Southeast Asian Populations Research Articles

88The Role of Visceral Adiposity in the Metabolic Phenotype of multi-ethnic South-East Asian population

Abstract Background Ethnic Asians are known to exhibit worse metabolic phenotypes as compared to Caucasians despite lower body mass index1, 2. Ethnic South-Asians and Malays were also found to display greater insulin resistance than Chinese3. One potential biological mechanism for this phenomenon is the inter-ethnic differences in the visceral adiposity deposition4. Here we hypothesised that visceral adiposity contributes to ethnic differences in metabolic phenotype more than subcutaneous adiposity. Methods We quantified total, subcutaneous and visceral adipose deposition (BMI, waist circumferences, Dual-energy X-ray absorptiometry [DEXA]) and metabolic phenotypes (blood pressure, fasting glucose and lipid profile, HbA1c) in 3403 participants. Analyses were adjusted for age, and sex. Results Participants were 40.6% male, mean age 49.7±11.4 years, Chinese: Malays: South-Asians in 72:9:19 ratio. Ethnic Malays and South-Asians had raised blood pressure, fasting glucose, triglycerides, HbA1c, reduced HDL, and higher total and visceral fat than Chinese (P < 0.001), independent of covariates. Increased adiposity was strongly associated with poorer metabolic phenotype (all P < 0.0001), with strongest associations found amongst visceral Fat Mass Index (□□95%CI]=0.48[0.20;0.23]) and android/gynoid ratio (□[95%CI]=0.55[1.31;1.63]) with triglycerides levels. Visceral adiposity contributed 17-40% (all P < 0.0001) to the variance in the associations of ethnic Malays and South-Asians with metabolic phenotypes, 3-7% higher than subcutaneous adiposity. Conclusions Visceral adiposity contributes to poorer metabolic phenotype in ethnic Malays and South Asians as compared to Chinese. Key messages Visceral adiposity expansion is an important determinant of metabolic health in Asian populations.

Postoperative delirium following total joint arthroplasties in a multi-ethnic population – A prospective observational study

BackgroundPostoperative delirium (POD) is a cause of poorer patient outcomes following total joint arthroplasties (TJA). However, it often goes undiagnosed. Although various risk factors have been documented, study heterogeneity leads to poor understanding within a South East Asian population. This study aims to evaluate POD within this demographic and elucidate its risk factors. MethodsThis was a single-centre prospective observational study comprising 462 patients. Inclusion criteria was patients 65–90 years old undergoing elective TJA. Exclusion criteria was patients unable to personally provide consent for TJA. Preoperative, intraoperative, and postoperative data was recorded to analyse treatment pathway factors. Patients were assessed for POD twice daily for 3 days after TJA using the Confusion Assessment Method (CAM). ResultsMean age of the study cohort was 72 ± 5 years; 70.1% were female; and mean MMSE score preoperatively was 27.3 ± 3.3. 419 patients underwent total knee arthroplasty (TKA) and 43 patients underwent total hip arthroplasty (THA). 164 patients received general anaesthesia, and 298 patients received regional anaesthesia. Overall, 0% (0/462) of patients tested positive for POD at any postoperative timepoint. While various CAM components were met, no patients were positive for the complete requisite criteria for POD diagnosis. ConclusionWe report zero incidence of POD in 462 patients who underwent elective TJA in our institution. We believe that our streamlined care process including pre-operative assessment, patient-specific anaesthesia regime as well as a strictly administered inpatient clinical care pathway with opioid-reducing strategy and early mobilization are protective factors against POD.

Water Literacy in the Southeast Asian Context: Are We There Yet?

The water situation in Southeast Asia has changed from one of relative abundance to one of relative scarcity. Conventional water management that strategized around the provision of adequate water supply to users has limited sustainability. Though nations in this region have adopted the United Nations Sustainable Development Plan into their water management framework, successful outcomes are limited thus far. Water literacy has a growing importance for improving water sustainability, especially in developing countries. A literature search was employed to extract data on the different dimensions of water literacy in Southeast Asia including the sources and consumption patterns, water governance and management, and sociodemographic elements as well as the various aspects of water related challenges faced. Results from the review and analysis show that a large proportion of Southeast Asian populations are not part of a water sustainable society, and this presents a major hurdle for the countries to meet United Nations Sustainable Development Goal 6 by 2030. Therefore, active cognitive engagement through the creation of a water literate environment is critical for breaking the chain of water illiteracy and to achieve long-term water sustainability in Southeast Asia countries. Overall, this paper provides a critical analysis on lessons learnt from the region that can be mirrored in other parts of the world.

