A candidate transacting modulator of fetal hemoglobin gene expression in the Arab—Indian haplotype of sickle cell anemia

Vathipadiekal, Vinod; Farrell, John; Wang, Shuai; Edward, Heather L.; Shappell, Heather; Al-Rubaish, Abdullah M.; Al-Muhanna, Fahad; Naserullah, Zaki A.; Alsuliman, Ahmed; Qutub, Hatem; Simkin, Irene; Farrer, Lindsay A.; Jiang, Zhihua; Luo, Hong-Yuan; Huang, Sheng‐Wen; Mostoslavsky, Gustavo; Murphy, George J.; Patra, Pradeep Kumar; Chui, David H.K.; Alsultan, Abdulrahman; Al-Ali, Amein K.; Sebastiani, Paola; Steinberg, Martin H.

doi:10.1002/ajh.24527

Cited by 17 publications

(14 citation statements)

References 55 publications

(57 reference statements)

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“…Here, we show that the 2 tested SNPs, previously identified in ANTXR1, were associated with a high level of HbF. The association was highly significant with the presence of the first SNP (rs4527238), which is in line with the results of Vathipadiekal et al [14] in the same population. Furthermore, when the subjects in our study were stratified according to genotype, the prevalence of CC genotype in subjects with low HbF was higher than in those with high HbF (Table 2).…”

Section: Discussionsupporting

confidence: 80%

“…These sickle cell disease (SCD) patients (homozygous for the sickle mutation) were recruited from the in-patient clinics at King Fahad Hospital, Al-Ahssa and King Fahd Hospital of the University, Al-Khobar, both located in the Eastern Province of Saudi Arabia. None of the patients in the previous study by Vathipadiekal et al [14] were included in the current cohort. Ethical approval was obtained from Imam Abdulrahman Bin Faisal University's Institutional Review Board and King Faisal University's Institutional Review Board in accordance with international human research ethics.…”

Section: Cohortmentioning

confidence: 99%

“…A recent study [14] identified novel intronic single nucleotide polymorphisms (2 SNPs) in the anthrax toxin receptor or ANTXR1 gene (chromosome 2p13). These ANTXR1 variants are associated with HbF level [14] and explain ∼10% of the HbF variability in these patients. Interestingly, BCL11A and ANTXR1 have independent, additive effects on HbF levels, and altogether explained ∼15% of HbF variability in Saudi AI sickle cell anemia.…”

Section: Antxr1mentioning

confidence: 99%

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ANTXR1 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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Section: Discussionsupporting

confidence: 80%

Section: Cohortmentioning

confidence: 99%

Section: Antxr1mentioning

confidence: 99%

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

et al. 2018

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“…If ANTXR1 represses HbF, what is its mechanism? Although BCL11A and ANTXR1 had independent effects on HbF and there was no linkage disequilibrium between SNPs in ANTXR1 and BCL11A [6]; both genes are on chromosome 2p, albeit in different chromosomal bands. Can there be some long-range interactions between these loci?…”

mentioning

confidence: 99%

“…To further examine this possibility, whole-genome sequencing was carried out in 14 highly selected adults with the AI haplotype, 7 with HbF of 8.2% and 7 with HbF of 23.5%. Intronic SNPs (rs4527237, rs35685045; D' = 1) in the gene ANTXR1 on chromosome 2p13, an anthrax toxin receptor, were found to be associated with HbF [6].…”

mentioning

confidence: 99%

A New Trans-Acting Modulator of Fetal Hemoglobin?

Steinberg¹

2018

Acta Haematol

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Sickle Cell Disease as a Multi‐Factorial Condition

Steinberg

Verhovsek

2017

Encyclopedia of Life Sciences

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The phenotype of sickle cell anaemia is heterogeneous. Although all patients have the identical sickle haemoglobin mutation, the type, severity and frequency of complications are variable. The products of epistatic modifying genes, along with environmental influences, interact to determine the disease phenotype. Haemoglobin F concentration and its distribution among erythrocytes are likely the most important genetic modulator of disease severity. Polymorphic variation in several genetic loci, including BCL11A in chromosome 2p, the HBS1L‐MYB locus in 6q23 and the C‐T polymorphism 5′ to HBG2 on chromosome 11p, are associated with differences in haemoglobin F gene expression. ZBTB7A in chromosome 19p, along with BCL11A, is a major suppressor of haemoglobin F expression. α ‐Thalassaemia is the other major modulator of sickle cell disease. In addition to haemoglobin F and α ‐thalassaemia, some evidence exists that genes influencing endothelial activation, inflammation, red blood cell hydration and haemostasis might contribute to phenotypic diversity. Key Concepts Sickle cell anaemia is a single‐gene disorder with heterogeneous clinical features. The phenotype of sickle cell anaemia is affected by epistatic modifier genes. Haemoglobin F is the best‐known genetic modifier of sickle cell anaemia. Polymorphisms in three established quantitative trait loci modulate haemoglobin F. High haemoglobin F levels are associated with reduced mortality and the rate of viscosity–vaso‐occlusive complications. The locus of the haemoglobin F effect is the sickle erythrocyte. The distribution of concentrations of haemoglobin F among sickle erythrocytes is likely to be the critical determinant of its clinical effects. Co‐inheritance of α‐thalassaemia is associated with reduced rates of haemolysis and vasculopathic complications, but an increased incidence of viscosity–vaso‐occlusive manifestations. Candidate gene and genome‐wide association studies have identified genes that potentially affect sickle cell disease phenotype by modifying disease pathogenesis. It is likely that many genes, each playing a small role, contribute to the phenotypic heterogeneity of disease.

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A candidate transacting modulator of fetal hemoglobin gene expression in the Arab—Indian haplotype of sickle cell anemia

Cited by 17 publications

References 55 publications

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

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

A New <b><i>Trans</i></b>-Acting Modulator of Fetal Hemoglobin?

Sickle Cell Disease as a Multi‐Factorial Condition

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