Abstract
Hemoglobin E/beta-thalassemia is a blood disorder with highly variable clinical phenotypes related to increased production of fetal hemoglobin (HbF), which can influence the degree of severity in beta-thalassemia. The aim of this study was to find out the disease modifying effects of two SNPs, rs-4671393 & rs-11886868 in BCL11A gene among HbE/beta-thalassemia patients. A total of 133 HbE/beta-thalassemia patients with mean of age 19.66 ± 10.22 years and 50 healthy controls with completely normal hematological parameters were recruited in this study and patients were classified as NTD/mild, moderate and severe, according to previously reported clinical scoring system. All the samples were subjected to Complete Blood Count analysis and Hemoglobin Electrophoresis. For SNP detection, Real-time PCR-based High Resolution Melt-Curve Analysis and Sanger Sequencing were performed. Statistical analysis including two-tailed unpaired T-test, one-way ANOVA test and Pearson Correlation were done using ‘Graphpad Prism version 7’. The allelic distribution of rs-4671393 in the BCL11A gene was 78.2% GG and 21.8% AG and for rs-11886868, there were 51.12% CC and 48.9% CT+TT. Both SNPs showed significant association with clinical severity score and induction of HbF (g/dl) (p= 0.03 and p= 0.02) in HbE/beta-thalassemia patients. In addition, HbF level was significantly higher (p<0.0001) in NTD/mildly severe group compared to other two groups having significant correlation with transfusion interval (r= 0.5) and clinical score (r= -0.45), while showed comparatively less correlation with the age of first blood transfusion (r= 0.32). Nevertheless, having both SNPs (17% minor allele for rs-4671393 and 25% minor allele for rs-11886868), no induction of HbF was found among SNP positive healthy individuals. The SNPs of BCL11A, rs-11886868 and rs-4671393 have significant effects on both HbF and clinical score in HbE/beta-thalassemia patients. However, any of the two SNPs showed no HbF inductive effect in the absence of anemic condition.
Highlights
The two single nucleotide polymorphisms (SNPs) of BCL11A rs11886868 and rs4671393 have significant effect on increased fetal hemoglobin level in the adult patients with HbE/beta-thalassemia in Bangladesh and shows similarity with the previous studies done on other populations
This study aimed to evaluate whether genetic variability at BCL11A locus influences HbF levels in HbE/beta-thalassemia patients in Bangladesh
For SNPs detection, High Resolution Melt-Curve (HRM) analysis based on Real-time PCR were accomplished on ‘BioRad CFX96 Touch Real-Time System’ by using ‘Precision Melt AnalysisTM Software (BioRad)’ according to manufacturer’s instruction and statistical analysis including two-tail unpaired Ttest, one-way ANOVA test and Pearson Correlation were done using ‘Graphpad Prism-version 7’
Summary
The two SNPs of BCL11A rs11886868 and rs4671393 have significant effect on increased fetal hemoglobin level in the adult patients with HbE/beta-thalassemia in Bangladesh and shows similarity with the previous studies done on other populations. Though rs4671393 showed no significant association with clinical severity of the patients, the mean value of the clinical score was much lower in the patients groups carring the minor alleles. Pearson correlation test showed that high level of HbF decreases blood transfusion rates and clinical scores in the patients, both SNPs can be correlated with less severity of the diseas
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