Hypoxia Inducible Factor-1α (HIF-1α): A Biomarker for Detection of Malignant Transformation in Oral Submucous Fibrosis

Oral submucous fibrosis (OSMF) is a premalignant condition, which involves the oral cavity as well as pharynx and upper third of the esophagus. It is a predominant disease of South and South-East Asian population. OSMF has the highest rate of malignant transformation among the other oral premalignant disorders (OPMD) that is 7-30% with a prevalence of about 0.03% to 6.42%. OSMF is described by extensive fibrosis of submucosa and reduced vascularity, which results in compromised blood supply guiding to hypoxia of tissue. This tissue hypoxia brings about the transcription of a set of genes associated with angiogenesis, breakdown of iron/glucose, cell division and cell stability. Hypoxia Inducible Factor-1α (HIF-1α) is the main biomarker intervening in this reaction. The alteration of cells to hypoxia emerges to be mediated through hypoxia inducible factor, which is said to be linked with malignant transformation of epithelium. Research-based studies covered on the probable mechanism of HIF-1α were explored using PubMed and Google Scholar. In this review, we analyzed over 40 articles from the years 2004-2021, which were published regarding the structure and function of HIF-1α, and its association with OSMF. Research articles in which HIF-1α is used separately or in combination with other biomarkers in oral submucous fibrosis have been selected. Keywords: Biomarker; Oral Submucous Fibrosis; Esophagus; Hypoxia.

Identification of a Digenic Inheritance of Pklr and KLF1 Mutations Resulting in Hemolytic Anemia in a Neonate from a Study of Genotype-Phenotype Correlation of Globin, Pklr and KLF1 in Thai Patients with Pyruvate Kinase (PK) Deficiency

