Prediction of Fetal Hemoglobin in Sickle Cell Anemia Using a Genetic Risk Score

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3216-3216
Author(s):  
Jacqueline N Milton ◽  
Paola Sebastiani ◽  
Clinton T. Baldwin ◽  
Efthymia Melista ◽  
Victor R. Gordeuk ◽  
...  
Keyword(s):  
Linear Regression ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Genetic Risk ◽  
Genetic Risk Score ◽  
Fetal Hemoglobin ◽  
P Value ◽  
Data Sets ◽  
Genome Wide ◽  
Hbf Level

Abstract Abstract 3216 Fetal hemoglobin (HbF) is the major genetic modifier of clinical course of sickle cell anemia (homozygosity for HBB glu6val). HbF level is also an important predictor of mortality. If it were possible to know at birth the HbF level likely to be present after stabilization of this measurement at about age 5 years, then an improved prognosis might be given and HbF-inducing treatments better informed. Levels of HbF in adults are highly heritable and the production of HbF is genetically regulated by several quantitative trait loci and by genetic elements linked to the HBB gene cluster. One of the most popular approaches to genetic risk prediction uses a summary of the risk alleles in the form of a genetic risk score (GRS) that is used as a covariate of the genetic prediction model. We present the development of a GRS for HbF in 841 patients from the Cooperative Study of Sickle Cell Disease (CSSCD) cohort patients and assessed its ability to predict HbF values in three independent cohorts that included PUSH (N=77), Walk-PHaSST (N=181), and C-Data from the Comprehensive Sickle Cell Centers program (N= 127). We used the results of a genome-wide association study (GWAS) of HbF in sickle cell anemia, in which patients were genotyped using the 610K Illumina array, and association of each of the ∼550K SNPs with HbF was tested using a linear regression model with gender adjusted additive genetic effects. To build the GRS, we sorted SNPs by increasing p-value, starting from the most significant SNP associated with HbF (rs766432, p-value=2.61×10−21), and pruned the list by removing SNPs in high LD (r2 > 0.8). We then used this list of SNPs to generate a sequence of nested GRS. We started with the GRS that included only the most significant SNP and generated the second GRS by adding the second SNP from the list of SNPs. The third GRS was generated by adding the 3rd SNP from the list of SNPs to the second GRS, and so on. We repeated this analysis including up to 10,000 SNPs (p-value< .02185) and hence generated 10,000 GRS, for each of the subjects in the CSSCD. Each of these GRS was included as covariate in a linear regression model and the regression coefficients of the resultant 10,000 linear regression models were estimated using Least Squares methods in the CSSCD data. The predictive value of these GRS models was then evaluated in three independent cohorts. In this evaluation, we computed the 10,000 GRS for each subjects in each data sets, and then used the 10,000 regression models estimated in the CSSCD data set to compute the expected HbF value of patients, given their GRS. We then assessed the predictive accuracy by computing the correlation between the observed and predicted values of HbF. To produce more stable predictions, we also created ensembles of predictive models. An ensemble of the first 14 GRS models including 14 SNPs had the best predictive value in all 3 data sets and explains 23.4% of the variability in HbF; the correlation between the predicted HbF and observed HbF was 0.44, 0.28 and 0.39 in the three different cohorts. Of these 14 SNPs, 6 were located in BCL11A; other SNPs were located in the olfactory receptor region and the in chromosome 11p15 and the site of the HBB gene cluster and were found previously to be associated with HbF. We next compared these results to predictive models in which we included gender, coincident alpha thalassemia, and HBB haplotypes for prediction. The model including gender and alpha thalassemia explained only 2.6% of the variability of HbF in the discovery cohort and the model including HBB haplotypes explained 2.35% of the variability of HbF in the discovery cohort and neither model showed a significant correlation between the predicted and observed HbF in the three other cohorts. In addition, combining the non-genetic information with the GRS did not help to explain more of the variability in HbF. With as few as 14 SNPs we can explain more of the variability in HbF and do a better job of prediction in comparison to using other non-genetic risk factors or genome-wide significant SNPs; however, we still cannot explain all of the variability in HbF that is due to heritability. These results suggest that knowing the genotype of a few SNPs can help to predict HbF that after they have stabilized. Prediction of HbF at an early age has the potential to help foretell some features of the severity of the clinical course of the disease and aid to optimize the clinical management of patients. Disclosures: No relevant conflicts of interest to declare.

