Phenotype-genotype correlation in β-thalassemia

The clinical manifestations of β-thalassemia are extremely heterogeneous, ranging from severe transfusion-dependent anemia, to the mild non transfusion dependent thalassemia intermedia and to the asymptomatic carrier state. The remarkable phenotypic variability is primary due to variations in the different globin genes (primary gene modifiers). The main pathophysiological determinant of the severity of β-thalassemia syndromes is the extent of a/non-a globin chain imbalance. Therefore, any factor capable of reducing the globin chain imbalance may have an ameliorating effect on the clinical picture. The most common mechanisms responsible of the amelioration of the phenotype are mild or silent β thalassemia alleles, coinheritance of a thalassemia, or of genetic determinants associated with increased g globin chain production. Rarely, other complex mechanisms including dominantly inherited β thalassemia, somatic deletion of β globin gene and coinheritance of extra a globin genes with heterozygous β thalassemia have been reported. In addition to the variability of the phenotype resulting from primary gene modifiers, other genetic factors (secondary gene modifiers), mapping outside the β and a globin cluster, may influence the disease complications. Among these factors the ones best so far defined are those affecting bilirubin, iron and bone metabolism. However, the new methods of DNA analysis (i.e. GWAS and related methods) are expect expand the number of genes or gene variants involved in the phenotypic variability and in the response to treatment of β thalassemia. 从严重的输液依赖型贫血症到轻度非输液依赖性中间型地中海贫血，再到无症状携带状态，β地中海贫血的临床表现极度异源性。 由于不同珠蛋白基因（初级基因修饰因子）发生各种变异，主要表现为显著的表型变异。 α/非α珠蛋白链不平衡程度是加重β地中海贫血综合症的主要病理生理因子。 因此，任何能减轻珠蛋白链不平衡的因子都能改善β地中海贫血的临床状况。 轻度或静息β地中海贫血等位基因、地中海贫血共同遗传，或与g珠蛋白链生成增加相关的基因决定因素是改善β地中海贫血表现型最常见的机制。 其他复合机制包括显性遗传的β地中海贫血、β珠蛋白基因的体细胞缺失、额外珠蛋白基因的共同遗传以及杂合子β地中海贫血甚为少见。 除了初级基因修饰因子引起的表现型变异，β和α珠蛋白簇外的其他遗传因子（二级基因修饰因子）可能影响疾病并发症。 在所有这些因子中，能影响胆红素、铁和骨代谢的因子是目前最好的。 然而，DNA分析的新方法（如GWAS及其相关方法）主要通过增加表现型变异中的基因数量或基因变体来治疗β地中海贫血。