Introduction: Pyruvate kinase deficiency (PK def) is an inherited disorder that affects red blood cells metabolism and causes a wide range of clinical manifestation from fetal anemia, severe neonatal jaundice, and chronic transfusion dependent anemia to fully compensated hemolytic anemia. This condition is rarely reported in Southeast Asian population due to a lack of knowledge and recognition by clinicians and unavailability of laboratory for confirmation. The majority of patients with PK def result from mutations of the PKLR genes encoding this enzyme. Our group has described for the first time (Viprakasit V et al., Blood 2014) that mutations in trans of an erythroid specific transcription factor; KLF1 that regulate PKLR expression, could result in clinical presentation mimic that of classical PK def. Moreover, α and β globin mutations are highly prevalent in our region (up to 40% carrier rate) but their roles as a genetic modifier in PK def remain unknown. In addition, mutations in KLF1 seems to be highly prevalent in our population (14.6 in 1000, n= 2464 chr.), it is of interest to determine the epistatic role of α and β globin, PKLR and KLF1 mutations in patients with classical presentation of PK def.Objectives: To characterize α and β globin, PKLR and KLF 1 mutations and correlate these with clinical presentation and outcome(s) of them in patients with PK def and their family members.Methods: After obtaining informed consent, 9 index PK def patients with their available family members were evaluated for PKLR and KLF1 mutations by direct genomic sequencing as previously described. Hematological parameters and hemoglobin analyses were performed using standard techniques. DNA analysis for all common α and β globin mutations leading to thalassemia and hemoglobinopathies found in this region was performed using our standard protocol.Results: We successfully identified PKLR mutations in 7 out of 9 index patients as shown in Table 1. All patients were diagnosed with clinical PK def following several measurement of biochemical activity. We found 11 different mutations in 6 compound heterozygotes (5 of two nucleotide mutations and one with 1 missense and a large PKLR deletion) and 1 homozygote. One mutation (c.941T>C =p.I314T) seemed to be recurrent since it was found in two families; one homozygous and one compounded with N118S. We failed to identified PKLR and KLF1 in only one patient (PK-9) suggesting that this patient might have a novel molecular mechanism that remains to be found. We found only one family with globin abnormality (Hb E trait in PK-1) without any deleterious effect on patient's clinical severity. Moreover, most of PK patients (except one) have no mutation in KLF1 genes. Interestingly, the PK-3 patient (who is an offspring of the PK-2) was subsequently found to be double heterozygous of PKLR (p.V548fs) and KLF1 (G176RfsX179 (+7bp)) mutations. This patient was previously diagnosed with PK def at birth when he had serious hemolytic anemia (Hb 10 g/dL, haptoglobin < 10 IU/L) with hyperbilirubinemia requiring phototherapy, based on a very low PK enzyme activity (6.5 IU/g Hb, 20% of normal level) and the PK level from his mother was also low (11 IU/g Hb). Since then, he had an uneventful history for 6 years, except mild anemia from iron deficiency anemia during infant period. Physical examination showed no hepatosplenomegaly. Currently his baseline Hb levels were around 12-12.5 g/dL with normal reticulocyte count (1%) and hypochromic microcytosis. There is no globin abnormality in this family. The PK enzyme activity at 6-year-of age showed an improved PK activity (41% of normal activity) without further hemolysis. Our finding showed for the first time a possible interaction between PKLR and KLF1 mutations in man and this digenic inheritance seems to cause a more serious phenotype than each of these carriers alone. However, since the clinical presentation of our index case (PK-3) appeared to be apparent only at the early age, this might suggest the possible impact of KLF1 mutations that were more serious at the early age (similar to those of patients with two KLF1 mutations; KLF1 disease) and might be further compensated by other hitherto mechanisms during erythroid development.Conclusions: We found no effects of globin mutations on the clinical phenotypes of patients with classical PK def. However, a mutation in KLF1 could deteriorate clinical presentations even in a carrier of PKLR mutation at the early age. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Efficacy of Chemotherapy for Locally Advanced and Metastatic Pancreatic Cancer: A Real-life Experience and Outcome from a Tertiary Care Centre.

To report response rates, progression-free survival (PFS) and overall survival (OS) in patients with advanced pancreatic cancer treated with different available chemotherapeutic regimens over 10 years. This is a retrospective observational study. All patients with locally advanced and metastatic pancreatic cancer (MPC) at Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan, from January 2008 to December 2017 were studied. Data were collected from the hospital information system. The characteristics and outcomes of all the patients were analysed. PFS and OS were also estimated. Kaplan-Meier curves and log-rank test were applied, and SPSS version 20 was used for data analysis. Eighty-seven subjects with a median age of 56 years (range 21-76) were included. Sixty-two (71%) subjects were male. The most common tumour location was the head of the pancreas in 46 (53%) of all the subjects. Sixty-three (72%) subjects had elevated carbohydrate antigen-19.9 values. About 47 (54%) subjects had locally advanced pancreatic cancer (LAPC), and 40 (46%) subjects had MPC. Chemotherapy regimens used were FOLFIRINOX in 23 (26%), gemcitabine (GEM) based in 66 (65%) and capecitabine (CAP) based in 8 (9%) of the subjects. One (1%) subject had a complete response, 12 (14%) had a partial response, 10 (11%) had stable disease and 59 (68%) of the subjects had progressive disease. The objective response rate (ORR) was 15% and the disease control rate (DCR) was 26%. In MPC, the ORR was 10%, DCR was 18% and tumour progression was seen in 72% of the patients, while in LAPC, the ORR was 19.1, DCR 34% and tumour progression was documented in 64% of the patients, respectively. The FOLFIRINOX chemotherapy regimen had better ORR, DCR and lesser number of progressions as compared to GEM- and CAP-based chemotherapy regimens. The median PFS of the whole group was 32 weeks, and the median OS was 54 weeks. The PFS was significantly higher for LAPC (39 weeks) as compared to the MPC group (25 weeks) (P = 0.028). There was no statistically significant difference between the OS of these two groups (P = 0.451). In addition, PFS was significantly higher with FOLFIRINOX chemotherapy as compared to the other chemotherapy regimens. Regarding OS, there was no statistically significant difference among all chemotherapy regimen groups (P = 0.267). Based on our results, FOLFIRINOX remained the most effective chemotherapy regimen despite the dose modifications and toxicities in all groups, indicating that modified FOLFIRINOX could be considered as a first-line regimen in Southeast Asian population.

