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Fulltext Using DNA Barcodes to Aid the Identification of Larval Fishes in Tropical Estuarine Waters (Malacca Straits, Malaysia)

Chu C, Loh KH, Ng CC, Ooi AL, Konishi Y, Huang SP, et al.

Zool Stud, 2019;58:e30.
PMID: 31966331 DOI: 10.6620/ZS.2019.58-30

Larval descriptions of tropical marine and coastal fishes are very few, and this taxonomic problem is further exacerbated by the high diversity of fish species in these waters. Nonetheless, accurate larval identification in ecological and early life history studies of larval fishes is crucial for fishery management and habitat protection. The present study aimed to evaluate the usefulness of DNA barcodes to support larval fish identification since conventional dichotomous keys based on morphological traits are not efficient due to the lack of larval traits and the rapid morphological changes during ontogeny. Our molecular analysis uncovered a total of 48 taxa (21 families) from the larval samples collected from the Klang Strait waters encompassing both spawning and nursery grounds of marine and estuarine fishes. Thirty-two (67%) of the larval taxa were identified at the species level, two taxa (4%) at the genus level, and 14 taxa (29%) at family level. The relatively low rate of species-level identification is not necessarily due to the DNA barcoding method per se, but a general lack of reference sequences for speciose and non- commercial fish families such as Gobiidae, Blenniidae, and Callionymidae. Larval morphology remains important in species diagnoses when molecular matches are ambiguous. A lower ethanol percentage (50%) for larva preservation is also useful to keep the body of larvae intact for morphological identification, and to preserve DNA for subsequent molecular analyses. The 10% Chelex resin used to extract DNA is also cost- effective for long term monitoring of larval fishes. Hence, the DNA barcoding method is an effective and easy way to aid the identification of estuarine larval fishes at the species level.
Investigating the decay rates of Escherichia coli relative to Vibrio parahemolyticus and Salmonella Typhi in tropical coastal waters

Lee CW, Ng AY, Bong CW, Narayanan K, Sim EU, Ng CC

Water Res, 2011 Feb;45(4):1561-70.
PMID: 21146847 DOI: 10.1016/j.watres.2010.11.025

Using the size fractionation method, we measured the decay rates of Escherichia coli, Salmonella Typhi and Vibrio parahaemolyticus in the coastal waters of Peninsular Malaysia. The size fractions were total or unfiltered, <250 μm, <20 μm, <2 μm, <0.7 μm, <0.2 μm and <0.02 μm. We also carried out abiotic (inorganic nutrients) and biotic (bacterial abundance, production and protistan bacterivory) measurements at Port Dickson, Klang and Kuantan. Klang had highest nutrient concentrations whereas both bacterial production and protistan bacterivory rates were highest at Kuantan. We observed signs of protist-bacteria coupling via the following correlations: Protistan bacterivory-Bacterial Production: r = 0.773, df = 11, p < 0.01; Protist-Bacteria: r = 0.586, df = 12, p < 0.05. However none of the bacterial decay rates were correlated with the biotic variables measured. E. coli and Salmonella decay rates were generally higher in the larger fraction (>0.7 μm) than in the smaller fraction (<0.7 μm) suggesting the more important role played by protists. E. coli and Salmonella also decreased in the <0.02 μm fraction and suggested that these non-halophilic bacteria did not survive well in seawater. In contrast, Vibrio grew well in seawater. There was usually an increase in Vibrio after one day incubation. Our results confirmed that decay or loss rates of E. coli did not match that of Vibrio, and also did not correlate with Salmonella decay rates. However E. coli showed persistence where its decay rates were generally lower than Salmonella.
Slow carbamazepine clearance in a nonadherent Malay woman with epilepsy and thyrotoxicosis

Yeap LL, Lim KS, Ng CC, Hui-Ping Khor A, Lo YL

Ther Drug Monit, 2014 Feb;36(1):3-9.
PMID: 24342894 DOI: 10.1097/FTD.0000000000000024

