Variants of ZBTB7A (LRF) and its β-globin gene cluster binding motifs in sickle cell anemia

Shaikho, Elmutaz M.; Habara, Alawi; Alsultan, Abdulrahman; Al-Rubaish, Abdullah M.; Al-Muhanna, Fahad; Naserullah, Zaki A.; Alsuliman, Ahmed; Qutub, Hatem; Patra, Pradeep Kumar; Sebastiani, Paola; Baltrusaitis, Kristin; Farrell, John; Jiang, Zhihua; Luo, Hong-Yuan; Chui, David H.K.; Al-Ali, Amein K.; Steinberg, Martin H.

doi:10.1016/j.bcmd.2016.04.001

Cited by 12 publications

(7 citation statements)

References 15 publications

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“…To study further the possibility of an effect of ZBTB7A single nucleotide polymorphisms (SNPs) on HbF, GWAS data was imputed to the 1000 Genomes (Phase 3) reference panel in African American HbS homozygotes of diverse HBB haplotypes, Saudi AI haplotype homozygotes and Saudi Benin haplotype homozygotes. Common variants in ZBTB7A and its promoters and enhancers 100 kb upstream and 100 kb downstream of this gene were not associated with HbF variation . This suggested that unlike the case of BCL11A , common variants in ZBTB7A were not associated with differential expression of HbF in sickle cell anemia.…”

Section: Introductionmentioning

confidence: 92%

“…Polymorphisms in BCL11A were associated with HbF levels in many genome‐wide association studies (GWAS). In contrast, polymorphisms of ZBTB7A , were not associated with HbF despite its profound effect on HbF expression . To study further the possibility of an effect of ZBTB7A single nucleotide polymorphisms (SNPs) on HbF, GWAS data was imputed to the 1000 Genomes (Phase 3) reference panel in African American HbS homozygotes of diverse HBB haplotypes, Saudi AI haplotype homozygotes and Saudi Benin haplotype homozygotes.…”

Section: Introductionmentioning

confidence: 99%

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Fetal hemoglobin in sickle cell anemia: The Arab‐Indian haplotype and new therapeutic agents

2017

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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 two-fold. 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.

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Section: Introductionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Fetal hemoglobin in sickle cell anemia: The Arab‐Indian haplotype and new therapeutic agents

2017

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“…This haplotype is characterized by HbF levels being more than 100% higher than those found in patients with the African origin haplotypes [3,7]. Studies have indicated that common variants in the trans-acting loci BCL11A (2p16) and MYB and cis-acting elements, including both cis-acting and transacting quantitative trait loci within the HBB gene cluster, influence HbF gene expression [7][8][9][10][11][12].…”

Section: Antxr1mentioning

confidence: 99%

<b><i>ANTXR1</i></b> Intronic Variants Are Associated with Fetal Hemoglobin in the Arab-Indian Haplotype of Sickle Cell Disease

et al. 2018

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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.

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“…Consequently, the disease, especially in childhood, when HbF levels are about 30%, is usually milder. [44][45][46] The genetic basis of high HbF levels in these persons might in part lie in haplotype-specific polymorphisms of the superenhancer of the HBB cluster and other variants exclusive to this haplotype [47][48][49] ( Table S4 in the Supplementary Appendix). Saudi patients with the Benin haplotype have HbF levels that are nearly twice as high as the levels in African patients with the same haplotype.…”

Section: Fetal Hemoglobinmentioning

confidence: 99%

Sickle Cell Disease

2017

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Variants of ZBTB7A (LRF) and its β-globin gene cluster binding motifs in sickle cell anemia

Cited by 12 publications

References 15 publications

Fetal hemoglobin in sickle cell anemia: The Arab‐Indian haplotype and new therapeutic agents

Fetal hemoglobin in sickle cell anemia: The Arab‐Indian haplotype and new therapeutic agents

<b><i>ANTXR1</i></b> Intronic Variants Are Associated with Fetal Hemoglobin in the Arab-Indian Haplotype of Sickle Cell Disease

Sickle Cell Disease

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