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].
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.
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 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].
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].
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].