The authors describe a case of a 37-year-old Malay lady with an unusually slow carbamazepine clearance, which may be related to genetic polymorphisms of drug metabolizing enzymes and transporters. When given a small daily dose of 200 mg immediate-release carbamazepine, this patient experienced drowsiness. Subsequently, she reduced her carbamazepine dose to 200 mg twice a week (on Mondays and Fridays), resulting in poor seizure control. At the same time, the patient was diagnosed with hyperthyroidism and was given carbimazole and propranolol. Hyperthyroidism and the concurrent use of these antihyperthyroid agents may have further slowed down the metabolism of carbamazepine. Therapeutic drug monitoring of carbamazepine was carried out, and a slow carbamazepine clearance of 1.45 L·h⁻¹ per 70 kg was observed. Genotyping of selected genetic variants in CYP3A4, CYP3A5, EPHX1, ABCB1, and ABCC2 revealed that she has CYP3A5*3/*3 and ABCB1 3435-CC genotypes. Both genotypes have been shown to be associated with higher adjusted mean serum carbamazepine concentration in Chinese and Korean patients with epilepsy. Physicians should be vigilant about the risk of adverse effects among patients with a slow carbamazepine clearance, especially in Malays. Simulations of carbamazepine dosing regimen based on the pharmacokinetic parameters of this patient were performed to allow individualization of drug therapy.
Association of HLA-B*15:13 and HLA-B*15:02 with phenytoin-induced severe cutaneous adverse reactions in a Malay population

Chang CC, Ng CC, Too CL, Choon SE, Lee CK, Chung WH, et al.

Pharmacogenomics J, 2017 03;17(2):170-173.
PMID: 26927288 DOI: 10.1038/tpj.2016.10

Phenytoin (PHT) is a common cause of severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS). Although HLA-B*15:02 is associated with PHT-induced SJS/TEN (PHT-SJS/TEN) in Han Chinese and Thais, the genetic basis for susceptibility to PHT-induced SCARs (PHT-SCAR) in other populations remains unclear. We performed a case-control association study by genotyping the human leukocyte antigen (HLA)-B alleles of 16 Malay PHT-SCAR patients (13 SJS/TEN and 3 DRESS), 32 PHT-tolerant controls and 300 healthy ethnicity-matched controls. A novel genetic biomarker, HLA-B*15:13, showed significant association with PHT-SJS/TEN (53.8%, 7/13 cases) (odds ratio (OR) 11.28, P=0.003) and PHT-DRESS (100%, 3/3 cases) (OR 59.00, P=0.003) when compared with PHT-tolerant controls (9.4%, 3/32 controls). We also confirmed HLA-B*15:02 association with PHT-SJS/TEN (61.5%, 8/13 cases vs 21.9%, 7/32 controls; OR 5.71, P=0.016) when compared with PHT-tolerant controls. These alleles may serve as markers to predict PHT-SCAR in Malays.
Ultrasound-guided central venous vascular access-novel needle navigation technology compared with conventional method: A randomized study

Chew SC, Beh ZY, Hakumat Rai VR, Jamaluddin MF, Ng CC, Chinna K, et al.

J Vasc Access, 2020 Jan;21(1):26-32.
PMID: 31148509 DOI: 10.1177/1129729819852057

PURPOSE: Central venous catheter insertion is a common procedure in the intensive care setting. However, complications persist despite real-time ultrasound guidance. Recent innovation in needle navigation technology using guided positioning system enables the clinician to visualize the needle's real-time position and trajectory as it approaches the target. We hypothesized that the guided positioning system would improve performance time in central venous catheter insertion.
METHODS: A prospective randomized study was conducted in a single-center adult intensive care unit. In total, 100 patients were randomized into two groups. These patients underwent internal jugular vein central venous catheter cannulation with ultrasound guidance (short-axis scan, out-of-plane needling approach) in which one group adopted conventional method, while the other group was aided with the guided positioning system. Outcomes were measured by procedural efficacy (success rate, number of attempts, time to successful cannulation), complications, level of operators' experience, and their satisfaction.
RESULTS: All patients had successful cannulation on the first attempt except for one case in the conventional group. The median performance time for the guided positioning system method was longer (25.5 vs 15.5 s; p = 0.01). And 86% of the operators had more than 3-year experience in anesthesia. One post-insertion hematoma occurred in the conventional group. Only 88% of the operators using the guided positioning system method were satisfied compared to 100% in the conventional group.
CONCLUSION: Ultrasound-guided central venous catheter insertion via internal jugular vein was a safe procedure in both conventional and guided positioning system methods. The guided positioning system did not confer additional benefit but was associated with slower performance time and lower satisfaction level among the experienced operators.
Prostaglandin-endoperoxide synthase (PTGS2) and Defensin beta 1 (DEFB1) gene polymorphisms are not associated with periodontitis in Malays

