and deletions, some of which have functional importance. Notably, there were significantly more deletions in individuals with high HbF levels (11% vs 0.9%). We identified deletions with high HbF levels and frameshift insertions in individuals with low HbF. CHD4 and MBD3 genes, interacting in the same sub-network, were identified to have a significant number of pathogenic or non-synonymous mutations in individuals with low HbF levels, suggesting an important role of epigenetic pathways in the regulation of HbF synthesis. Conclusions: This study provides new insights in selecting essential variants and identifying potential biological pathways associated with extreme HbF levels in SCD using multiple genomic variants associated with HbF in SCD.

scholarly journals A cautionary note regarding hydroxyurea in sickle cell disease

Blood ◽  
1994 ◽  
Vol 83 (4) ◽  
pp. 1124-1128
Author(s):  
EP Vichinsky ◽  
BH Lubin
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Clinical Course ◽  
Fetal Hemoglobin ◽  
Organ Damage ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Transfusion Therapy ◽  
History Of ◽  
Hbf Level

Hydroxyurea can increase fetal hemoglobin (HbF) and improve the clinical course of sickle cell disease (SCD) patients. However, several issues of hydroxyurea therapy remain unresolved, including differences in patients' drug clearance, predictability of drug response, reversibility of sickle cell disease-related organ damage by hydroxyurea, and the efficacy of elevated HbF. We treated two patients with hydroxyurea for periods of 1 to 4 years, monitoring clinical course and laboratory parameters at regular intervals. The first patient (patient A) had a history of chronic pain and extensive hospitalizations. The second patient (patient B) had a history of stroke and refused to continue with chronic transfusion therapy and chelation. Both patients showed a fivefold to tenfold increase in HbF (5% to 25%, 3% to 31%). However, patient A developed an acute chest syndrome, despite an HbF level of 20%. After red blood cell transfusions for hypoxia, the HbF level decreased to 5%. When hydroxyurea dosage was increased, pancytopenia developed and was not resolved until 2 months after hydroxyurea was discontinued; Patient B developed a cerebral hemorrhage on hydroxyurea; he died shortly thereafter. His HbF level was 21% before death. We noted an increase in HbF and a general improvement in the two patients. However, both experienced major SCD-related complications despite HbF levels over 20%. Our findings also suggest that the progressive vascular changes associated with SCD are unlikely to be dramatically affected by increased HbF levels. Because neither the efficacy nor the toxicity of hydroxyurea have been thoroughly investigated, physicians should be cautious in prescribing hydroxyurea for patients with SCD before completion of the National Clinical Trial.

scholarly journals High fetal hemoglobin production in sickle cell anemia in the eastern province of Saudi Arabia is genetically determined

Blood ◽  
1986 ◽  
Vol 67 (5) ◽  
pp. 1404-1410
Author(s):  
BA Miller ◽  
M Salameh ◽  
M Ahmed ◽  
J Wainscoat ◽  
G Antognetti ◽  
...  
Keyword(s):  
Saudi Arabia ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Fetal Hemoglobin ◽  
Cell Disease ◽  
Chromosome 11 ◽  
Eastern Province ◽  
Genetically Determined ◽  
Hemoglobin Production

Homozygous sickle cell disease in the eastern province of Saudi Arabia is clinically mild. Circulating fetal hemoglobin levels of 16.0 +/- 7.4% were found in these anemic patients, but only 1.09 +/- 0.97% in their sickle trait parents. To determine whether these sickle cell anemia patients inherit an increased capacity to synthesize fetal hemoglobin, a radioimmunoassay of fetal and adult hemoglobin was performed on erythroid progenitor (BFU-E)-derived erythroblasts from Saudi Arabian sickle cell patients and their parents. Mean fetal hemoglobin content per BFU-E-derived erythroblast from Saudi Arabian sickle cell patients was 6.2 +/- 2.4 pg/cell or 30.4 +/- 8.6% fetal hemoglobin (normal 1.1 +/- 0.7 pg/cell and 5.1 +/- 1.8%). Linear regression analysis of % HbF in peripheral blood versus % HbF per BFU-E- derived cell showed a positive correlation with an r of 0.65. The variance of the intrinsic capacity to produce HbF may account for almost 40% (r2) of the variance of circulating fetal hemoglobin but other factors, particularly selective survival of F cells, must also contribute significantly. Despite virtually normal HbF levels in sickle trait parents of these Saudi patients, mean fetal hemoglobin production per BFU-E-derived erythroblast in these individuals was elevated to 3.42 +/- 1.79 pg/cell or 16.1 +/- 6.4% fetal hemoglobin, and the magnitude of fetal hemoglobin production found in parents correlated with that of the patients. These data indicate that the high fetal hemoglobin in Saudi sickle cell disease is genetically determined but expressed only during accelerated erythropoiesis. Further evidence of such genetic determination was provided by analysis of DNA polymorphisms within the beta-globin gene cluster on chromosome 11. This revealed a distinctive 5′ globin haplotype (+ + - + +) on at least one chromosome 11 in all high F SS and AS tested. The precise relationship of this haplotype to HbF production in this population remains to be defined.