Fetal Hemoglobin in Sickle Cell Anemia: A Genome-Wide Association Study of the Response to Hydroxyurea

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2471-2471 ◽  
Author(s):  
Nadia Timofeev ◽  
Paola Sebastiani ◽  
Steven H. Hartley ◽  
Clinton T. Baldwin ◽  
Martin H. Steinberg
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Association Studies ◽  
Fetal Hemoglobin ◽  
Significant Snps ◽  
Genome Wide Association ◽  
P Value ◽  
Genome Wide ◽  
Genome Wide Significance

Abstract Fetal hemoglobin (HbF) is the major genetic modulator of sickle cell anemia. Candidate gene-based and genome-wide association studies (GWAS) have provided strong evidence that single nucleotide polymorphisms (SNPs) linked to genes on chromosome 6q (HBS1L-MYB) and 2p (BCL11A), along with elements in cis to HBG help determine HbF concentration in untreated patients with sickle cell anemia and β thalassemia, and in normal individuals. The HbF response to hydroxyurea (HU) varies considerably among treated patients, even when compliance with treatment is good and patients are treated under controlled conditions. This suggests that genetic factors might affect the response to treatment with this agent. In the Multicenter Study of Hydroxyurea, 299 patients were randomized to receive either HU titrated to maximum tolerated doses, or a placebo, and HbF levels were measured before and at the completion of the randomized phase of the study. In 123 HU-treated patients, we completed GWAS using Illumina 370K chips that include approximately 350,000 haplotype tagging SNPs, and studied the association of SNPs with the change in HbF from baseline levels to levels measured at the end of the active treatment portion of the study. We conducted a GWAS using the analytical program PLINK, of approximately 273K SNPs with minor allele frequency &gt;0.05, using linear regression and an additive model of inheritance. We selected for further investigation those SNPs with association that reached 0.05 significance, after we adjusted for sex. Because of the limited sample size that results in relatively large p-values, no single SNP reached so-called genome-wide significance after correcting for multiple comparisons using a Bonferroni correction (p-value &lt;10-7) or 5% false discovery rate. Two SNPs had an association with p value &lt;10–6 and 27 SNPs reached at least 10–5 significance. Noticeably, the SNP rs6899351 in FABP7 in 6q22.31 was associated with the largest increment in HbF after treatment with HU (6.9% change per copy of allele G, p-value 4 ×10–5). We also identified 2 SNPs in PDE7B (6q23.3) that were significantly associated with positive changes of HbF and 3 SNPs in MAP7 (6q23.3) that were significantly associated with a reduction of HbF after treatment. Using candidate gene association studies, we had previously shown that PDE7B and MAP7 were significantly associated with differential expression of HbF in sickle cell anemia. These new GWAS results suggest a regulatory role for these genes, or this region of chromosome 6q, in the HbF response to HU in sickle cell anemia. Analysis of the distribution of significant SNPs per chromosome also showed that chromosome 20 had a larger number of significant SNPs than expected at random, especially in CST9, one of a family of protease inhibitors. CST9 is tagged by 3 SNPs in the 370K array (rs2983639, rs2983640, rs10485646), 2 of which were associated with significant positive changes in HbF after treatment with HU and one with significant negative changes of HbF. Specifically, the average increase in HbF was 1.5% for each copy of allele G for SNP rs2983639 (p = 0.025), and 1.6% for each copy of allele A for SNP rs2983640 (p = 0.047), while the level of HbF decreased by approximately 1.5% for each copy of allele A for SNP rs10485646 (p = 0.035). The SNP rs2983640 is an exon variant that produces the amino acid change F-L. Although these SNPs do not individually reach genome-wide significance, cumulatively they provide strong evidence of association, as the probability that they are all simultaneously associated by chance is 10-4. Furthermore, we identified significant variants in other genes that belong to the same family of type 2 cysteine protease inhibitors, specifically 2 SNPs in CTS3 and 1 SNP in CTS5. Although the small sample size and the large number of SNPs tested suggest caution until these results are replicated in independent patient treatment groups, these preliminary findings suggest that type 2 cystatin genes and pseudogenes are associated with the HbF response to HU. If confirmed, it might be possible to use results like these to build a prognostic model of the HbF response to HU in sickle cell anemia.

