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Fulltext Detection of CYP2C19 Genetic Variants in Malaysian Orang Asli from Massively Parallel Sequencing Data

Ang GY, Yu CY, Subramaniam V, Abdul Khalid MI, Tuan Abdu Aziz TA, Johari James R, et al.

PLoS One, 2016;11(10):e0164169.
PMID: 27798644 DOI: 10.1371/journal.pone.0164169

The human cytochrome P450 (CYP) is a superfamily of enzymes that have been a focus in research for decades due to their prominent role in drug metabolism. CYP2C is one of the major subfamilies which metabolize more than 10% of all clinically used drugs. In the context of CYP2C19, several key genetic variations that alter the enzyme's activity have been identified and catalogued in the CYP allele nomenclature database. In this study, we investigated the presence of well-established variants as well as novel polymorphisms in the CYP2C19 gene of 62 Orang Asli from the Peninsular Malaysia. A total of 449 genetic variants were detected including 70 novel polymorphisms; 417 SNPs were located in introns, 23 in upstream, 7 in exons, and 2 in downstream regions. Five alleles and seven genotypes were inferred based on the polymorphisms that were found. Null alleles that were observed include CYP2C19*3 (6.5%), *2 (5.7%) and *35 (2.4%) whereas allele with increased function *17 was detected at a frequency of 4.8%. The normal metabolizer genotype was the most predominant (66.1%), followed by intermediate metabolizer (19.4%), rapid metabolizer (9.7%) and poor metabolizer (4.8%) genotypes. Findings from this study provide further insights into the CYP2C19 genetic profile of the Orang Asli as previously unreported variant alleles were detected through the use of massively parallel sequencing technology platform. The systematic and comprehensive analysis of CYP2C19 will allow uncharacterized variants that are present in the Orang Asli to be included in the genotyping panel in the future.
Exploration of the diversity of multi-drug resistant Mycobacterium tuberculosis complex in Lagos, Nigeria using WGS: Distribution of lineages, drug resistance patterns and genetic mutations

Noorizhab MNF, Zainal Abidin N, Teh LK, Tang TH, Onyejepu N, Kunle-Ope C, et al.

Tuberculosis (Edinb), 2023 May;140:102343.
PMID: 37080082 DOI: 10.1016/j.tube.2023.102343

Multidrug-resistant (MDR) or extensively drug-resistant (XDR) Tuberculosis (TB) is a major challenge to global TB control. Therefore, accurate tracing of in-country MDR-TB transmission are crucial for the development of optimal TB management strategies. This study aimed to investigate the diversity of MTBC in Nigeria. The lineage and drug-resistance patterns of the clinical MTBC isolates of TB patients in Southwestern region of Nigeria were determined using the WGS approach. The phenotypic DST of the isolates was determined for nine anti-TB drugs. The sequencing achieved average genome coverage of 65.99X. The most represented lineages were L4 (n = 52, 83%), L1 (n = 8, 12%), L2 (n = 2, 3%) and L5 (n = 1, 2%), suggesting a diversified MTB population. In term of detection of M/XDR-TB, while mutations in katG and rpoB genes are the strong predictors for the presence of M/XDR-TB, the current study also found the lack of good genetic markers for drug resistance amongst the MTBC in Nigeria which may pose greater problems on local tuberculosis management efforts. This high-resolution molecular epidemiological data provides valuable insights into the mechanistic for M/XDR TB in Lagos, Nigeria.
Systematic characterization and comparison of the CYP2C9 variability of the Orang Asli in Malaysia with 12 populations

Teh LK, Subramaniam V, Tuan Abdu Aziz TA, Lee LS, Ismail MI, Yu CY, et al.

Drug Metab. Pharmacokinet., 2016 Aug;31(4):304-13.
PMID: 27325019 DOI: 10.1016/j.dmpk.2016.04.004

We conducted a systematic characterization of CYP2C9 variants in 61 Orang Asli and 96 Singaporean Malays using the whole genome sequences data and compared the variants with the other 11 HapMap populations. The frequency of rs1057910 (CYP2C9*3) is the highest in the Orang Asli compared to other populations. Three alleles with clinical implication were detected in the Orang Asli while 2 were found in the Singaporean Malays. Large numbers of the Orang Asli are predicted to have reduced metabolic capacity and therefore they would require a lower dose of drugs which are metabolized by CYP2C9. They are also at increased risks of adverse effects and therapeutic failures. A large number of CYP2C9 variants in the Orang Asli were not in the Hardy Weinberg Equilibrium which could be due to small sample size or mutations that disrupt the equilibrium of allele frequencies. In conclusion, different polymorphism patterns, allele frequencies, genotype frequencies and LD blocks are observed between the Orang Asli, the Singaporean Malays and the other populations. The study provided new information on the genetic polymorphism of CYP2C9 which is important for the implementation of precision medicine for the Orang Asli.
Fulltext A partially randomised trial of pretomanid, moxifloxacin and pyrazinamide for pulmonary TB

Tweed CD, Wills GH, Crook AM, Amukoye E, Balanag V, Ban AYL, et al.