Molecular genetic analysis of Mia -positive hybrid glycophorins revealed two novel alleles of GP.Vw and multiple variant transcripts of GYPB existing in both the homozygous GP.Mur and wild-type GPB individuals.

The hybrid glycophorins of MNS blood group system express a series of low incidence antigens including Mia , which are commonly found in Southeast Asian populations. In this study, the molecular basis of Mia -positive hybrid glycophorins was firstly clarified in the Chinese Southern Han population. RNA transcripts of GYPB gene in the homozygous GP.Mur individuals were also analyzed. DNAs were extracted from the whole blood samples of 111 Mia -positive donors. Then, high-resolution melting (HRM) analysis for GYP(B-A-B) was used to analyze the genotypes. Sequencing of GYPB pseudoexon 3 was conducted in the samples with variant melting curves. TA-cloning and subsequent sequencing of GYPA exons 2-4 were performed in the Mia -positive samples with normal GYPB/GYPB genotype by HRM. The transcript analysis of GYPB was conducted in homozygous GP.Mur and wild-type glycophorin B (GPB) individuals using RNA extracted from the cultured erythroblast. The heterozygous GYP*Mur/GYPB (n= 101), homozygous GYP*Mur/GYP*Mur (n= 7) including one novel GYP*Mur allele with an extra GYPA/GYPE specific nucleotide substitution (c.229+110A>T), heterozygous GYP*Bun/GYPB (n= 1) and GYP*Vw/GYPA (n= 2) with two novel GYP*Vw alleles were identified. RNA transcript analysis revealed multiple transcripts of GYPB existing in both homozygous GP.Mur and normal GPB individuals. The results showed the genetic diversity of hybrid glycophorins in the Chinese population. Besides, the successful analysis of GYPB transcripts indicates that the cultured erythroblast is a good source for RNA transcript analysis for the protein only expressed on the red blood cells.

Neuroimaging Functional Magnetic Resonance Imaging Task-Based Dorsolateral Prefrontal Cortex Activation Following 12 Weeks of Cosmos caudatus Supplementation Among Older Adults With Mild Cognitive Impairment.

Cosmos caudatus (CC) is traditional Asian vegetable, commonly consumed among the Southeast Asian population. It has been reported to be high in flavonoids and might potentially improve brain activity among older adults with mild cognitive impairment (MCI). The effect of CC in brain activation improvement using neuroimaging is yet to be discovered. To investigate the effects of CC supplement on brain activity using functional magnetic resonance imaging (fMRI) among older adults with MCI. Prospective, randomized, double-blind, placebo-controlled trial. Twenty older adults with mild cognitive impairment (60-75 years old), 14 of them (70%) were female subjects. A 3.0-T, T1-weighted anatomical images, T2*-weighted imaging data, A single shot, gradient echo-echo planar imaging (EPI) sequence. All subjects were asked to consume two 500 mg capsules of either CC supplement or placebo (maltodextrin) daily for 12 weeks. Cognitive function was measured using validated neuropsychological tests (i.e. Mini-mental State Examination and Digit Span) and task-based fMRI (N-back and Stroop Color Word Test) at baseline and 12th week. Brodmann's area 9, 46 and anterior cingulate cortex were selected as the regions of interest to define dorsolateral prefrontal cortex (DLPFC) in fMRI analysis. Normality test was performed with the Shapiro-Wilk test. Two-way repeated ANOVA determined the intervention effects of the CC supplementation on brain activity after adjustments for covariates. Significance level at P < 0.05 for independent-t test and Chi square test; adjusted P < 0.0042 for two-way repeated ANOVA after Bonferroni correction. Findings showed significant improvements in digit span (partial η2 =0.559), increment in right DLPFC activation while performing 1-back task (partial η2 =0.586) and left DLPFC activation while performing Stroop Color Word Test (SCWT) (congruent) task (partial η2 =0.432) at 12th week of CC supplementation. CC supplementation might have the ability to improve DLPFC activation, potentially leading to improved working memory among older adults with MCI after 12 weeks of administration. 1 TECHNICAL EFFICACY: Stage 4.