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 Genome Wide Association Study of Fetal Hemoglobin in Sickle Cell Anemia in Tanzania

PLoS ONE ◽  
2014 ◽  
Vol 9 (11) ◽  
pp. e111464 ◽  
Author(s):  
Siana Nkya Mtatiro ◽  
Tarjinder Singh ◽  
Helen Rooks ◽  
Josephine Mgaya ◽  
Harvest Mariki ◽  
...  
Keyword(s):  
Association Study ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Genome Wide Association Study ◽  
Fetal Hemoglobin ◽  
Genome Wide Association ◽  
Genome Wide

scholarly journals Fetal hemoglobin in sickle cell anemia: genome-wide association studies suggest a regulatory region in the 5′ olfactory receptor gene cluster

Blood ◽  
2010 ◽  
Vol 115 (9) ◽  
pp. 1815-1822 ◽  
Author(s):  
Nadia Solovieff ◽  
Jacqueline N. Milton ◽  
Stephen W. Hartley ◽  
Richard Sherva ◽  
Paola Sebastiani ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Olfactory Receptor ◽  
Association Studies ◽  
Receptor Gene ◽  
Fetal Hemoglobin ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Olfactory Receptor Gene ◽  
Genome Wide

Abstract In a genome-wide association study of 848 blacks with sickle cell anemia, we identified single nucleotide polymorphisms (SNPs) associated with fetal hemoglobin concentration. The most significant SNPs in a discovery sample were tested in a replication set of 305 blacks with sickle cell anemia and in subjects with hemoglobin E or β thalassemia trait from Thailand and Hong Kong. A novel region on chromosome 11 containing olfactory receptor genes OR51B5 and OR51B6 was identified by 6 SNPs (lowest P = 4.7E−08) and validated in the replication set. An additional olfactory receptor gene, OR51B2, was identified by a novel SNP set enrichment analysis. Genome-wide association studies also validated a previously identified SNP (rs766432) in BCL11A, a gene known to affect fetal hemoglobin levels (P = 2.6E−21) and in Thailand and Hong Kong subjects. Elements within the olfactory receptor gene cluster might play a regulatory role in γ-globin gene expression.

scholarly journals Novel Genetic Loci That Influence Fetal Hemoglobin Expression in Children with Sickle Cell Anemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 33-34
Author(s):  
Anu Marahatta ◽  
Thad A. Howard ◽  
Susan E. Stuber ◽  
Kathryn L McElhinney ◽  
Leon Tshilolo ◽  
...  
Keyword(s):  
United States ◽  
Allele Frequency ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Fetal Hemoglobin ◽  
The United States ◽  
Sub Saharan Africa ◽  
Cell Surface Receptor ◽  
Genome Wide ◽  
The Caribbean

