Labie D, Pagnier J, Lapoumeroulie C, Rouabhi F, Dunda-Belkhodja O, Chardin P, Beldjord C, Wajcman H, Fabry M E, Nagel R L
Proc Natl Acad Sci U S A. 1985 Apr;82(7):2111-4. doi: 10.1073/pnas.82.7.2111.
We have studied 42 homozygous beta-thalassemia patients from Algeria and 34 sickle cell anemia patients from Senegal and Benin, determining the relationship between haplotypes, Hb F, and G gamma-globin/A gamma-globin ratios. Populations selected have a high frequency of haplotype homozygotes because of consanguinity (Algeria) and geographic homogeneity (West Africa). We find in beta-thalassemia patients, that haplotype IX in haplotypic homozygotes and heterozygotes, haplotype III in heterozygotes, and the Senegal haplotype in sickle cell anemia patients are all linked to high G gamma-globin expression. In addition, haplotypes IX and Senegal, but not haplotype III, have high Hb F levels. All of these haplotype have a common subhaplotype (+- ) in the gamma-globin gene region. In addition, haplotypes IX, III, and Senegalese sickle cell anemia patients exhibit hematological amelioration of their disease. Conversely, haplotypes I, V, and A in thalassemia patients, which also have a common subhaplotype (-----), and the Benin subhaplotype (--++-) in sickle cell anemia patients are all associated with low G gamma-globin and low Hb F levels. Low G gamma-globin expression in the adult is associated with two haplotypes that are not common between thalassemia and sickle cell anemia patients. We conclude that the determinant for high G gamma-globin expression is haplotype-linked to common and genetically dominant subhaplotypes in the two diseases. The total Hb F level, unlike the high G gamma-globin expression, however, is linked to haplotypes but not to subhaplotypes, thus dissociating the two genetic effects.
我们研究了42名来自阿尔及利亚的纯合子β地中海贫血患者以及34名来自塞内加尔和贝宁的镰状细胞贫血患者，确定了单倍型、胎儿血红蛋白（Hb F）以及Gγ珠蛋白/Aγ珠蛋白比率之间的关系。由于近亲结婚（阿尔及利亚）和地理同质性（西非），所选人群中单倍型纯合子的频率较高。我们发现，在β地中海贫血患者中，单倍型纯合子和杂合子中的单倍型IX、杂合子中的单倍型III以及镰状细胞贫血患者中的塞内加尔单倍型均与高Gγ珠蛋白表达相关。此外，单倍型IX和塞内加尔单倍型（而非单倍型III）具有较高的Hb F水平。所有这些单倍型在γ珠蛋白基因区域都有一个共同的亚单倍型（+-）。此外，单倍型IX、III以及塞内加尔镰状细胞贫血患者的病情在血液学方面有所改善。相反，地中海贫血患者中的单倍型I、V和A（它们也有一个共同的亚单倍型（-----））以及镰状细胞贫血患者中的贝宁亚单倍型（--++-）均与低Gγ珠蛋白和低Hb F水平相关。成年人中低Gγ珠蛋白表达与两种单倍型相关，这两种单倍型在地中海贫血和镰状细胞贫血患者中并不常见。我们得出结论，高Gγ珠蛋白表达的确决定因素是与两种疾病中常见且具有遗传优势的亚单倍型相关的单倍型。然而，与高Gγ珠蛋白表达不同，总Hb F水平与单倍型相关，而与亚单倍型无关，从而使这两种遗传效应相互分离。
