Alsaleh, Heba A. A.
(2022)
Differential gene expression
Analyses in HBE/BETA thalassaemia
patients and their relationship to
disease severity.
PhD thesis, Universiti Sains Malaysia.
Abstract
Haemoglobin E-beta thalassaemia (Hb E/β-thalassaemia) is a common
inherited genetic disorder. It is responsible for approximately half of all severe betathalassaemia
cases globally. In the state of Kelantan, 50.93% of thalassaemic patients
have Hb E/β-thalassaemia, and most of the cases are commonly seen in Malay
compared to Chinese and Indian. Clinical heterogeneity is the most outstanding criteria
among these patients ranging from mild to severe clinical courses that need a regular
blood transfusion. There are many modifiers found to affect the disease presentation.
However, the exact reasons behind this heterogeneity are not fully understood. This
research aimed to study the differential gene expression and their possible role in the
disease presentation and complications development in both transfusion-dependent
(TDT) and non-transfusion dependent (NTDT) HbE/β-thalassaemia patients. It was
conducted with the aid of RT2 profiler PCR array and microarray that were used in
gene expressional study in reticulocytes and erythroid progenitors, respectively. Three
normal controls and a total of 20 patients were enrolled in this study; 10 (50%) were
TDT, and 10 (50%) NTDT. The reticulocytes study showed the up-regulation of BAX
and BAD genes in TDT patients, which have a role in apoptosis induction through the
mitochondrial apoptotic pathway. Their up-regulation in TDT may play a role in the
reticulocytes’ apoptosis, mature RBCs' short life span and eryptosis. Flow cytometry
study showed higher apoptosis in the erythroid progenitors of TDT patients. The
increased apoptosis in erythroid progenitors and the up-regulation of BAD and BAX of reticulocytes in TDT may be linked to the down-regulation of the genes involved in
the PI3k/AKT pathway in the same patients’ group genes. Pathway and ontology
analysis showed the involvement of osteoporosis and bone regulating factors related
to the VDR pathway and the negative regulation of osteoclast differentiation in the
TDT group. The genes involved can be therapeutic targets like SPP1 and MAFB. Their
activation act to reduce the disease burden by reducing anaemia and alleviating bone
marrow complications. In summary, our study showed the expression of interesting
genes and pathways that may potentially modify the disease presentation and the
development of the complications.
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