Introduction: Elevated levels of fetal hemoglobin (HbF) are known to ameliorate both the morbidity and mortality of sickle cell anemia (SCA). Sustained post-natal HbF expression is heritable and regulated by multiple quantitative trait loci. Previous genomic studies have identified three major gene loci (BCL11A, HBS1L-MYB, and HBG2) that account for ~40% of HbF variation in SCA, but additional genetic modifiers remain to be discovered. We performed a genome wide association study (GWAS) using DNA collected from multiple cohorts of children with SCA, to identify novel genes and variants involved in HbF expression. Methods: We analyzed genomic DNA from 1009 children with SCA and pre-treatment steady-state HbF levels who enrolled in prospective research trials from the United States (HUSTLE, SWiTCH, TWiTCH), the Caribbean (SACRED) or sub-Saharan Africa (REACH, NOHARM). Whole blood DNA was first genotyped using the H3Africa SNP array (Illumina) that identifies over 2.2 million single nucleotide variants (SNVs) across the genome. Most samples also underwent whole exome sequencing (WES) using NimbleGen VCRome 2.1 capture reagents and the Illumina HiSeq2500 platform analysis, which identifies coding variants in all known exons. Square root transformed HbF values were the continuous variable for association testing using single-locus mixed model (EMMAX) adjusted for population stratification, with both age and sex as co-variates. The GWAS approach included 3 distinct steps. First, we performed two independent GWAS discovery steps using distinct African populations; these were designated Discovery I (N=211) and Discovery II (223). Second, only SNVs that were significant (p&lt;0.05) in both datasets were then selected for two independent replication steps; these were designated either African-American (N=157) or African (N=269). Third, the SNVs that were significant in both dual discovery and at least one of the replication cohorts were then verified using an additional Caribbean cohort (N=149) with TaqMan techniques for genotyping specific variants. Through this multistep process, we searched for genomic loci with consistent HbF associations across multiple cohorts. Results: From the combined SNP and WES dataset, 8 BCL11A variants passed genome wide significance (p&lt;10-8) in the discovery analysis, and 1,048 additional variants were identified with nominal HbF association (p&lt;0.001). We found that 173 of these novel variants had sustained association in at least one of the replication cohorts (p&lt;0.05). We selected 20 variants with the strongest and most consistent associations with HbF from the discovery and replication analyses for further verification (Table 1). Expected HbF associations with BCL11A (rs1427407) and HBS1L-MYB (rs4895441) were identified. Among other 18 novel candidate variants, the rs77737207 variant (allele frequency ~0.10) near the RUNX1T1 locus was strongly associated with lower HbF levels, while coding variant rs2279587 (allele frequency ~0.03) in the ITGA1 gene approached statistical significance (p&lt;0.08) in the final verification cohort and was associated with higher levels of HbF. Conclusions: Our large GWAS of HbF with diverse global cohorts of children with SCA from Africa, the United States, and the Caribbean validated the strong associations of HbF with common genetic variants near the BCL11A and HBS1L-MYB gene loci. We also identified two novel gene loci, ITGA1 and RUNX1T1, that have statistical associations with HbF expression. The RUNX1T1 gene is a broad transcriptional corepressor known to impact myeloid differentiation in hematopoiesis, while ITGA1 encodes the integrin alpha subunit of a cell-surface receptor involved in cell-cell adhesion and inflammation. Both of these genes represent novel loci that may be involved in the regulation of HbF expression in children with SCA and should be investigated further using cellular and animal models. Disclosures No relevant conflicts of interest to declare.

scholarly journals Polymorphisms Associated with the Arab-Indian Haplotype of Sickle Cell Anemia Are Candidate Fetal Hemoglobin Gene Modulators

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3388-3388
Author(s):  
Vinod Vathipadiekal ◽  
Abdulrahman Alsultan ◽  
John Farrell ◽  
A.M Al-Rubaish ◽  
Fahad Al-Muhanna ◽  
...  
Keyword(s):  
African Americans ◽  
Gene Cluster ◽  
Allele Frequency ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Olfactory Receptor ◽  
Receptor Gene ◽  
Fetal Hemoglobin ◽  
Olfactory Receptor Gene ◽  
Genome Wide