Jagender Singh JK, Vaithilingam RD, Ng CC, Baharuddin NA, Hasnur Safii S, Rahman MT

Malays J Pathol, 2021 Dec;43(3):425-434.
PMID: 34958064

INTRODUCTION: In line with the association of prostaglandin-endoperoxide synthase 2 (PTGS2) and defensin beta 1 (DEFB1) single nucleotide polymorphisms (SNPs) with periodontitis among the Chinese and European populations, the current study was aimed to assess the same association among the Malays in Malaysia.
METHODS: Blood samples of individuals with periodontitis (PD) (n=72) and periodontally healthy (PH) (n=62) donors were obtained from Malaysian Periodontal Database and Biobanking system (MPDBS). Genomic DNA samples were analyzed for three PTGS2 SNPs (rs5275, rs20417, rs689466,) and one DEFB1 SNP (rs1047031) using Taqman SNP genotyping assays. Notably, rs20417 and rs689466 were located in the promoter region while rs5275 and rs1047031 were located in the 3' untranslated region of the transcript. Association between the SNPs and PD were then analyzed using genotypic association analysis (additive, dominant and recessive models).
RESULTS: The allelic frequency for the rs689466-G was higher in PD group (35.2%) compared that in PH group (29.0%). However, the association of rs689466-G and other SNPs with PD was not statistically significant (at 95% CI). No associations were observed for genotypic associations between the PTGS2 and DEFB1 SNPs with PD susceptibility.
CONCLUSIONS: PTGS2 (rs5275, rs20417, and rs689466) and DEFB1 (rs1047031) polymorphism was not associated with PD in Malays, unlike the Chinese, Taiwanese & European population. This suggests that other causal variants might be involved in the development and progression of PD among Malays.
Fulltext Heavy metals phyto-assessment in commonly grown vegetables: water spinach (I. aquatica) and okra (A. esculentus)

Ng CC, Rahman MM, Boyce AN, Abas MR

Springerplus, 2016;5:469.
PMID: 27119073 DOI: 10.1186/s40064-016-2125-5

The growth response, metal tolerance and phytoaccumulation properties of water spinach (Ipomoea aquatica) and okra (Abelmoschus esculentus) were assessed under different contaminated spiked metals: control, 50 mg Pb/kg soil, 50 mg Zn/kg soil and 50 mg Cu/kg soil. The availability of Pb, Zn and Cu metals in both soil and plants were detected using flame atomic absorption spectrometry. The concentration and accumulation of heavy metals from soil to roots and shoots (edible parts) were evaluated in terms of translocation factor, accumulation factor and tolerance index. Okra recorded the highest accumulation of Pb (80.20 mg/kg) in its root followed by Zn in roots (35.70 mg/kg) and shoots (34.80 mg/kg) of water spinach, respectively. Different accumulation trends were observed with, Pb > Zn > Cu in okra and Zn > Pb > Cu in water spinach. Significant differences (p
Tranexamic Acid in Pediatric Scoliosis Surgery: A Prospective Randomized Trial Comparing High-dose and Low-dose Tranexamic Acid in Adolescent Idiopathic Scoliosis Undergoing Posterior Spinal Fusion Surgery

Hasan MS, Yunus SN, Ng CC, Chan CYW, Chiu CK, Kwan MK

Spine (Phila Pa 1976), 2021 Nov 15;46(22):E1170-E1177.
PMID: 33882541 DOI: 10.1097/BRS.0000000000004076