Hidradenitis suppurativa in East and Southeast Asian populations: a systematic review and meta-analysis.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition that presents with recurrent inflammatory nodules and draining tunnels in the skin. Most HS studies have focused on Western populations, and the understanding of how HS characteristics differ in specific Asian ethnicities is poor. We conducted the first systematic review and meta-analysis to characterize HS patients from East and Southeast Asia. PubMed, Embase, and Ovid MEDLINE databases were searched from inception to June 12, 2020. English-language case-series, cross-sectional, observational, and randomized controlled trial studies investigating HS in East and Southeast Asian populations were screened by titles, abstracts, and articles in duplicate. Of 136 citations, 10 studies were included in the meta-analysis. Data on gender distribution, lesion distribution in the axilla and gluteal regions, and family history were extracted in duplicate. A random effects model was used for the meta-analysis. A total of 30,125 HS patients were included in the analysis. Most patients were male (66%, 95% CI=60-72%). About half of Asian patients with HS develop lesions in the axilla (52%, 95% CI=33-72%) and the buttocks (48%, 95% CI=38-57%). Only a small subset had positive family history of HS (5%, 95% CI=2-8%). We report an up-to-date characterization of HS in East and Southeast Asian populations and highlight differences in their Western counterparts. These results will hopefully improve understanding for how HS may manifest, lead to more personalized treatments for Asian patients with HS, and usher in a proper patient-centered approach to treating the disease.

A Pilot Study of External Counterpulsation on Reactive Hyperemia, Levels of Glycemia and Metabolic Parameters in Type 2 Diabetes Mellitus

Introduction: External counter-pulsation (ECP) involves cuff inflation over the lower extremities to generate sheer stress, thereby improving endothelial function and anginal symptoms in coronary artery disease. Endothelial dysfunction is also involved in the pathogenesis of T2DM. We hypothesized that 1) ECP will be associated with an improvement in endothelial function in T2DM as measured by peripheral artery tonometry, and 2) explored whether this would vary with different dose and frequency regimens. A shorter or less intensive regimen could potentially reduce cost and improve patient compliance if a similar therapeutic response is achieved. Methods: This single-center prospective study in a tertiary institute in Singapore involving 46 adults with T2DM of HbA1c between 7 to 10%, who were randomly assigned to receive 35 sessions of ECP at different regimens and duration. Subjects in arm 1 received 1-hour daily sessions 5x per week for 7 consecutive weeks, subjects in arm 2 received 0.5-hour sessions 5x per week for 7 consecutive weeks, and subjects in arm 3 received 1-hour sessions 3x per week for 12 consecutive weeks. Endothelial function was evaluated by reactive hyperemia index (RHI) via peripheral arterial tonometry measured at the start, midpoint and end of study. Other secondary outcomes included fasting glucose, homeostatic model assessment of insulin resistance (HOMA-IR), HbA1c, blood pressure, lipid profile, weight and vibration sense. Results: 42 subjects completed the 35-session course of ECP. Mean age was 56.1±9.3 years, duration of diabetes 8.8±4.7 years, baseline RHI 2.0 (1.3–3.7) and baseline HOMA-IR was 3.1 (0.5–18.7). All regimes of ECP were well-tolerated. There was no change in RHI across all 3 regimens of ECP individually or collectively at the end of the study (ΔRHI +0.01%, p=0.458). Glycaemic markers of fasting glucose, HbA1c and HOMA-IR, as well as blood pressure, lipid profile, weight and vibration sense also remained unchanged at endpoint. Subgroup analysis showed a significant improvement in RHI (ΔRHI +20.6%, p=0.0178) in 7 subjects with more severe endothelial dysfunction (defined by RHI<1.67) at baseline who had a trend to having a longer duration of diabetes, however there was no improvement in fasting glucose, HbA1c, HOMA-IR or metabolic parameters in this group. Conclusion: ECP did not show a beneficial effect on endothelial function, glycemic control or metabolic parameters in this South-East Asian population with T2DM at any of the three regimens. This may partly be explained by less severe endothelial dysfunction and less insulin resistance in our population at baseline. Future studies of ECP may investigate its potential benefits in a larger population of T2DM with more severe endothelial dysfunction, higher insulin resistance and/or longer duration of diabetes at baseline.