Abstract Fetal hemoglobin (HbF) inhibits HbS polymerization. Because of this, sufficient HbF in most sickle erythrocytes can lead to a milder disease phenotype. HbF levels differ amongst the β-globin gene (HBB) cluster haplotypes of sickle cell anemia. In the Arab-Indian (AI) haplotype, HbF was about 20% compared with 5-10% in the Bantu, Benin, and Senegal haplotypes. Functional elements linked to the HBB haplotype are likely to regulate the expression of HbF in addition to the effects of trans-acting modulators. To identify cis-acting SNPs in the HBB gene cluster that differentiate the AI haplotype from all others, including the Senegal haplotype-the Senegal haplotype shares some SNPs with the AI haplotype but its carriers have lower HbF-we studied patients with sickle cell anemia who were homozygous for HBB haplotypes by genome-wide SNP association analysis (GWAS; Table). First, we compared the results of GWAS of 42 Saudi AI haplotype homozygotes with GWAS in 71 Saudi Benin haplotype homozygotes. The only variants distinguishing these 2 populations with genome-wide significance (p-values between 9.6E-07 and 2.7E-45) were 223 SNPs in chromosome 11p15 from positions 3.5 to 6.5 mb. This region included the HBB gene cluster, its locus control region (LCR) and the upstream and downstream olfactory receptor gene clusters. The minor allele frequency of SNPs in MYB (chr 6q23), BCL11A (chr 2p16) and KLF1 (chr 19), trans-acting loci that affect expression of the HbF genes, were similar in these 2 cohorts. A novel candidate trans-acting locus was not found, however our power to detect such an association was low. We followed-up these observations by comparing allele frequencies in 303 African American cases homozygous for the haplotypes shown in the Table. Thirteen GWAS-significant SNPs, in addition to rs7482144 and rs10128556, were present in all AI haplotype cases but not in 83 Senegal haplotype chromosomes. The allele frequency of these SNPs was replicated in 62 independent AI haplotype cases. Rs2472530 is in the coding region of OR52A5; rs16912979, rs4910743 and rs4601817 are in the HBB gene cluster LCR; rs16912979 in DNase I hypersensitive site-4 altered motifs for POLR2A, GATA1, and GATA2 binding.The minor allele of rs10837771 causes a missense mutation in OR51B4 an upstream olfactory receptor gene. To see if any of these or other alleles might sometimes be associated with HbF in the Bantu and Benin haplotyes, we selected homozygotes and compound heterozygous for these haplotypes who had unexplained and uncharacteristically high HbF. Thirty-one African Americans, aged ≥5 yrs. who had a HbF of 21% were compared with 350 similar cases who had a mean HbF of 3%. Four additional SNPs on chromosome 11, from positions ranging from 5536415 to 5543705 in the UBQLNL/HBG2, region and present in 45-48% of AI haplotype and 3-13% of other haplotypes, were found at higher frequencies in the high HbF group compared with the low HbF group. These SNPs also altered transcription factor binding motifs. Loci marked by SNPs that distinguish the AI from the Senegal and other HBB haplotypes might contain functionally important polymorphisms and account in part for high HbF in AI haplotype sickle cell anemia, independent of, or in addition to, the effects associated with rs7482144 or rs10128556. They might also be rarely associated with high HbF found in other haplotypes. These observations provide a foundation for mechanistic studies focused on the role of these variants in the expression of their linked HbF genes.Table 1.non-codedallelegenomic locationSaudi AI(n=42)Saudi ben.ben(n=71)AA ben.ben(n=264)AA ban.ban(n=31)AA sen.sen(n=8)HbF (%)1711669rs10837771Gexon OR51B410.020.0200rs4601817GLCR10.020.0400rs4910743CLCR10.010.0100rs16912979CLCR00.960.920.111rs10488675Gintron HBE110.01000rs7482144*AHBG210001rs10128556#TIntron HBBP110001rs7935470COR51V110.020.0300rs10837582GOR51V1100.0200rs11036227TOR51V110000rs10734485COR51A1P00.990.9711rs10837461AOR52A110.01000rs2472522GOR52A110.01000rs2472530Gexon OR52A510.01000rs2499948TOR52A510.020.010.020Allele frequencies in haplotypes of sickle cell anemia. * Xmn1 5' HBG 2 restriction site. This SNP, not present on the SNP microarray, was genotyped independently; # LD with rs7482144; AA designates African Americans; ben-Benin; ban-Bantu; sen-Senegal. Disclosures No relevant conflicts of interest to declare.