scholarly journals Fetal hemoglobin in sickle cell anemia

Blood ◽  
2011 ◽  
Vol 118 (1) ◽  
pp. 19-27 ◽  
Author(s):  
Idowu Akinsheye ◽  
Abdulrahman Alsultan ◽  
Nadia Solovieff ◽  
Duyen Ngo ◽  
Clinton T. Baldwin ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Sickle Cell Disease ◽  
Gene Cluster ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Fetal Hemoglobin ◽  
Cell Disease ◽  
Sickle Hemoglobin ◽  
Sickle Erythrocytes ◽  
Asymptomatic Disease

Abstract Fetal hemoglobin (HbF) is the major genetic modulator of the hematologic and clinical features of sickle cell disease, an effect mediated by its exclusion from the sickle hemoglobin polymer. Fetal hemoglobin genes are genetically regulated, and the level of HbF and its distribution among sickle erythrocytes is highly variable. Some patients with sickle cell disease have exceptionally high levels of HbF that are associated with the Senegal and Saudi-Indian haplotype of the HBB-like gene cluster; some patients with different haplotypes can have similarly high HbF. In these patients, high HbF is associated with generally milder but not asymptomatic disease. Studying these persons might provide additional insights into HbF gene regulation. HbF appears to benefit some complications of disease more than others. This might be related to the premature destruction of erythrocytes that do not contain HbF, even though the total HbF concentration is high. Recent insights into HbF regulation have spurred new efforts to induce high HbF levels in sickle cell disease beyond those achievable with the current limited repertory of HbF inducers.

scholarly journals Identifying genetic variants and pathways associated with extreme levels of fetal hemoglobin in sickle cell disease in Tanzania

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Siana Nkya ◽  
Liberata Mwita ◽  
Josephine Mgaya ◽  
Happiness Kumburu ◽  
Marco van Zwetselaar ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Genetic Variants ◽  
Fetal Hemoglobin ◽  
Cell Disease

scholarly journals Association of FOXO3A Polymorphisms with Hematocrit, LDH and Longevity in Patients with Sickle Cell Anemia from CSSCD, Walk-Phasst, and PUSH Clinical Trials

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2176-2176
Author(s):  
Harold T Bae ◽  
Paola Sebastiani ◽  
Victor R. Gordeuk ◽  
Yingze Zhang ◽  
Martin H. Steinberg ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Survival Analysis ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Reticulocyte Count ◽  
Fetal Hemoglobin ◽  
Human Longevity ◽  
Age At Death ◽  
Cell Disease