STUDY DESIGN: Prospective randomized double-blinded trial.
OBJECTIVE: The objective of this study is to determine the efficacy of high-dose versus low-dose tranexamic acid (TXA) in adolescent idiopathic scoliosis (AIS) corrective surgery.
SUMMARY OF BACKGROUND DATA: Corrective surgery for AIS is associated with significant blood loss. Evidence on the optimum TXA dose to reduce bleeding in pediatric population is scarce.
METHODS: A total of 166 AIS patients aged between 10 and 21 years, of American Society of Anesthesiologists (ASA) physical status I and II, preoperative hemoglobin >10 g/dL, platelet count >150,000 cells/L and Cobb angle of >45° scheduled for elective single-stage posterior spinal fusion (PSF) surgery by two attending surgeons were included between March 2017 and November 2018. Patients were randomized into Group A (High Dose, 30 mg/kg TXA loading dose followed by 10 mg/kg/h infusion) and Group B (Low Dose, 10 mg/kg TXA loading dose followed by 1 mg/kg/h infusion). The primary outcome was total surgical blood loss between both groups. Secondary outcomes were transfusion requirement, perioperative changes in hemoglobin and coagulation profiles, adverse events, and factors that influence total blood loss.
RESULTS: The mean total surgical blood loss between the two groups was not significant (Group A: 928.8 ± 406.1 mL [range: 348-1857 mL]; Group B: 918.1 ± 406.2 mL [range: 271-2000 mL], P = 0.865). The median duration of surgery was 120 minutes. One patient in each group received allogenic blood transfusion during the perioperative period. There were no significant changes in hemoglobin and coagulation profile at pre-operation, post-operation 0 hour and 48 hours. Sex, number of vertebral levels fused, and duration of surgery were independently associated with total surgical blood loss. No adverse events were observed perioperatively.
CONCLUSION: Low-dose TXA was as efficacious as high-dose TXA in reducing blood loss and allogenic blood transfusion for AIS patients undergoing PSF surgery.Level of Evidence: 1.
Is pre-stroke frailty as determined by the Clinical Frailty Scale version 2.0 associated with stroke outcomes?

Ng CC, Lim WC, Tan KM, Wong KY, Kanagarajah RR, Singh HSAK, et al.

Singapore Med J, 2023 Mar 06.
PMID: 36926745 DOI: 10.4103/singaporemedj.SMJ-2021-187
Association of common genetic variants with vitamin D status in Malaysian children with epilepsy

Kong AN, Fong CY, Ng CC, Mohamed AR, Khoo TB, Ng RL, et al.

Seizure, 2020 Jul;79:103-111.
PMID: 32464532 DOI: 10.1016/j.seizure.2020.05.009

PURPOSE: Children with epilepsy (CWE) are at risk of vitamin D deficiency. Single nucleotide polymorphisms (SNPs) affecting the vitamin D pathway are potentially important risk factors for serum 25-hydroxyvitamin D [25(OH)D] concentration. The aims of our study were to evaluate the association of vitamin d-related SNPs to serum 25(OH)D concentrations in Malaysian CWE.
METHODS: Cross-sectional study of Malaysian ambulant CWE on antiseizure medication for >1 year. Sixteen SNPs in 8 genes (GC, VDR, CYP2R1, CYP24A1, CYP27B1, CYP27A1, CYP3A4, NADSYN1/DHCR7) were genotyped. Linear and logistic regression models and co-variates adjusted analyses were used. SNPs with significant associations were further analysed in a group of ethnically-matched healthy Malaysian children.
RESULTS: 239 CWE were recruited (52.7% Malay, 24.3% Chinese and 23.0% Indian) with mean serum 25(OH)D of 58.8 nmol/L (SD 25.7). Prevalence of vitamin D deficiency (≤37.5 nmol/L) was 23.0%. Minor allele of GC-rs4588-A was associated with lower serum 25(OH)D in the meta-analysis of both CWE (β -8.11, P = 0.002) and Malaysian healthy children (β -5.08, P < 0.001), while VDR-rs7975232-A was significantly associated with reduced odds of vitamin D deficiency in Malay subgroup of CWE (OR: 0.16; 95% CI: 0.06-0.49; P = 0.001) and this association was not found in the healthy children group.
CONCLUSIONS: Our results suggest that GC-rs4588 is associated with lower serum 25(OH)D concentration in both Malaysian CWE and healthy children, while VDR-rs7975232A is associated with lower risk of vitamin D deficiency in Malaysian CWE of Malay ethnicity. Our findings may assist in the genetic risk stratification of low vitamin D status among CWE.
Ethnic variation of genetic (idiopathic) generalized epilepsy in Malaysia