Co-Inheritance of Delta Thalassemia Might Contribute to the High Fetal Hemoglobin in Sickle Cell Anemia Patients with the Saudi-Indian Haplotype

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1056-1056
Author(s):  
Abdulrahman Alsultan ◽  
Duyen A. Ngo ◽  
John J. Farrell ◽  
Hazem Ghabbour ◽  
Idowu Akinsheye ◽  
...  
Keyword(s):  
Saudi Arabia ◽  
African Americans ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Conflicts Of Interest ◽  
Fetal Hemoglobin ◽  
Transcriptional Level ◽  
Eastern Province ◽  
Hbf Level ◽  
Positively Charged

Abstract Abstract 1056 Most sickle cell anemia patients (HBB glu6val homozygotes) indigenous to the Eastern Province of Saudi Arabia have a fetal hemoglobin (HbF) level of about 20% that is associated with a mild clinical phenotype. Their HbS gene is on the Saudi-Indian (SI) haplotype characterized by an Xmn1 restriction site at position −158 5' to HBG2 (rs7482144), a Hinc2 site 5' to HBE (rs3834466) and other polymorphisms in the HBB gene-like cluster. However, the functional elements within the HBB gene-like cluster and elsewhere in the genome causing high HbF are yet to be determined. In a previous study we found that Saudi HbS homozygotes with the SI haplotype had a common region of autozygosity that spanned about 126 kb and included the complete HBB cluster. We have sequenced 13.6 kb in the HBD-HBG1 intergenic region (chr11:5255683-5269326, HG19), the region of the Corfu deletion. We found a SNP at position −68 bp 5' to HBD (c.-118 C>T) only in individuals with a SI haplotype. This SNP was not present in dbSNP build 132 or the 1000 Genomes databases. No other mutation in HBD was identified. This same SNP was recently associated with δ thalassemia (Phylipsen et al. Int. J. Lab. Hematol. 2011, 33: 85–91). Homozygotes for the −68 HBD SNP, who were not on hydroxyurea, had a mean HbF of 23%, range 12.1%-33.4% and mean HbA2 of 2.1%, range 1.2%-3%. We did not find the −68 HBD SNP in 15 African Americans with sickle cell anemia selected because of their unusually high HbF (mean HbF 17.2%, range 11%-28.9%). Parents and sickle cell trait carriers from the families of Saudi Eastern Province patients were heterozygous for the −68 HBD mutation (mean HbF 1.6%, range 0–4.2% and mean HbA2 2.7%, range 2.4%-3.2%) and one normal sibling did not carry this mutation (HbF 0 and HbA2 2.9%). Thirty patients with sickle cell disease indigenous to the Southwestern Province of Saudi Arabia, with the HbS gene on an African origin haplotype, (mean HbF 15.5%, range 4.5%-23% and mean HbA2 2.9%, range 2.1%-3.4% in HbS homozygotes) and 13 normal Saudi controls were examined and none carried the −68 HBD mutation. We also sequenced HBD and its promoter in 8 Southwestern Province HbS homozygotes with a Benin haplotype, 4 with HbF <5% and 4 with HbF >15%, and none had the −68 HBD SNP or any other mutation in HBD. Inverse relationships between percent HbF level and percent HbA2 was seen in 3 groups of HbS homozygotes:1) SI haplotype homozygotes; 2) Benin haplotype homozygotes from the Southwestern Province; 3) African Americans with diverse HbS haplotypes. The increased HbF in sickle cell anemia with δ thalassemia might involve both post-translational and transcriptional mechanisms. Increased HbF levels might in part be due to the preferential post-translational assembly of αγ dimers compared with αδ and αβS dimers. When δ thalassemia reduces available δ-globin chains, this might further favor preferential binding of less positively charged γ-globin subunits to positively charged α-globin compared with more positively charged δ-globin subunits. Perhaps more importantly, at the transcriptional level, the −68 HBD δ+-thalassemia promoter mutation might favor the interactions of transcription complexes with HBG promoters. The stimulus of hemolytic anemia and expanded erythropoiesis might be required before the favorable genetic milieu for increased HbF production can be fully utilized with the achievement of clinically significant increases in HbF that modulates the course of disease. For example, increased HbF levels of only 3.3%-4.7% have been reported in some hematologically normal individuals with homozygous δ0 thalassemia (Ohta et al. Hemoglobin 1980, 4: 417–425). High HbF levels in SI haplotype HbS homozygotes might involve the interactions of one or more HBG regulatory regions linked to the HBB gene-like cluster, like the −68 HBD SNP, perhaps with trans acting elements. Although the −68 HBD δ+-thalassemia mutation is associated with the SI haplotype and high HbF, functional studies are needed to establish causation. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Prediction of Fetal Hemoglobin in Sickle Cell Anemia Using an Ensemble of Genetic Risk Prediction Models

