This study targeted two candidate genes from the best known regulator of blood pressure; the rennin angiotensin system; the ACE gene I/D polymorphism and the angiotensinogen M235T polymorphism. The study aimed to determine the genotypes trend between two different populations; the primary hypertensive patients, and the normal populations. 126 subjects were involved in this study (86 primary hypertensive patients and 40 normal individuals). All demographic factors were considered and analyzed. Insertion/deletion polymorphisms of the ACE gene were determined by an assay based on the polymerase chain reaction (PCR). Polymorphism analysis using PCR-RFLP procedure was used to identify the missense mutation M235T of the AGT gene. All significant data was collected using standardized case report form. The association of the different genotypes and the subjects’ condition was analyzed using the chi squared and odds ratio analyses. In the pooled analysis of both groups, it was shown that the polymorphisms in these genes were significantly associated with the incidence of primary hypertension, p<0.05. Results also showed that the D allele of the ACE gene may be associated with increased risk of primary hypertension (p<0.05, O.R: 3.0 [C.I: 1.25 – 5.35]). The angiotensinogen M235T polymorphism also showed a significant result; the T allele is associated with increased risk of primary hypertension (p<0.05, O.R: 2.56[C.I: 1.55 – 5.28]). This knowledge of the candidate genes of rennin angiotensin system has rendered it possible to show that gene polymorphism in symphony leads to the individual risk of primary hypertension.
Keywords: ACE, M235T, rennin, hypertension
Study site: University Kebangsaan Malaysia Medical Center and International Medical University Cardiology Clinic
Glioblastoma multiforme (GBM) is a high-grade brain tumor of which the survival patients remain poor.
Tousled-like kinase 1 (TLK1), a serine-threonine kinase, was identified to be overexpressed in cancers such
as GBM. TLK1 plays an important role in controlling survival pathways. To date, there is no structure
available for TLK1 as well as its inhibitors. We aimed to create a homology model of TLK1 and to identify
suitable molecular inhibitors that are likely to bind and inhibit TLK1 activity via in silico high-throughput
virtual screening (HTVS) protein-ligand docking. The 3D homology models of TLK1 were derived from
various servers. All models were evaluated using Swiss Model QMEAN server. Validation was performed
using multiple tools. Energy minimization was performed using YASARA. Subsequently, HTVS was
performed using Molegro Virtual Docker 6.0 and ligands derived from ligand.info database. Drug-like
molecules were filtered using ADME-Tox filtering program. Best homology model was obtained from the
Aurora B kinase (PDB ID:4B8M) derived from Xenopus levias structure that share sequence similarity with
human TLK1. Two compounds were identified from HTVS to be the potential inhibitors as it did not violate
the Lipinski rule of five and the CNS-based filter as a potential drug-like molecule for GBM
Clinical pathways have been implemented in many healthcare systems with mix results in improving the quality of care and controlling the cost. CP is a methodology used for mutual decision making and organization of care for a well-defined group of patients within a well-defined period. In developing the CPs for a medical centre, several meetings had been carried out involving expert teams which consist of physicians, nurses, pharmacists and physiotherapists. The steps used to develop the pathway were divided into 5 phases. Phase 1: the introduction and team development, Phase II: determining the cases and information gathering, Phase III: establishing the draft of CP, Phase IV: is implementing and monitoring the effectiveness of CP while Phase V: evaluating, improving and redesigning of the CP. Four CPs had been developed: Total Knee Replacement (TKR), ST Elevation Myocardial Infarction (AMI), Chronic Obstructive Airways Diseases (COAD) and elective Lower Segment Caesarean Section (LSCS). The implementation of these CPs had supported the evidence-based medicine, improved the multidisciplinary communication, teamwork and care planning. However, the rotation of posts had resulted in lack of document ownership, lack of direction and guidance from senior clinical staff, and problem of providing CPs prior to admission. The development and implementation of CPs in the medical centre improved the intra and inter departmental communication, improved patient outcomes, promote patient safety and increased patient satisfaction. However, accountability and understanding of the CPs must be given more attention.