Abstract Background The FOXO3A genotype is strongly associated with longevity in humans. It encodes a transcription factor that appears to regulate anti-oxidant genes during erythroid differentiation in mice, resulting in a hemolytic anemia. The gene has also been implicated in the regulation of fetal hemoglobin expression in children with sickle cell disease. We performed a gene-wide association study to identify and replicate variants of FOXO3A that might be associated with seven biomarkers in patients with sickle cell anemia. Methods 1198 patients from the Cooperative Study of Sickle Cell Disease (CSSCD) study, 308 patients from the Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy (walk-PHaSST) study, and 220 patients from the Pulmonary Hypertension and the Hypoxic Response in Sickle Cell Disease (PUSH) study were analyzed. Biomarkers included hematocrit, reticulocyte count, fetal hemoglobin (HbF), serum levels of lactate dehydrogenase (LDH), aspartate aminotransferase and bilirubin, and the calculated hemolytic component, each appropriately transformed to achieve normality. A total of 189 single nucleotide polymorphisms (SNP) that were either genotyped or imputed (quality r2 > 0.9) were used. Association between each biomarker and SNP was tested using linear regression assuming an additive genetic model, adjusted for age and sex. None of the patients in the CSSCD were treated with hydroxyurea at the time of measurements of the biomarker variables. In the Walk-PHaSST and PUSH, we first examined whether there was a significant association between the biomarker and treatment effect of hydroxyurea; if there was a significant treatment effect, then we looked at potential SNP-by-treatment interaction. For those with significant interactions, only patients without hydroxyurea treatment were included in the analysis. The genetic analysis results from the three studies were then combined to produce meta-analyzed results. Finally, a survival analysis using Cox regression was performed to model age at death in a subset of 54 patients in the CSSCD. Results Among the seven biomarkers, hematocrit showed the most robust enrichment of associations with FOXO3A SNPs. Eight of the 16 published variants had meta-analyzed p-value <0.05. Of those, six had a consistent direction of effects across all three cohorts. Overall, there were 8 loci with 34 SNPs that had meta-analyzed p<0.05 in hematocrit. The most significantly associated SNP (rs6911407; meta-analyzed Beta=-0.0127, meta-analyzed p=0.0013) is one previously associated with human longevity. LDH was most significantly associated with variant rs12206094 (meta-analyzed Beta=0.0256, meta-analyzed p=0.0072), another SNP previously associated with human longevity. Four of the allelic variants associated with LDH were also associated with hematocrit in the appropriate direction. There were also some evidence of enrichment of associations with reticulocyte counts (2 loci with 22 SNPs), HbF (1 locus with 11 SNPs; 10 SNP associations overlapped with reticulocyte count in the appropriate direction), and hemolytic component (2 loci with 8 SNPs); however, the strengths of associations in these biomarkers were marginal (0.01<p<0.05). The survival analysis revealed one locus significantly associated with age at death in the CSSCD patients (rs2802297; p=0.028). Conclusion FOXO3A genetic polymorphisms are associated with hematocrit and serum LDH in this meta-analysis of patients with sickle cell anemia, with less robust associations with fetal hemoglobin level and reticulocyte count. Our genetic findings are biologically consistent with published knockout mouse data indicating that FOXO3A regulates red cell antioxidant capacity and hemolytic severity. Our observation of fetal hemoglobin association with FOXO3A helps to validate previously presented results from Sheehan and colleagues. Parallel to well-documented results in the general population, we find preliminarily that a FOXO3A allelic variant predicts longevity in patients with sickle cell anemia. FOXO3A appears to play a significant role in phenotypic variation in sickle cell anemia. Disclosures No relevant conflicts of interest to declare.

scholarly journals Analysis of hemoglobin F production in Saudi Arabian families with sickle cell anemia

Blood ◽  
1987 ◽  
Vol 70 (3) ◽  
pp. 716-720 ◽  
Author(s):  
BA Miller ◽  
M Salameh ◽  
M Ahmed ◽  
N Olivieri ◽  
G Antognetti ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Cell Disease ◽  
Erythroid Progenitors ◽  
Hemoglobin F ◽  
Gamma Globin ◽  
Hemoglobin Production

Erythrocytes and progenitor-derived erythroblasts of sickle cell anemia patients from the Eastern Province of Saudi Arabia contain increased fetal hemoglobin and G gamma globin. A distinctive DNA polymorphism haplotype in the beta globin gene cluster (++- +-), tightly coupled to a C----T substitution at position -158 5′ to the cap site of the G gamma globin gene, is strongly associated with sickle cell disease in this region. To determine whether the increased fetal hemoglobin production and/or elevated G gamma globin content are tightly linked to this haplotype, we studied 55 members of five Saudi families in which sickle cell disease is present. The results did not suggest a tight linkage of the haplotype to increased fetal hemoglobin production. On the other hand, several sickle trait family members heterozygous for the haplotype had normal fetal hemoglobin production in culture but elevated G gamma to A gamma ratios in peripheral blood. This observation suggests that in this genetic background increased expression of the G gamma globin gene may occur without a measurable increase in total fetal hemoglobin production. The family studies also clearly demonstrate that increased fetal hemoglobin production by erythroid progenitors is dependent on zygosity for the sickle gene in this population. These findings strongly suggest that other factors, such as the products of genes stimulated by hemolytic stress or other genetic determinants associated with the Saudi beta S chromosome, may interact with the -158 C----T substitution and influence gamma globin gene expression in this population.

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