2014 ◽  
Vol 7 (2) ◽  
pp. 110-115 ◽  
Author(s):  
Jacqueline N. Milton ◽  
Victor R. Gordeuk ◽  
James G. Taylor ◽  
Mark T. Gladwin ◽  
Martin H. Steinberg ◽  
...  
Keyword(s):  
Risk Prediction ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Genetic Risk ◽  
Prediction Models ◽  
Fetal Hemoglobin ◽  
Risk Prediction Models ◽  
Genetic Risk Prediction

scholarly journals Fetal Hemoglobin in Sickle Cell Anemia: Determinants of Response to Hydroxyurea

Blood ◽  
1997 ◽  
Vol 89 (3) ◽  
pp. 1078-1088 ◽  
Author(s):  
Martin H. Steinberg ◽  
Zhi-Hong Lu ◽  
Franca B. Barton ◽  
Michael L. Terrin ◽  
Samuel Charache ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Central African Republic ◽  
Fetal Hemoglobin ◽  
First Year ◽  
F Cells ◽  
Baseline Levels ◽  
Hbf Level

Abstract Hydroxyurea (HU) can increase fetal hemoglobin (HbF) in sickle cell anemia (HbSS). To identify determinants of the HbF response, we studied 150 HU-treated patients grouped by quartiles of change in HbF from baseline to 2 years. Half of the HU-assigned patients had long-term increments in HbF. In the top two quartiles, HbF increased to 18.1% and 8.8%. These patients had the highest baseline neutrophil and reticulocyte counts, and largest treatment-associated decrements in these counts. In the lower two quartiles, 2-year HbF levels (4.2% and 3.9%) and blood counts changed little from baseline. In the highest HbF response quartile, myelosuppression developed in less than 6 months, compliance was best, and final doses of HU were 15 to 22.5 mg/kg. All four quartiles had substantial increases of F cells in the first year. This was maintained for 2 years only in the top three quartiles. Leukocyte and reticulocyte counts decreased initially in all quartiles, but drifted back toward baseline levels in the lowest HbF response quartile. Initial HbF level and phenotype of the F-cell production (FCP) locus were not associated with HbF response, but absence of a Central African Republic (CAR) haplotype was. Bone marrow ability to withstand HU treatment may be important for sustained HbF increases during HU treatment of HbSS.

scholarly journals Longitudinal Analysis of Hydroxyurea and Fetal Hemoglobin in Adult Patients with Sickle Cell Anemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2054-2054
Author(s):  
Aryeh Pelcovits ◽  
Giancarlo Riotto ◽  
Katie Cherenzia ◽  
Patrick T. McGann ◽  
John L Reagan
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Conflicts Of Interest ◽  
Surrogate Marker ◽  
Fetal Hemoglobin ◽  
P Value ◽  
Significant Difference ◽  
Dosing Strategies ◽  
Over Time ◽  
Painful Crisis