Study site: Pusat Perubatan Universiti Kebangsaan Malaysia (PPUKM)
Gestational Diabetes Mellitus (GDM) is associated with pregnancy complications, however its mechanism has not been fully understood. The aim of this study was to investigate the single nucleotide polymorphism (SNP) for identifying candidate genes involve in risk factors and complications of GDM. A total of 174 pregnant women with GDM and 114 healthy pregnant women were genotyped with 384 SNPs from 236 genes. The SNPs identified were rs10946398 (CDKAL1) in GDM risk factors; rs328 (LPL) and rs1042778 (OXTR) in complications of caesarean section; rs5404 (SLC2A2), rs5400 (SLC2A2) and rs13306465 (IRS1) for neonatal intensive care admission. Whereby SNPs rs12255372, rs7901695 and rs7903146 from TCF7L2 gene had six times higher risk (OR, 6.40-6.53) for T2DM at postpartum. In conclusion, although the above SNPs were identified with GDM risk factors and complications among pregnant Malaysian women with GDM, a larger study is needed to ascertain this candidate genes actual association.
Glioma is the most common primary brain tumour of the central nervous system. Many genetic alterations
and mutations have been identified in glioma using various approaches. We performed DNA sequencing on
the tumours of 16 patients with Grade I, II, III and IV glioma. The AmpliSeq Cancer Primers Pool was used
to generate the amplicons. The targeted-ion sphere particles were prepared using the Ion One Touch and
Ion Enrichment systems. DNA sequencing was performed on the Ion Torrent Personal Genome Machine
(PGM) and the data were analysed using the Torrent Suite Software.
In total, 14 mutations were identified in the following genes: KDR (Q472H), MLH1 (V384D), MET (N375S),
PTPN11 (E69K), BRAF (V600E), TP53 (D149E, E154K, V157F), IDH1 (R132H), PIK3CA (H1047R), CSF1R
(c1061_1061 ins A), KIT (M541L), PTEN (c1373_1373 del A) and PDGFRA (E556V). In addition, there were
four novel mutations identified; TP53 (E154K, and D149E), CSF1R (c1061_1061 ins A) and PDGFRA
(E556V). The pathogenicity prediction showed that only three mutations were pathogenic: PTPN11 (E69K),
BRAF (V600E) and Tp53 (E154K). These mutations result in changes of the proteins’ structure and could
affect their functions. Pathway analyses suggested that these genes are closely related to the pathogenesis of
GBM through several pathways such as proliferation and invasion, metabolism and angiogenesis.
In conclusion, PGM in combination with the AmpliSeq Cancer Panel could be utilised as a potential
molecular diagnostic tool not only for glioma but also for other cancers.
BACKGROUND: This study was proposed to develop a composite of outcome measures using forced expiratory volume percentage of predicted, exercise capacity and quality of life scores for assessment of chronic obstructive pulmonary disease (COPD) severity.
MATERIALS AND METHODS: Eighty-six patients with COPD were enrolled into a prospective, observational study at the respiratory outpatient clinic, National University Hospital Malaysia (Hospital Universiti Kebangsaan Malaysia--HUKM), Kuala Lumpur.
RESULTS: Our study found modest correlation between the forced expiratory volume in 1 s (FEV(1)), 6 min walk distance and the SGRQ scores with mean (SD) values of 0.97 (0.56) litres/s, 322 (87) m and 43.7 (23.6)%, respectively. K-Means cluster analysis identified four distinct clusters which reached statistical significance which was refined to develop a new cumulative staging system. The SAFE Index score correlated with the number of exacerbations in 2 years (r = 0.497, p<0.001).
CONCLUSION: We have developed the SGRQ, Air-Flow limitation and Exercise tolerance Index (SAFE Index) for the stratification of severity in COPD. This index incorporates the SGRQ score, the FEV(1) % predicted and the 6 min walk distance. The SAFE Index is moderately correlated with the number of disease exacerbations.
Study site: Respiratory clinic, Pusat Perubatan Universiti Kebangsaan Malaysia (PPUKM), Kuala Lumpur, Malaysia
Over-expression of P-glycoprotein, encoded by the ABCB1 gene, is proposed to be involved in resistance to antiepileptic drugs in about 30% of patients with epilepsy. Here, we investigated the possible association between ABCB1 polymorphisms and sodium valproate (VPA) treatment in Malaysian epilepsy patients. Genotypes were assessed in 249 drug-resistant and 256 drug-responsive Malaysian patients for C1236T, G2677T/A, and C 5T polymorphisms in the ABCB1 gene. No genotypes, alleles, or haplotypes were associated with the response to VPA in either the overall group or Chinese, Indian, and Malay subgroups. Our data suggest that C1236T, G2677T/A, and C3435T polymorphisms in the ABCB1 gene do not contribute to the response to VPA in patients with epilepsy.