β-Globin gene cluster polymorphisms are strongly associated with severity of HbE/β⁰-thalassemia

Abstract

We evaluated the contribution of 67 single nucleotide polymorphisms (SNPs) within the β-globin gene cluster to disease severity in groups of 207 mild- and 305 severe unrelated patients from Thailand with Hemoglobin E (HbE)/β0-thalassemia and normal α-globin genes. Our analysis showed that these SNPs comprise two distinct linkage disequilibrium blocks, one containing the β-globin gene and the other extending from the locus control region (LCR) to the δ gene, which are separated by a recombination hotspot in the narrow region of the β-globin gene promoter. Forty-five SNPs within the interval including the LCR region and the δ gene showed strong association with disease severity. The strongest association was observed with the Xmn I polymorphism located 158-bp upstream to the Gγ gene (p = 4.6E-12). Carriers of the T allele of Xmn I were more likely to have a milder disease course and higher level of fetal hemoglobin (HbF) in both the mild (p = 0.005) and severe (p = 8.7E-06) patient groups. Haplotype analysis revealed that the T allele of Xmn I was nearly always in cis with the HbE allele. The high frequency of this haplotype may be favored by positive selection against malarial infection. Further studies are needed to validate this hypothesis and determine whether Xmn I or another closely linked variant modulates severity and HbF levels in patients with β0-thalassemia/ HbE disease. © 2007 The Authors Journal compilation © 2007 Blackwell Munksgaard.