Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and Amelioration of the phenotype of β-thalassemia
Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and Amelioration of the phenotype of β-thalassemia
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DOI：
10.1073/pnas.0711566105
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发表时间：
2008-02-05
影响因子：
11.1
通讯作者：
Cao, Antonio
中科院分区：
文献类型：
--
作者：
Uda, Manuela;Galanello, Renzo;Cao, Antonio
β-地中海贫血和镰状细胞病都显示出大量的表型异质性，尽管它们通常被认为是简单的孟德尔疾病。其原因尚不清楚，尽管胎儿血红蛋白（HbF）水平是这两种情况的一个良好表征的改善因素。为了更好地了解这种异质性的遗传基础，我们对4，305名撒丁岛人进行了362，129个常见SNP的全基因组扫描，以寻找与HbF水平以及其他红细胞相关性状的遗传连锁和关联。在影响HbF水平的主要变异中，BCL 11 A基因中的SNP rs 11886868与该性状密切相关（P < 10（-35））。C等位基因频率在HbF水平升高的撒丁岛个体中显著更高，通过筛查β-地中海贫血检测到，并且β-地中海贫血减毒型患者与重型地中海贫血患者相比。我们还表明，在一个大型的镰状细胞患者队列中，相同的BCL 11 A变异与HbF水平密切相关。这些结果表明，BCL 11 A变体通过调节HbF水平，作为β-地中海贫血表型的重要改善因子，并且它们可能有助于改善其他血红蛋白疾病。我们希望我们的研究结果将有助于描述胎儿珠蛋白调节的分子机制，并最终有助于β地中海贫血和镰状细胞贫血的新治疗方法的发展。
beta-Thalassemia and sickle cell disease both display a great deal of phenotypic heterogeneity, despite being generally thought of as simple Mendelian diseases. The reasons for this are not well understood, although the level of fetal hemoglobin (HbF) is one well characterized ameliorating factor in both of these conditions. To better understand the genetic basis of this heterogeneity, we carried out genome-wide scans with 362,129 common SNPs on 4,305 Sardinians to look for genetic linkage and association with HbF levels, as well as other red blood cell-related traits. Among major variants affecting HbF levels, SNP rs11886868 in the BCL11A gene was strongly associated with this trait (P < 10(-35)). The C allele frequency was significantly higher in Sardinian individuals with elevated HbF levels, detected by screening for beta-thalassemia, and patients with attenuated forms of beta-thalassemia vs. those with thalassemia major. We also show that the same BCL11A variant is strongly associated with HbF levels in a large cohort of sickle cell patients. These results indicate that BCL11A variants, by modulating HbF levels, act as an important ameliorating factor of the beta-thalassemia phenotype, and it is likely they could help ameliorate other hemoglobin disorders. We expect our findings will help to characterize the molecular mechanisms of fetal globin regulation and could eventually contribute to the development of new therapeutic approaches for beta-thalassemia and sickle cell anemia.