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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. [ABSTRACT FROM AUTHOR]

β-Thalassemia (β-thal) is the most common inherited hemolytic anemia worldwide. Elevated Hb A2is a mark of β-thal carriers. The aim of this study was to identify the pathogenic variants associated with the Hb A2levels. One thousand and thirty β-thal carriers were recruited for this study. Using positive natural expression quantitative trait loci (eQTL) analysis, a significant variant was selected. Genotyping for the rs231841 polymorphism was performed by the Sequenom MassARRAY IPLEX platform. All genetic association analyses were performed with the PLINK program. The linear regression analysis showed that rs231841 in the intron region of the potassium voltage-gated channel subfamily Q member 1 (KCNQ1) gene on chromosome 11p15 was significantly associated with Hb A2levels. The presence of the C allele was associated with elevated Hb A2levels. Our results suggest that rs231841 on theKCNQ1gene with positive natural selection is related to Hb A2levels in Chinese β-thal carriers, andKCNQ1is probably associated with the expression of the β-like globin gene cluster. [ABSTRACT FROM AUTHOR]

Hb E [β26(B8)Glu→Lys]/β-thalassemia (β-thal) is a worldwide inherited disorder. We determined the phenotype of 65 unrelated Hb E/β-thal subjects and 70 healthy individuals in the Guangxi Province of the Republic of China (ROC). Single nucleotide polymorphism (SNP) rs35959442 in HBS1L analysis was performed using the polymerase chain reaction (PCR)/restriction enzyme method. The data suggested that the frequency of the rs35959442 polymorphism was relatively high in patients with Hb E/β-thal in Guangxi Province, ROC, when associated with Hb F augmentation. [ABSTRACT FROM AUTHOR]