Lim KS, Ng CC, Chan CK, Foo WS, Low JS, Tan CT

Seizure, 2017 Feb;45:24-27.
PMID: 27912112 DOI: 10.1016/j.seizure.2016.11.011

PURPOSE: Ethnic variation in epilepsy classification was reported in the Epilepsy Phenome/Genome Project. This study aimed to determine the ethnic variation in the prevalence of genetic (idiopathic) generalized epilepsy (GGE) and GGE with family history in a multi-ethnic Asian population in Malaysia.

METHOD: In this cross-sectional study, 392 patients with a clinical diagnosis of GGE were recruited in the neurology outpatient clinic, University of Malaya Medical Centre (UMMC), from January 2011 till April 2016.

RESULTS: In our epilepsy cohort (n=2100), 18.7% were diagnosed to have GGE. Of those, 28.6% >(N=112) had family history of epilepsy with a mean age of seizure onset of 16.5 years old, and 42.0% had myoclonic seizures (N=47). The lifetime prevalence of epilepsy among first-degree relative of those with GGE and positive family history was 15.0%. Analysis according to ethnicity showed that Malaysian Chinese had the lowest percentage of GGE among those with epilepsy (12.3%), as compared with Indian and Malay (25.3% and 21.3%, p<0.001). In addition, 32.1% of these Indian patients with GGE had positive family history, which is more than the Malay (26.4%) and Chinese (27.5%) ethnic groups. Consanguineous marriage was noted in 5 Indian families with positive family history (9.6%).

CONCLUSION: There was ethnic variation in the prevalence of GGE, whereby the Malaysian Chinese had the lowest percentage of GGE as compared with Indian and Malay. A substantial proportion of GGE had positive family history among the three ethnics groups.

Study site: neurology outpatient clinic, University of Malaya Medical Centre (UMMC)
Fulltext Development of High Resolution Melting Analysis for the Diagnosis of Human Malaria

Chua KH, Lim SC, Ng CC, Lee PC, Lim YA, Lau TP, et al.

Sci Rep, 2015;5:15671.
PMID: 26507008 DOI: 10.1038/srep15671

Molecular detection has overcome limitations of microscopic examination by providing greater sensitivity and specificity in Plasmodium species detection. The objective of the present study was to develop a quantitative real-time polymerase chain reaction coupled with high-resolution melting (qRT-PCR-HRM) assay for rapid, accurate and simultaneous detection of all five human Plasmodium spp. A pair of primers targeted the 18S SSU rRNA gene of the Plasmodium spp. was designed for qRT-PCR-HRM assay development. Analytical sensitivity and specificity of the assay were evaluated. Samples collected from 229 malaria suspected patients recruited from Sabah, Malaysia were screened using the assay and results were compared with data obtained using PlasmoNex(TM), a hexaplex PCR system. The qRT-PCR-HRM assay was able to detect and discriminate the five Plasmodium spp. with lowest detection limits of 1-100 copy numbers without nonspecific amplifications. The detection of Plasmodium spp. in clinical samples using this assay also achieved 100% concordance with that obtained using PlasmoNex(TM). This indicated that the diagnostic sensitivity and specificity of this assay in Plasmodium spp. detection is comparable with those of PlasmoNex(TM). The qRT-PCR-HRM assay is simple, produces results in two hours and enables high-throughput screening. Thus, it is an alternative method for rapid and accurate malaria diagnosis.
Fulltext SNP variants associated with non-Hodgkin lymphoma (NHL) correlate with human leukocyte antigen (HLA) class II expression

Ten LC, Chin YM, Tai MC, Chin EF, Lim YY, Suthandiram S, et al.