Int J Tuberc Lung Dis, 2021 Apr 01;25(4):305-314.
PMID: 33762075 DOI: 10.5588/ijtld.20.0513

BACKGROUND: Treatment for TB is lengthy and toxic, and new regimens are needed.METHODS: Participants with pulmonary drug-susceptible TB (DS-TB) were randomised to receive: 200 mg pretomanid (Pa, PMD) daily, 400 mg moxifloxacin (M) and 1500 mg pyrazinamide (Z) for 6 months (6Pa200MZ) or 4 months (4Pa200MZ); 100 mg pretomanid daily for 4 months in the same combination (4Pa100MZ); or standard DS-TB treatment for 6 months. The primary outcome was treatment failure or relapse at 12 months post-randomisation. The non-inferiority margin for between-group differences was 12.0%. Recruitment was paused following three deaths and not resumed.RESULTS: Respectively 4/47 (8.5%), 11/57 (19.3%), 14/52 (26.9%) and 1/53 (1.9%) DS-TB outcomes were unfavourable in patients on 6Pa200MZ, 4Pa200MZ, 4Pa100MZ and controls. There was a 6.6% (95% CI -2.2% to 15.4%) difference per protocol and 9.9% (95%CI -4.1% to 23.9%) modified intention-to-treat difference in unfavourable responses between the control and 6Pa200MZ arms. Grade 3+ adverse events affected 68/203 (33.5%) receiving experimental regimens, and 19/68 (27.9%) on control. Ten of 203 (4.9%) participants on experimental arms and 2/68 (2.9%) controls died.CONCLUSION: PaMZ regimens did not achieve non-inferiority in this under-powered trial. An ongoing evaluation of PMD remains a priority.
APPaRENT 3: Asthma Patients' and Physicians' Perspectives on the Burden and Management of Asthma in Seven Countries

Aggarwal B, Al-Moamary M, Allehebi R, Alzaabi A, Al-Ahmad M, Amin M, et al.

Adv Ther, 2024 Aug;41(8):3089-3118.
PMID: 38874879 DOI: 10.1007/s12325-024-02900-2

INTRODUCTION: Asthma management is strongly dependent on physician and patient beliefs and perceptions about the disease and its long-term treatment. The APPaRENT 3 study was conducted to explore factors influencing treatment choice and to understand patients' and physicians' attitudes and perspectives on the use of controller inhalers in regular versus flexible dosing for asthma management.
METHODS: This cross-sectional survey of patients with asthma and treating physicians was conducted in seven countries: Indonesia, Malaysia, Philippines, Thailand, Vietnam (patient survey only), Saudi Arabia, and the United Arab Emirates. Assessment was carried out through an online/face-to-face questionnaire, where patients' viewpoints were focused on their attitudes and beliefs about asthma and treatment adherence, whereas physicians' viewpoints were gathered on their attitudes and beliefs about asthma management, knowledge of and adherence to asthma treatment guidelines, and asthma treatment regimens.
RESULTS: Overall, 1400 patients (mean age, 34 years) and 599 physicians (mean age, 43 years) were included in the survey. Physicians similarly prioritised symptom control (39%) and exacerbation reduction (40%) in moderate asthma, whereas patients prioritised symptom control (41%) over exacerbation reduction (22%). Although both groups (physicians, 86%; patients, 84%) perceived asthma as well-controlled, poor management was evident based on Asthma Control Test (ACT) scores (mean, 15.7; standard deviation, 4.14; 82% had an ACT score
Fulltext Protocol of health screening related to occupational diseases in 100 000 workers in critical sectors: a cross-sectional study with worksite risk assessment

Yasin SM, Ismail N, Masngut MI, Abdullah NN, Yasin NE, Omar M, et al.

BMJ Open, 2024 Aug 29;14(8):e083796.
PMID: 39209791 DOI: 10.1136/bmjopen-2023-083796

BACKGROUND: Occupational diseases are one of the most important health problems related to employment However, in Malaysia, there are few epidemiological studies discussing these issues, especially among workers in the industry. For that, this study aimed to screen workers from high-risk industrial sectors, identify hazards in the workplace and recommend improvement measures in the workplace to prevent occupational diseases.
METHODS AND ANALYSIS: This is a 3-year project in which a survey of 100 000 workers from all 13 states in Malaysia will be conducted using a web-based screening tool that is comprised of two parts: occupational disease screening tool and hazard identification, risk assessment and risk control method. Data will be collected using a multistage stratified sampling method from 500 companies, including seven critical industrial sectors. The independent variables will be sociodemographic characteristics, comorbidities, previous medical history, high-risk behaviour and workplace profile. The dependent variable will be the types of occupational diseases (noise-induced hearing loss, respiratory, musculoskeletal, neurotoxic, skin and mental disorders). Subsequently, suggestions of referral for medium and high-risk workers to occupational health clinics will be attained. The approved occupational health service clinics/providers will make a confirmatory diagnosis of each case as deemed necessary. Subsequently, a walk-through survey to identify workplace hazards and recommend workplace improvement measures to prevent these occupational diseases will be achieved. Both descriptive and inferential statistics will be used in this study. Simple and adjusted binary regression will be used to find the determinants of occupational diseases.
ETHICS AND DISSEMINATION: This study has been approved by the MARA University of Technology Research Ethics Board. Informed, written consent will be obtained from all study participants. Findings will be disseminated to the Department of Occupational Health and Safety, involved industries, and through peer-reviewed publications.