Detection of the weak-secretor rs1047781 (385A>T) single nucleotide polymorphism using an unlabeled probe high-resolution melting-based method.

FUT2 encodes galactoside 2-α-l-fucosyltransferase 2 which determines the secretor status of ABO(H) blood group antigens. Secretors have at least one functional FUT2 allele (Se), while nonsecretors or weak secretors are homozygous for nonfunctional (non- or weak secretor) FUT2 alleles (se or Sew ). The Sew having the 385A>T missense SNP (rs1047781) is the prevalent nonfunctional allele in East and Southeast Asians. In this study, we developed an unlabeled-probe high-resolution melting (HRM) analysis for genotyping of 385A>T and validated the method by analyzing 72 Japanese whose 385A>T genotypes were confirmed by DNA sequencing. The unlabeled-probe HRM analysis clearly discriminated three genotypes of 385A>T. In addition, the results obtained for the 72 Japanese by this method were fully concordant with previous ones. Estimation of secretor status using this cost-effective method may be useful in East and Southeast Asian populations.

The difference in the location of the malar summit between genders in Southeast Asians with appropriate references.

BackgroundFacial feminization surgery and malarplasty require information concerning facial features in the malar area. Such information varies as a function of sex and race. The objectives of this study aimed to quantitatively evaluate the location of malar prominence across sexes in the Southeast Asian population, and identify sex-specific differences in malar prominence using a combination of two-dimensional (2D) computed tomography (CT) and three-dimensional (3D) CT.MethodsThe location of malar prominence was evaluated in 101 Thai adults, consisting of 52 men and 49 women. This study used both 2D CT and 3D CT to achieve greater accuracy, in which 2D CT was used to measure malar distance, malar summit width, facial width, and malar summit-to-facial width ratio whereas 3D CT was used to evaluate the positional relationship between the zygomatic summit and four reference points of the zygoma.ResultsThe malar summit was positioned more laterally in males (p<0.01) and was more projected in females (p=0.01). The other 2D-parameters were wider in males. The ratio between the malar summit width and facial width showed similar results for both sexes. The vertical dimension did not show any statistically significant differences; however, a higher summit position was observed in males.ConclusionThe zygomatic summit is positioned more laterally in males and is more projected in females. However, the ratio was similar, which indicates that the male cranium is larger in size. Based on the results in this study, when facial feminization surgery or malarplasty is performed on a Southeast Asian patient, the malar bone should be reduced horizontally and moved forward for better outcomes.

Analysis of whole-genome re-sequencing data of ducks reveals a diverse demographic history and extensive gene flow between Southeast/South Asian and Chinese populations

BackgroundThe most prolific duck genetic resource in the world is located in Southeast/South Asia but little is known about the domestication and complex histories of these duck populations.ResultsBased on whole-genome resequencing data of 78 ducks (Anas platyrhynchos) and 31 published whole-genome duck sequences, we detected three geographic distinct genetic groups, including local Chinese, wild, and local Southeast/South Asian populations. We inferred the demographic history of these duck populations with different geographical distributions and found that the Chinese and Southeast/South Asian ducks shared similar demographic features. The Chinese domestic ducks experienced the strongest population bottleneck caused by domestication and the last glacial maximum (LGM) period, whereas the Chinese wild ducks experienced a relatively weak bottleneck caused by domestication only. Furthermore, the bottleneck was more severe in the local Southeast/South Asian populations than in the local Chinese populations, which resulted in a smaller effective population size for the former (7100–11,900). We show that extensive gene flow has occurred between the Southeast/South Asian and Chinese populations, and between the Southeast Asian and South Asian populations. Prolonged gene flow was detected between the Guangxi population from China and its neighboring Southeast/South Asian populations. In addition, based on multiple statistical approaches, we identified a genomic region that included three genes (PNPLA8, THAP5, and DNAJB9) on duck chromosome 1 with a high probability of gene flow between the Guangxi and Southeast/South Asian populations. Finally, we detected strong signatures of selection in genes that are involved in signaling pathways of the nervous system development (e.g., ADCYAP1R1 and PDC) and in genes that are associated with morphological traits such as cell growth (e.g., IGF1R).ConclusionsOur findings provide valuable information for a better understanding of the domestication and demographic history of the duck, and of the gene flow between local duck populations from Southeast/South Asia and China.

