Genetic Modifiers in β-Thalassemia Intermedia: A Study on 102 Iraqi Arab Patients

Abstract

To determine the molecular basis of β-thalassemia intermedia (TI) and the contribution of the three hemoglobin F (HbF) quantitative trait loci (QTLs) on chromosomes 11, 2, and 6 to the milder phenotype, a total of 102 Iraqi Arab patients with TI were studied. The β and α genotypes as well as HBG2 g. 158 C>T (rs7482144), BCL11A (rs1427407 and rs10189857), and HBS1L-MYB (rs28384513 and rs9399137) by multiplex polymerase chain reaction and reverse hybridization were studied. A total of 21 different β-thalassemia mutations arranged in 35 different genotypes were identified. The genotypes encompassed β⁺/β⁺ mutations in 33 cases, β⁺/β⁰ in 17 cases, β⁰/β⁰ in 47 cases, β⁰/wild type in 3 and β⁰/Hb E in 2 cases. The most common was IVS-II-1 (G>A)/IVS-II-1 (G>A), followed by IVS-I-6 (T>C)/IVS-I-6 (T>C) and IVS-I-110 (G>A)/IVS-I-110 (G>A), in 31.4%, 17.6%, and 6.9%, respectively. Alpha-thalassemia mutations were found in 15.2% of those homozygous for the β-mutations, while α gene triplication was identified in all three heterozygotes. Of the five QTLs tested, only rs7482144 and rs10189857 were significantly associated with β⁰/β⁰ when compared to β⁺/β⁺, with odds ratios of 6.4 (95% confidence interval [CI] 2.9-14.0) and 3.2 (95% CI 1.2-8.6), respectively. In conclusion, this study has demonstrated that among Iraqi patients with thal intermedia, the main contributors to the milder phenotype were β⁺ alleles, XmnI polymorphism, and BCL11A (rs10189857), while other QTLs on chromosomes 2 and 6, as well as alpha-thalassemia, were not significantly relevant.