Ma Q, Abel K, Sripichai O, Whitacre J, Angkachatchai V, Makarasara W, Winichagoon P, Fucharoen S, Braun A, Farrer L A
Department of Medicine (Genetics Program), Boston University School of Medicine, Boston, MA 02118, USA.
Clin Genet. 2007 Dec;72(6):497-505. doi: 10.1111/j.1399-0004.2007.00897.x. Epub 2007 Sep 25.
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.
我们评估了β-珠蛋白基因簇内67个单核苷酸多态性（SNP）对来自泰国的207例轻度和305例重度非亲缘关系的血红蛋白E（HbE）/β⁰-地中海贫血且α-珠蛋白基因正常患者疾病严重程度的影响。我们的分析表明，这些SNP包含两个不同的连锁不平衡区域，一个包含β-珠蛋白基因，另一个从基因座控制区（LCR）延伸至δ基因，它们在β-珠蛋白基因启动子的狭窄区域被一个重组热点隔开。包括LCR区域和δ基因在内的区间内的45个SNP与疾病严重程度显示出强关联。在位于Gγ基因上游158bp处的XmnI多态性位点观察到最强关联（p = 4.6×10⁻¹²）。在轻度（p = 0.005）和重度（p = 8.7×10⁻⁶）患者组中，XmnI的T等位基因携带者更有可能有较轻的病程和较高水平的胎儿血红蛋白（HbF）。单倍型分析显示，XmnI的T等位基因几乎总是与HbE等位基因处于顺式状态。这种单倍型的高频率可能因针对疟疾感染的正选择而受到青睐。需要进一步研究来验证这一假设，并确定XmnI或另一个紧密连锁的变异体是否调节β⁰-地中海贫血/HbE病患者的疾病严重程度和HbF水平。