Sci Rep, 2017 01 31;7:41400.
PMID: 28139690 DOI: 10.1038/srep41400

Large consortia efforts and genome-wide association studies (GWASs) have linked a number of genetic variants within the 6p21 chromosomal region to non-Hodgkin lymphoma (NHL). Complementing these efforts, we genotyped previously reported SNPs in the human leukocyte antigen (HLA) class I (rs6457327) and class II (rs9271100, rs2647012 and rs10484561) regions in a total of 1,145 subjects (567 NHL cases and 578 healthy controls) from two major ethnic groups in Malaysia, the Malays and the Chinese. We identified a NHL-associated (PNHL_add = 0.0008; ORNHL_add = 0.54; 95% CI = 0.37-0.77) and B-cell associated (PBcell_add = 0.0007; ORBcell_add = 0.51; 95% CI = 0.35-0.76) SNP rs2647012 in the Malaysian Malays. In silico cis-eQTL analysis of rs2647012 suggests potential regulatory function of nearby HLA class II molecules. Minor allele rs2647012-T is linked to higher expression of HLA-DQB1, rendering a protective effect to NHL risk. Our findings suggest that the HLA class II region plays an important role in NHL etiology.
Fulltext CD24, CD44 and EpCAM enrich for tumour-initiating cells in a newly established patient-derived xenograft of nasopharyngeal carcinoma

Hoe SLL, Tan LP, Abdul Aziz N, Liew K, Teow SY, Abdul Razak FR, et al.

Sci Rep, 2017 09 28;7(1):12372.
PMID: 28959019 DOI: 10.1038/s41598-017-12045-8

Subpopulations of nasopharyngeal carcinoma (NPC) contain cells with differential tumourigenic properties. Our study evaluates the tumourigenic potential of CD24, CD44, EpCAM and combination of EpCAM/CD44 cells in NPC. CD44br and EpCAMbr cells enriched for higher S-phase cell content, faster-growing tumourigenic cells leading to tumours with larger volume and higher mitotic figures. Although CD44br and EpCAMbr cells significantly enriched for tumour-initiating cells (TICs), all cells could retain self-renewal property for at least four generations. Compared to CD44 marker alone, EpCAM/CD44dbr marker did not enhance for cells with faster-growing ability or higher TIC frequency. Cells expressing high CD44 or EpCAM had lower KLF4 and p21 in NPC subpopulations. KLF4-overexpressed EpCAMbr cells had slower growth while Kenpaullone inhibition of KLF4 transcription increased in vitro cell proliferation. Compared to non-NPC, NPC specimens had increased expression of EPCAM, of which tumours from advanced stage of NPC had higher expression. Together, our study provides evidence that EpCAM is a potentially important marker in NPC.
Fulltext Sex-specific disease modifiers in juvenile myoclonic epilepsy

Shakeshaft A, Panjwani N, Collingwood A, Crudgington H, Hall A, Andrade DM, et al.

Sci Rep, 2022 Feb 21;12(1):2785.
PMID: 35190554 DOI: 10.1038/s41598-022-06324-2

Juvenile myoclonic epilepsy (JME) is a common idiopathic generalised epilepsy with variable seizure prognosis and sex differences in disease presentation. Here, we investigate the combined epidemiology of sex, seizure types and precipitants, and their influence on prognosis in JME, through cross-sectional data collected by The Biology of Juvenile Myoclonic Epilepsy (BIOJUME) consortium. 765 individuals met strict inclusion criteria for JME (female:male, 1.8:1). 59% of females and 50% of males reported triggered seizures, and in females only, this was associated with experiencing absence seizures (OR = 2.0, p
Recombinant production of Epstein-Barr virus BZLF1 trans-activator and characterization of its DNA-binding specificity

Lim CS, Goh SL, Krishnan G, Ng CC

Protein Expr Purif, 2014 Mar;95:8-12.
PMID: 24291446 DOI: 10.1016/j.pep.2013.11.007

