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 beta-globin gene cluster to disease severity in groups of 207 mild- and 305 severe unrelated patients from Thailand with Hemoglobin E (HbE)/beta(0)-thalassemia and normal alpha-globin genes. Our analysis showed that these SNPs comprise two distinct linkage disequilibrium blocks, one containing the beta-globin gene and the other extending from the locus control region (LCR) to the delta gene, which are separated by a recombination hotspot in the narrow region of the beta-globin gene promoter. Forty-five SNPs within the interval including the LCR region and the delta gene showed strong association with disease severity. The strongest association was observed with the XmnI polymorphism located 158-bp upstream to the G gamma gene (p = 4.6E-12). Carriers of the T allele of XmnI 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 XmnI 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 XmnI or another closely linked variant modulates severity and HbF levels in patients with beta(0)-thalassemia/HbE disease.

Genetics of fetal hemoglobin in tribal Indian patients with sickle cell anemia

“…Three major HbF QTLs have been identified, which can modulate HbF levels and disease severity in SCD and b-thalassemia, 18,[26][27][28][29] namely, the BCL11A locus on chromosome 2p16, 16 the HMIP on chromosome 6q23, 20 and the b-globin locus. This study explores for the first time the frequency and association with HbF levels of genetic variants in these QTLs in SCD population from India.…”

A genome-wide association identified the common genetic variants influence disease severity in β0-thalassemia/hemoglobin E

“…-thalassemia). Several mutations such as the b E -mutation at codon 26 or the mutation at IVSI-1 (G[T) are reported to be linked with the T allele of the XmnI polymorphism that is associated with a milder phenotype (Ma et al 2007;Winichagoon et al 2000). However, evidence regarding the most common b 0 -thalassemia mutation, codons 41/42 (-TCTT), showed that there was no effect to the results of this study, as an analysis conducted on a subset of patients with the same mutation also demonstrated similar results to those obtained from the analysis including all patients (Supplementary Table 3).…”

A 3-bp deletion in the HBS1L-MYB intergenic region on chromosome 6q23 is associated with HbF expression

“…2 Three major HbF quantitative trait loci (QTL) have been identified: the C/T single nucleotide polymorphism (SNP, rs7482144) at promoter nucleotide (nt) 158 bp 5Ј upstream of HBG2 on chromosome 11p15, 3 the HBS1L-MYB intergenic polymorphism (HMIP) on chromosome 6q23, 4 and the BCL11A polymorphism on chromosome 2p16. 5 They can modulate HbF and disease severity in ␤-thalassemia, [6][7][8][9] and sickle cell anemia. 10 The relative contributions of these 3 QTLs to HbF regulation appear to differ among populations.…”