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ARHGAP18 is a novel gene under positive natural selection that influences HbF levels in β-thalassaemia

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Abstract

Foetal haemoglobin (HbF) plays a dominant role in ameliorating the morbidity and mortality of β-thalassaemia. A better understanding of the loci and genes involved in HbF expression would be beneficial for the treatment of β-thalassaemia major. However, the genes associated with HbF expression remain largely unknown. In this study, we first explored large-scale data sets and examined the human genome for evidence of positive natural selection to screen out single nucleotide polymorphisms (SNPs). A genetic analysis of HbF levels was conducted in a Chinese cohort of patients with β-thalassaemia to confirm the bioinformatics results. A total of 1141 subjects with β-thalassaemia were recruited. The results showed that the SNP rs11759328 in the ARHGAP18 gene was significantly associated with HbF levels (Ρ = 5.1 × 10−4). ARHGAP18 belongs to the RhoGAP family and controls angiogenesis, cellular morphology and motility. Second, after determining that ARHGAP18 was highly expressed in the human K562 cell line, we used lentiviral-mediated small interfering RNA to knock down ARHGAP18 expression and subsequently assessed cell proliferation and apoptosis using cell proliferation assays and flow cytometry, respectively. ARHGAP18 downregulation in K562 cells significantly increased HBG1/2 expression and apoptosis, but proliferation was not significantly affected in vitro. Our data suggest that ARHGAP18, which was located by the SNP rs11759328 via positive selection, plays a potential role in regulating HbF expression in β-thalassaemia and may be a promising therapeutic target. Knockout studies of ARHGAP18 warrant further investigation into its aetiology in HbF.

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Acknowledgements

This study was sponsored by the National Natural Science Foundation of China (No. 81360093) and Guangxi Key Laboratory of Thalassaemia Research (16-380-34). The authors would like to thank Professor Liang Rong (Department of Pediatrics-Neonatology, Baylor College of Medicine, Houston, Texas, USA) for helpful discussions regarding this manuscript.

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Authors and Affiliations

  1. Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Guangxi Key Laboratory of Thalassaemia Research, No. 6, Shuangyong Road, Qingxiu District, Nanning, 530021, Guangxi, People’s Republic of China

    Yunyan He, Jianming Luo & Xuan Xiao

  2. Guangxi Medical University, No. 6, Shuangyong Road, Qingxiu District, Nanning, 530021, Guangxi, People’s Republic of China

    Yang Chen, Xiaoheng Zhou, Shanjuan Yu & Siyuan Jia

  3. Department of Pediatrics, The First Affiliated Hospital of Guangxi Technology University, Nanning, People’s Republic of China

    Ling Jin

  4. Department of Pediatrics Surgery, The First Affiliated Hospital of Guangxi Medical University, No. 6, Shuangyong Road, Qingxiu District, Nanning, 530021, Guangxi, People’s Republic of China

    Qiang Liu

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  1. Yunyan He
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  2. Jianming Luo
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  3. Yang Chen
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Correspondence to Yunyan He.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the First Affiliated Hospital of Guangxi Medical University and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

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He, Y., Luo, J., Chen, Y. et al. ARHGAP18 is a novel gene under positive natural selection that influences HbF levels in β-thalassaemia. Mol Genet Genomics 293, 207–216 (2018). https://doi.org/10.1007/s00438-017-1377-2

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