This paper describes the recombinant production of a biologically active Epstein-Barr virus BZLF1 trans-activator, i.e., Z-encoded broadly reactive activator (ZEBRA), that recognized specific DNA motifs. We used auto-induction for histidine-tagged BZLF1 expression in Escherichia coli and immobilized cobalt affinity membrane chromatography for protein purification under native conditions. We obtained the purified BZLF1 at a yield of 5.4mg per gram of wet weight cells at 75% purity, in which 27% of the recombinant BZLF1 remained biologically active. The recombinant BZLF1 bound to oligonucleotides containing ZEBRA response elements, either AP-1 or ZIIIB, but not a ZIIIB mutant. The recombinant BZLF1 showed a specific DNA-binding activity which could be useful for functional studies.
Fulltext A Genome Wide Study of Copy Number Variation Associated with Nasopharyngeal Carcinoma in Malaysian Chinese Identifies CNVs at 11q14.3 and 6p21.3 as Candidate Loci

Low JS, Chin YM, Mushiroda T, Kubo M, Govindasamy GK, Pua KC, et al.

PLoS One, 2016;11(1):e0145774.
PMID: 26730743 DOI: 10.1371/journal.pone.0145774

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a neoplasm of the epithelial lining of the nasopharynx. Despite various reports linking genomic variants to NPC predisposition, very few reports were done on copy number variations (CNV). CNV is an inherent structural variation that has been found to be involved in cancer predisposition.
METHODS: A discovery cohort of Malaysian Chinese descent (NPC patients, n = 140; Healthy controls, n = 256) were genotyped using Illumina® HumanOmniExpress BeadChip. PennCNV and cnvPartition calling algorithms were applied for CNV calling. Taqman CNV assays and digital PCR were used to validate CNV calls and replicate candidate copy number variant region (CNVR) associations in a follow-up Malaysian Chinese (NPC cases, n = 465; and Healthy controls, n = 677) and Malay cohort (NPC cases, n = 114; Healthy controls, n = 124).
RESULTS: Six putative CNVRs overlapping GRM5, MICA/HCP5/HCG26, LILRB3/LILRA6, DPY19L2, RNase3/RNase2 and GOLPH3 genes were jointly identified by PennCNV and cnvPartition. CNVs overlapping GRM5 and MICA/HCP5/HCG26 were subjected to further validation by Taqman CNV assays and digital PCR. Combined analysis in Malaysian Chinese cohort revealed a strong association at CNVR on chromosome 11q14.3 (Pcombined = 1.54x10-5; odds ratio (OR) = 7.27; 95% CI = 2.96-17.88) overlapping GRM5 and a suggestive association at CNVR on chromosome 6p21.3 (Pcombined = 1.29x10-3; OR = 4.21; 95% CI = 1.75-10.11) overlapping MICA/HCP5/HCG26 genes.
CONCLUSION: Our results demonstrated the association of CNVs towards NPC susceptibility, implicating a possible role of CNVs in NPC development.
Fulltext R54C Mutation of NOTCH3 Gene in the First Rungus Family with CADASIL

Lim KS, Tan AH, Lim CS, Chua KH, Lee PC, Ramli N, et al.

PLoS One, 2015;10(8):e0135470.
PMID: 26270344 DOI: 10.1371/journal.pone.0135470

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary stroke caused by mutations in NOTCH3 gene. We report the first case of CADASIL in an indigenous Rungus (Kadazan-Dusun) family in Kudat, Sabah, Malaysia confirmed by a R54C (c.160C>T, p.Arg54Cys) mutation in the NOTCH3. This mutation was previously reported in a Caucasian and two Korean cases of CADASIL. We recruited two generations of the affected Rungus family (n = 9) and found a missense mutation (c.160C>T) in exon 2 of NOTCH3 in three siblings. Two of the three siblings had severe white matter abnormalities in their brain MRI (Scheltens score 33 and 50 respectively), one of whom had a young stroke at the age of 38. The remaining sibling, however, did not show any clinical features of CADASIL and had only minimal changes in her brain MRI (Scheltens score 17). This further emphasized the phenotype variability among family members with the same mutation in CADASIL. This is the first reported family with CADASIL in Rungus subtribe of Kadazan-Dusun ethnicity with a known mutation at exon 2 of NOTCH3. The penetrance of this mutation was not complete during the course of this study.
HLA-A*31: 01 and HLA-B*15:02 association with Stevens-Johnson syndrome and toxic epidermal necrolysis to carbamazepine in a multiethnic Malaysian population

Khor AH, Lim KS, Tan CT, Kwan Z, Tan WC, Wu DB, et al.

