Abstract
Hemoglobin (Hb) F has a modulatory effect on the clinical phenotype of β-thalassemia disease. High expression of Hb F in Hb E-related disorders has been noted, but the mechanism is not well understood. We have examined the association of a novel SNP rs11759328 on ARHGAP 18 gene and other known modulators with a variability of Hb F in Hb E-related disorders. Genotyping of SNP rs11759328 (G/A) was performed based on high-resolution melting analysis. The rs11759328 (A allele) was shown to be significantly associated with Hb F levels (p < 0.05) in heterozygous and homozygous Hb E. High levels of Hb F in both heterozygous and homozygous Hb E were also found to be associated with SNPs in the study of other modifying genes including KLF 1 mutation, rs7482144 (Gγ-XmnI), rs4895441, rs9399137 of (HBS1L-MYB), and rs4671393 (BCL11A). Multivariate analysis showed that KLF1 mutation and SNP rs11759328 (GA) (ARHGAP18) modulated Hb F expression in heterozygous Hb E. For homozygous Hb E, this was found to be related to five modifying factors, i.e., KLF1 mutation, rs4895441 (GG), rs9399137 (CC), rs4671393 (AA), and rs4671393 (GA). These results indicate that a novel SNP rs11759328 is a genetically modifying factor associated with increased Hb F in Hb E disorder.
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References
Weatherall DJ (2011) The Thalassaemia syndromes. Blackwell Scientific, Oxford
Stamatoyannopoulos G (2005) Control of globin gene expression during development and erythroid differentiation. Exp Hematol 33:259–271
Fanis P, Kousiappa I, Phylactides M, Kyrri A, Hadjigavriel M, et al (2019) A novel mutation in the erythroid transcription factor KLF1 is likely responsible for ameliorating beta-thalassemia major. Hum Mutat (in press).
Rund D, Rachmilewitz E (2005) Beta-thalassemia. N Engl J Med 353:1135–1146
Tepakhan W, Yamsri S, Fucharoen G, Sanchaisuriya K, Fucharoen S (2015) Kruppel-like factor 1 mutations and expression of hemoglobins F and A2 in homozygous hemoglobin E syndrome. Ann Hematol 94:1093–1098
Radmilovic M, Zukic B, Petrovic MS, Bartsakoulia M, Stankovic B et al (2013) Functional analysis of a novel KLF1 gene promoter variation associated with hereditary persistence of fetal hemoglobin. Ann Hematol 92:53–58
Gallienne AE, Dreau HM, Schuh A, Old JM, Henderson S (2012) Ten novel mutations in the erythroid transcription factor KLF1 gene associated with increased fetal hemoglobin levels in adults. Haematologica 97:340–343
He Y, Luo J, Chen Y, Zhou X, Yu S et al (2018) ARHGAP18 is a novel gene under positive natural selection that influences HbF levels in beta-thalassaemia. Mol Genet Genomics 293:207–216
Orkin SH, Kazazian HH Jr, Antonarakis SE, Ostrer H, Goff SC et al (1982) Abnormal RNA processing due to the exon mutation of beta E-globin gene. Nature 300:768–769
Kazazian HH, Waber PG, Boehm CD, Lee JI, Antonarakis SE et al (1984) Hemoglobin E in Europeans: further evidence for multiple origins of the beta E-globin gene. Am J Hum Genet 36:212–217
Fucharoen G, Fucharoen S, Sanchaisuriya K, Sae-Ung N, Suyasunanond U et al (2002) Frequency distribution and haplotypic heterogeneity of beta(E) globin gene among eight minority groups of northeast Thailand. Hum Hered 53:18–22
Sae-ung N, Srivorakun H, Fucharoen G, Yamsri S, Sanchaisuriya K, Fucharoen S (2012) Phenotypic expression of hemoglobins A2, E and F in various hemoglobin E related disorders. Blood Cells Mol Dis 48:11–16
Fucharoen G, Fucharoen S (1994) Rapid and simultaneous non-radioactive method for detecting alpha-thalassemia 1 (SEA type) and Hb Constant Spring genes. Eur J Haematol 53:186–187
Fucharoen S, Fucharoen G, Sanchaisuriya K, Pengjam Y (2002) Molecular analysis of a Thai beta-thalassaemia heterozygote with normal haemoglobin A2 level: implication for population screening. Ann Clin Biochem 39:44–49
Panyasai S, Sringam P, Fucharoen G, Sanchaisuriya K, Fucharoen S (2002) A simplified screening for alpha-thalassemia 1 (SEA type) using a combination of a modified osmotic fragility test and a direct PCR on whole blood cell lysates. Acta Haematol 108:74–78
Fucharoen S, Fucharoen G, Fukumaki Y (1990) Simple non-radioactive method for detecting haemoglobin Constant Spring gene. Lancet 335:1527
Fucharoen S, Fucharoen G, Ratanasiri T, Jetsrisuparb A, Fukumaki Y (1994) A simple non-radioactive assay for hemoglobin E gene in prenatal diagnosis. Clin Chim Acta 229:197–203
Tepakhan W, Yamsri S, Sanchaisuriya K, Fucharoen G, Xu X, Fucharoen S (2016) Nine known and five novel mutations in the erythroid transcription factor KLF1 gene and phenotypic expression of fetal hemoglobin in hemoglobin E disorder. Blood Cells Mol Dis 59:85–91
Humphries B, Wang Z, Li Y, Jhan JR, Jiang Y, Yang C (2017) ARHGAP18 Downregulation by miR-200b suppresses metastasis of triple-negative breast cancer by enhancing activation of RhoA. Cancer Res 77:4051–4064
Wahlberg K, Jiang J, Rooks H, Jawaid K, Matsuda F et al (2009) The HBS1L-MYB intergenic interval associated with elevated Hb F levels shows characteristics of a distal regulatory region in erythroid cells. Blood 114:1254–1262
Phanrahan P, Yamsri S, Teawtrakul N, Fucharoen G, Sanchaisuriya K et al (2019) Molecular analysis of non-transfusion dependent thalassemia associated with hemoglobin E-beta-thalassemia disease without alpha-thalassemia. Mediterr J Hematol Infect Dis 11:e2019038
Acknowledgments
The researchers thank Mr. Robert Areelon, who is a native speaker for helpful comments and proofread on the manuscript. WJ is supported by the Royal Golden Jubilee PhD Advanced program (Contract no. RAP61K0018) of the Thailand Research Fund. SF is a recipient of the TRF Research Team Promotion Grant (RTA) of the Thailand Science Research and Innovation (TSRI), Thailand (Contract ID RTA6280005).
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WJ performed the experiment and wrote the initial manuscript. GF helped in research design and data analysis. HS, WT, and SY helped in data analysis and provided suggestions. WJ and SF were involved in research design, analysis of data, and acquisition of the grant, editing, and guaranteeing the paper. All authors approved the final version.
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Jomoui, W., Tepakhan, W., Yamsri, S. et al. A novel SNP rs11759328 on Rho GTPase-activating protein 18 gene is associated with the expression of Hb F in hemoglobin E-related disorders. Ann Hematol 99, 23–29 (2020). https://doi.org/10.1007/s00277-019-03862-0
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DOI: https://doi.org/10.1007/s00277-019-03862-0