Genetic Modifiers in Hemoglobinopathies

Abstract

Hereditary anemias show considerable variation in their clinical presentation. In some cases, the causes of these variations are easily apparent. In thalassemia (or in HbE/thalassemia), genetic variation is primarily caused by the severity of the thalassemia mutation. However, not uncommonly, there is variation unexplained by the globin gene mutations themselves, which may be caused by genetic modifiers. In sickle cell disease, the primary mutation is the same in all patients. Therefore, variations in disease severity generally are due to genetic modifiers. In most genetic diseases involving beta globin, the most clearcut influence on phenotype results from elevated fetal hemoglobin levels. In addition, alpha globin gene number can influence disease phenotype. In thalassemia major or intermedia, reduction in the number of alpha globin genes can ameliorate the disease phenotype; conversely, excess alpha globin genes can convert beta thalassemia trait to a clinical picture of thalassemia intermedia. In sickle cell disease, the number of alpha globin genes has both ameliorating and exacerbating effects, depending on which disease manifestation is being examined. Unlinked genetic factors have substantial effects on the phenotype of hereditary anemias, both on the anemia and other disease manifestations. Recently, studies using genome-wide techniques, particularly studying QTLs causing elevated HbF, or affecting HbE/thalassemia, have revealed other genetic elements whose mechanisms are under study. The elucidation of genetic modifiers will hopefully lead to more rational and effective management of these diseases.

Transition metal homeostasis: from yeast to human disease

“…Anemias can result from insufficient dietary iron uptake but there are also a multitude of other environmental causes (Umbreit 2005). Mutations in genes coding globin polypeptide chains, iron uptake and processing proteins and other proteins required for the synthesis and assembly of hemoglobin and red blood cells are among the many genetic bases for anemias (Rund and Fucharoen 2008;Camaschella 2009;Iolascon et al 2009). Symptoms of anemias usually consist of a general feeling of weakness and fatigue due to a lack of oxygen delivery to skeletal muscles combined with other symptoms that are indicative of the underlying cause of the disease.…”

β-Globin Gene Cluster Haplotypes in a Cohort of 221 Children with Sickle Cell Anemia or Sβ⁰-Thalassemia and Their Association with Clinical and Hematological Features

“…In Brazil, the majority of families with sickle cell disease have a low income, and health care is provided by a unified public system called the SUS [5]. Even though it is determined by a single genetic mutation, SCA has many genetic modulators that influence clinical and laboratory diversity, such as the expression of fetal hemoglobin (Hb F), the coinheritance of α-thalassemia, and β S -globin gene cluster haplotypes (β S -haplotypes) [6,7]. Sβ⁰-thal presents a similar clinical picture but is less studied than SCA; this is probably because it is uncommon [8].…”

Neurologic complications of sickle cell disease

“…If the primary mutation is the same, variations in disease severity generally are due to genetic modifiers. In most genetic diseases involving b-globin, the most clear-cut influence on phenotype results from elevated fetal hemoglobin levels (Rund and Fucharoen, 2008). Other factors include b-globin cluster haplotypes, a-globin gene 1018…”