Pharmacogenet Genomics, 2017 07;27(7):275-278.
PMID: 28570299 DOI: 10.1097/FPC.0000000000000287

The majority of the carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis CBZ-SJS/TEN are associated with HLA-B*15:02 in Asian populations where this allele is common. In contrast, the association with HLA-A*31:01 is only reported in Japanese and Europeans. This study aimed to further investigate the association with HLA-A*31:01 besides HLA-B*15:02 in a multiethnic Malaysian population. Twenty-eight CBZ-SJS/TEN cases and 227 CBZ-tolerant controls were recruited. Association was tested by comparing carrier frequencies of the alleles between cases and controls. Significant associations were detected between HLA-B*15:02 and CBZ-SJS/TEN in independent ethnic groups: Malays [P=2.00×10; odds ratio (OR): 49.0; 95% confidence interval (CI): 9.36-256.81], Chinese (P=0.0047; OR: 14.3; 95% CI: 2.38-86.03) and Indians (P=0.04; OR: 13.8; 95% CI: 1.51-124.99). Combined analysis of all ethnic groups showed a significant association with OR Cochran-Mantel-Haenszel (ORCMH) of 26.6 (95% CI: 12.80-55.25; PCMH=2.31×10). In Indians, HLA-A*31:01 was found to be associated significantly with CBZ-SJS/TEN (P=0.023; OR: 10.4; 95% CI: 1.64-65.79) and combined analyses of both variants, HLA-A*31:01 and HLA-B*15:02, increased the strength of the association (P=0.0068; OR: 14.3; 95% CI: 2.20-92.9). Besides HLA-B*15:02, our study found a new association between HLA-A*31:01 and CBZ-SJS/TEN in Indians.
Fulltext Association of NOD1, CXCL16, STAT6 and TLR4 gene polymorphisms with Malaysian patients with Crohn's disease

Chua KH, Ng JG, Ng CC, Hilmi I, Goh KL, Kee BP

PeerJ, 2016;4:e1843.
PMID: 27069792 DOI: 10.7717/peerj.1843

Crohn's disease (CD) is a prominent type of inflammatory bowel disease (IBD) that can affect any part of the gastrointestinal tract. CD is known to have higher prevalence in the Western countries, but the number of cases has been increasing in the past decades in Asia, including Malaysia. Therefore, there is a need to investigate the underlining causes of CD that may shed light on its prevention and treatment. In this study, genetic polymorphisms in NOD1 (rs2075820), CXCL16 (rs2277680), STAT6 (rs324015) and TLR4 (rs4986791) genes were examined in a total of 335 individuals (85 CD patients and 250 healthy controls) with PCR-RFLP approach. There was no significant association observed between NOD1 rs2075820 and STAT6 rs324015 with the onset of CD in the studied cohort. However, the G allele of CXCL16 rs2277680 was found to have a weak association with CD patients (P = 0.0482; OR = 1.4310). The TLR4 rs4986791 was also significantly associated to CD. Both the homozygous C genotype (P = 0.0029; OR = 0.3611) and C allele (P = 0.0069; OR = 0.4369) were observed to confer protection against CD. On the other hand, the heterozygous C/T genotype was a risk genotype (P = 0.0015; OR = 3.1392). Further ethnic-stratified analysis showed that the significant associations in CXCL16 rs2277680 and TLR4 rs4986791 were accounted by the Malay cohort. In conclusion, the present study reported two CD-predisposing loci in the Malay CD patients. However, these loci were not associated to the onset of CD in Chinese and Indian patients.

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