Abstract Introduction: Hydroxyurea (HU) was the first FDA-approved therapy for sickle cell anemia (SCA) and remains the most well-established disease-modifying therapy, reducing painful crisis and improving morbidity and mortality. HU improves outcomes through the upregulation of fetal hemoglobin (HbF). Dosing is highly variable with doses ranging from &lt;10-35 mg/kg/day. Most dosing strategies escalate with a goal of mild myelosuppression, commonly defined using an absolute neutrophil count (ANC) between 2,000-4,000 and platelets &gt;80,000. Macrocytosis is often used as a surrogate marker for compliance and effect. Despite its well-established effectiveness, clinical use remains limited with only 12% of adults with SCA taking HU. The reasons for this are multifactorial but include skepticism by both providers and patients regarding its effectiveness in the adult population. Some experts suggest up to 30% of adults are non-responders with no significant HbF change, and many believe that the effect of HU fades with time. Dosing strategies are usually quite conservative to prevent excessive myelosuppression, though dose is highly correlated with clinical effect and ultimate %HbF. There is very limited real-world data regarding long term effectiveness of HU in adults with SCA over time. Methods: We retrospectively analyzed the records of the 109 adults with SCA currently treated in our multidisciplinary sickle cell clinic. Data from 1/1/2011-6/30/2021 was collected, including genotype, HU prescription status, current and maximum laboratory values (HbF, MCV, ANC), and number of admissions for painful crisis. We performed Wilcoxon rank sum testing between pts prescribed and not prescribed HU and measures of HbF (peak, average and current) and number of admissions for painful crisis over the study period. Results: Among 106 pts (3 excluded from analysis, 2 for lack of data and 1 for post-transplant status), 79 are currently prescribed HU (75%). Among our 63 pts with HbSS genotype 58 are prescribed HU (92%). Average HbF over time for all pts prescribed HU was 11.9%. Average peak HbF was 18.1% and average current HbF is 12.4%. In the pts not prescribed HU HbF average, peak and current levels were 5.5%, 6.7%, and 5.0% respectively. HU prescription was significantly associated with increased HbF at peak, average, and current levels (p-value &lt;0.001, Figure A). HU prescription was also significantly associated with decreased number of admissions for painful crisis (p-value 0.001). Among pts prescribed HU, MCV levels &gt;100 at time of peak HbF were associated with higher peak levels than pts with MCV &lt;100 (p-value &lt;0.001, Figure B). Larger peak HU doses were also correlated with higher MCVs at the time of peak HbF levels (Figure C). Larger current HU doses were also significantly associated with higher current HbF levels (Figure, D). Doses &gt;9.9m/kg were associated with significantly higher HbF levels however there was no significant difference between dose levels 10-19.9mg/kg and 20-29.9 or 20-29.9 and 30-39.9mg/kg (p-values 0.02, 0.68 and 0.84 respectively). Among pts prescribed HU, 34 obtained ANC levels &lt;4000 at the times of peak HbF and 24 at the current dosing level (43% and 30% respectively). 24 pts obtained both MCV&gt;100 and ANC &lt;4000 at time of peak HbF and only 11 achieved both at current dosing levels (30% and 14% respectively). Conclusion: In our adult multidisciplinary sickle cell clinic prescribing rates are well above current HU usage for adults with SCA. Our data notes that elevated HbF levels can be maintained over long periods of time. HU prescription was significantly associated with increased HbF levels and reduced admissions for painful crisis. This was despite a majority of pts not meeting target prescribing levels of ANC &lt;4000 and MCV &gt;100. While higher peak HbF levels were significantly associated with higher HU doses, this was only true for doses above 9.9 mg/kg. Further investigation is needed to explore the factors contributing to suboptimal HbF and MCV response, including careful assessment with medication adherence and dose selection. Overall, these data illustrate the importance of dosing and suggest that one size dosing of HU for adults with SCA does not fit all. We hypothesize that there may be a role individualized dosing strategies in adults with SCA, incorporating factors such as pharmacokinetics and renal function to achieve the optimal dose for each patient. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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