Characterisation of protein-truncating and missense variants in PALB2 in 15 768 women from Malaysia and Singapore

BackgroundRare protein-truncating variants (PTVs) in partner and localiser of BRCA2 (PALB2) confer increased risk to breast cancer, but relatively few studies have reported the prevalence in South-East Asian populations. Here,...

Functional Characterization of the Effects of N-acetyltransferase 2 Alleles on N-acetylation of Eight Drugs and Worldwide Distribution of Substrate-Specific Diversity.

Variability in the enzymatic activity of N-acetyltransferase 2 (NAT2) is an important contributor to interindividual differences in drug responses. However, there is little information on functional differences in N-acetylation activities according to NAT2 phenotypes, i.e., rapid, intermediate, slow, and ultra-slow acetylators, between different substrate drugs. Here, we estimated NAT2 genotypes in 990 Japanese individuals and compared the frequencies of different genotypes with those of different populations. We then calculated in vitro kinetic parameters of four NAT2 alleles (NAT2∗4, ∗5, ∗6, and ∗7) for N-acetylation of aminoglutethimide, diaminodiphenyl sulfone, hydralazine, isoniazid, phenelzine, procaineamide, sulfamethazine (SMZ), and sulfapyrizine. NAT2∗5, ∗6, and ∗7 exhibited significantly reduced N-acetylation activities with lower Vmax and CLint values of all drugs when compared with NAT2∗4. Hierarchical clustering analysis revealed that 10 NAT2 genotypes were categorized into three or four clusters. According to the results of in vitro metabolic experiments using SMZ as a substrate, the frequencies of ultra-slow acetylators were calculated to be 29.05–54.27% in Europeans, Africans, and South East Asians, whereas Japanese and East Asian populations showed lower frequencies (4.75 and 11.11%, respectively). Our findings will be helpful for prediction of responses to drugs primarily metabolized by NAT2.

Genomic analysis reveals independent evolution of Plasmodium falciparum populations in Ethiopia

BackgroundPlasmodium falciparum parasite populations in Ethiopia have been experiencing local selective pressures from drugs and immunity, leading to evolutionary adaptation. However, there was a paucity of data on genomic characterization and evolutionary adaptations of P. falciparum isolates from the central area of Ethiopia.MethodsWhole-genome analysis of 25 P. falciparum isolates from central Ethiopia, specifically from West Arsi, were studied to determine their genetic diversity, population structures, and signatures of selection in known drug resistance alleles against global isolates from Cambodia, Thailand, DR Congo, and Malawi.ResultsA total of 18,517 high-quality single-nucleotide polymorphisms (SNPs) were identified in Ethiopian P. falciparum isolates. About 84% of the Ethiopian P. falciparum isolates had a FWS value > 0.95 showing a dominant single genotype infection in most isolates at the time of collection with little potential for out-crossing as expected in areas with low transmission intensity. Within-host diversity of Ethiopian infections was significantly different from East African (p < 0.001), but not Southeast Asian infections (P > 0.05). A significant population structure has been observed by PCA and population differentiation between Ethiopian parasites and East African (Fst ~ 10%) and Southeast Asian populations (Fst ~ 18%), suggesting limited gene flow and the independent evolution of the Ethiopian parasite population. Moreover, a total of 125 genes under balancing selection was found that include ama1, trap, eba175, and lsa3, previously identified as targets of human host immunity. Recent directional selection analysis using integrated standardized haplotype score (IHS) did not detect any selection signatures in the Pfcrt, Pfdhfr, Pfdhps, Pfmdr1, and PfK13 genes. However, known drug resistance-conferring mutations analysis showed that at least one SNP marker was fixed in these genes, but not in Pfdhps and PfK13.ConclusionPlasmodium falciparum populations in the central region of Ethiopia was structurally diverged from both Southeast Asian and other East African populations. Malaria infections in Ethiopia had low within-host diversity, and parasites carry fixed chloroquine resistance markers despite the withdrawal of this drug for the treatment of P. falciparum.

