Predictive SNPs for β0-thalassemia/HbE disease severity

Abstract

Abstractβ-Thalassemia/HbE disease has a wide spectrum of clinical phenotypes ranging from asymptomatic to dependent on regular blood transfusions. Ability to predict disease severity is helpful for clinical management and treatment decision making. A thalassemia severity score has been developed from Mediterranean β-thalassemia patients. However, different ethnic groups may have different allele frequency and linkage disequilibrium structures. Here, Thai β0-thalassemia/HbE disease genome-wild association studies (GWAS) data of 487 patients were analyzed by SNP interaction prioritization algorithm, interacting Loci (iLoci), to find predictive SNPs for disease severity. Three SNPs from two SNP interaction pairs associated with disease severity were identifies. The three-SNP disease severity risk score composed of rs766432 in BCL11A, rs9399137 in HBS1L-MYB and rs72872548 in HBE1 showed more than 85% specificity and 75% accuracy. The three-SNP predictive score was then validated in two independent cohorts of Thai and Malaysian β0-thalassemia/HbE patients with comparable specificity and accuracy. The SNP risk score could be used for prediction of clinical severity for Southeast Asia β0-thalassemia/HbE population.

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“…The frequency of the two alleles A and C in patients with A (0.56) and C (0.44) as for the control A (0.52) and C (0.48), is illustrated in Table 4 and Figure 3. The results of using ARMS-PCR showed that there are two alleles A and C with three genotypes AA, AC, and CC which are consistent with the previous studies [19,20]. The results of the frequency distribution of the A and C alleles of the BCL11A gene showed that their distribution percentage was not equal among the βthalassemia major patient and control samples, where the A allele percentage in patients was 56%, while in the control it was 52% and the percentage of the C allele was in the patient at 44 % and in the control, it was 48%, as summarized in Table 5.…”

“…The β-globin gene cluster, an intergenic interval among the HBS1L and MYB genes (HMIP), and BCL11A are among these loci. The results of using ARMS-PCR showed that there are two alleles A and C with three genotypes AA, AC, and CC which are consistent with the previous studies[19,20]. The results of the frequency distribution of the A and C alleles of the BCL11A gene showed that their distribution percentage was not equal among the βthalassemia major patient and control samples, where the A allele percentage in patients was 56%, while in the control it was 52% and the…”

Genetic predictions of life expectancy in southern Thai patients with β0‑thalassemia/Hb E

“…A possible reason is that the coinheritance of α-thalassemia 1 leads to mild β-thalassemia; thus, these patients were not found in a hospital-based sample collection ( 35 ). Furthermore, several genetic markers in the HBB cluster ( 10 , 15 , 17 , 51 ), BCL11A ( 15 , 17 , 19 ), and HBS1L - MYB ( 15 , 17 ) have been associated with fetal hemoglobin and disease severity in several populations. In addition, mutations in human Krüppel-like factor 1 ( KLF1 ) were found to be associated with increased fetal hemoglobin (Hb F) and hemoglobin A 2 (Hb A 2 ) ( 53 , 54 ).…”

“…In Thailand, several SNPs located in the HBB cluster, HBS1L-MYB , and BCL11A have been identified by two genome-wide association studies with different platforms ( 17 , 18 ). Several informative SNPs for predicting disease severity in Thai and Malaysian β 0 -thalassemia/Hb E patients have recently been developed ( 19 ). In Thailand, the average life expectancy in β-thalassemia/Hb E patients is ~30 years ( 20 , 21 ).…”

Spatial and Temporal Expression Characteristics of the HBB Gene Family in Six Different Pig Breeds

“…These gene alterations often cause either a decrease in β-globin synthesis or completely block synthesis [ 13 ]. For example, HbE/β-thalassemia is a G A substitution at the 26 position of the β-globin gene and replaces Glu with Lys, resulting in a decrease in the β-globin chain [ 14 , 15 , 16 , 17 ]. As such, 1–3% of the people in Southern China carry a β-thalassemia allele and over 20 β-thalassemia mutations have been reported in the Chinese population [ 18 ].…”