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Pleiotropic Effects

The phenotype of an individual with SCD often includes a complex set of features. The single bS gene mutation causes or is associated with a few primary effects, as well as a myriad of secondary cellular effects, all of which impact on SCD pathophysiology[38].

Phenotypic Variability in SCD

It is well documented that the severity of the symptoms and life expectancy in SCD patients varies considerably[38], even among individuals with a similar SCD genotype[96-98]. Thus, in addition to the bS mutation, other genetic factors have been implicated in determining phenotypic variability[96,97,99,100]. Accordingly, the gravity in patients ranges from the very severe cases previously described, to mild cases as occurs in individuals with high levels of fetal Hb (Hb F), compound sickle/ b -thalassemia, or Hb SS and concurrent a-thalassemia.

Epistatic Factors

There are epistatic genes (factors) that are linked to and unlinked to the b S-globin gene. Linked epistatic factors include the b -globin gene cluster haplotypes (e.g., Saudi, Senegal, Benin and Central African Republic or "Bantu", each with its own characteristic Hb F-globin expression patterns[101]), and the b S interaction with  the b -globin genotype[100]. Unlinked epistatic effects include the putative X-linked F-cell production (FCP) locus (Xp22.2-22.3)[102] and the a -globin genotype[100].

The Thalassemias And SCD

The thalassemias are a heterogeneous group of blood disorders characterized by the accumulation of either unpaired a –globin chains ( b -thalassemia) or b –globin chains ( a - thalassemia) [103]. In turn, this class of hemoglobinopathies is marked by peripheral hemolysis that leads to complications of variable severity[103]. Both types of thalassemia are reported to affect the SCD phenotype[100].

b -Thalassemia and SCD

In b -thalassemia the unbalanced globin production results in insoluble a 4 Hb precipitates [105], which cause severe peripheral RBC hemolysis and intramedullary destruction of precursors (ineffective erythropoiesis)[104]. At the genetic level, b -thalassemia is usually the result of gene-regulatory and/or translational mutations[103,104]. The effects of b -thalassemia are dependent on the amount of functional b -globin chain produced[103]. Accordingly, in the compound Hb S/b-thalassemic states, reduced or complete lack of b-globin production can ameliorate the SCD phenotype[106,107]. However, controversy persists over the universality of this findings since this often results in a thalassemic phenotype[108].

a - Thalassemia and SCD

In a -thalassemia the unbalanced globin production results in insoluble b 4 HbH precipitates[105], which cause less severe RBC destruction than b -thalassemia[109]. At the genetic level, a -thalassemia usually results from structural deletions of one or more the a -globin genes[103,104]. The effects of a -thalassemia are also dependent on the number of functional a -globin genes deleted[103], as well as the arrangement of the deletion(s)[110]. In the mild to moderate cases, HbH disease results from a corresponding reduction in a -globin chain production (deletion of 1 to 3 genes).  In the most severe case, Hb Bart's hydrops fetalis results from the complete lack of a -globin chains (deletion all 4 genes)[103]. It is also interesting to note that typically the a -thal 1 ( a a /--) mutation is more severe than the a -thal 2 ( a -/ a -) mutation[110].

Alpha thalassemia has particular  implications for SCD[111-113]. Patients with Hb SS and concurrent a -thal 2 ( a -/ a -) show a small decrease in hemolysis[114], improved mean RBC survival[114], and a longer mean lifespan[115]. Presumably, the decrease in the number of functional a –globin genes lowers the cellular Hb S concentration[111-113] and, therefore, lessens the cellular effects of Hb S and polymerization (i.e., hemolysis ,anemia)[111-113]. Controversy persists, however, as to whether or not a -thal 2 changes the natural course of the disease[108]. In contrast, the rare Hb SS with concurrent a -thal 1 condition results in persistent expression of the (a -like) z -globin in adult RBCs and with moderately severe HbH disease[116].