Darker Skin Color Measured by Von Luschan Chromatic Scale and Increased Sunlight Exposure Time Are Independently Associated with Decreased Odds of Vitamin D Deficiency in Thai Ambulatory Patients.

Background Little is known about the association among skin color, sunlight exposure. and vitamin D status in Southeast Asian population. Objective To investigate the association between skin color measured by von Luschan chromatic scale (VLCS) and vitamin D status in Thai medical ambulatory patients. Methods Medical ambulatory patients were enrolled. The eligibility criteria were as follows: aged >18 years, stable medical conditions, and no conditions directly affecting vitamin D status. Serum 25-hydroxyvitamin D [25(OH)D] levels were assessed. Skin color at the outer forearm was assessed using VLCS which grades skin color from the lightest score of 1 to the darkest score of 36. Patients were systematically interviewed to estimate daily sunlight exposure time. Results A total of 334 patients were enrolled. Data were expressed as mean ± SD. The mean serum 25(OH)D was 25.21 ± 10.06 ng/mL. There were 17 (5.1%), 217 (65.0%), and 100 (29.9%) patients who had light brown (VLCS score 18–20), medium brown (VLCS score 21–24), and dark brown (VLCS score 25–27) skin colors, respectively. The mean serum 25(OH)D level was higher in patients with dark brown skin than in patients with medium brown and light brown skin (28.31 ± 10.34 vs. 24.28 ± 9.57 and 19.43 ± 9.92 ng/mL, respectively, both p < 0.05). Multivariate analysis showed that darker skin color and increased sunlight exposure time were independently associated with decreased odds of vitamin D deficiency (dark brown vs. light brown: odds ratio, 0.263, 95% CI: 0.081–0.851, p=0.026; medium brown vs. light brown: odds ratio, 0.369, 95% CI: 0.987–1.003, p=0.067; sunlight exposure time odds ratio per 1 minute/day increase 0.955, 95% CI: 0.991–1.000, p=0.037), after adjusting for possible confounders. Conclusions We found that darker skin color at sunlight exposure area and increased sunlight exposure time were independently associated with decreased odds of vitamin D deficiency in Thai medical ambulatory patients.

Shared paternal ancestry of Han, Tai-Kadai-speaking, and Austronesian-speaking populations as revealed by the high resolution phylogeny of O1a-M119 and distribution of its sub-lineages within China.

The aim of this research was to explore the origin, diversification, and demographic history of O1a-M119 over the past 10,000 years, as well as its role during the formation of East Asian and Southeast Asian populations, particularly the Han, Tai-Kadai-speaking, and Austronesian-speaking populations. Y-chromosome sequences (n = 141) of the O1a-M119 lineage, including 17 newly generated in this study, were used to reconstruct a revised phylogenetic tree with age estimates, and identify sub-lineages. The geographic distribution of 12 O1a-M119 sub-lineages was summarized, based on 7325 O1a-M119 individuals identified among 60,009 Chinese males. A revised phylogenetic tree, age estimation, and distribution maps indicated continuous expansion of haplogroup O1a-M119 over the past 10,000 years, and differences in demographic history across geographic regions. We propose several sub-lineages of O1a-M119 as founding paternal lineages of Han, Tai-Kadai-speaking, and Austronesian-speaking populations. The sharing of several young O1a-M119 sub-lineages with expansion times less than 6000 years between these three population groups supports a partial common ancestry for them in the Neolithic Age; however, the paternal genetic divergence pattern is much more complex than previous hypotheses based on ethnology, archeology, and linguistics. Our analyses contribute to a better understanding of the demographic history of O1a-M119 sub-lineages over the past 10,000 years during the emergence of Han, Austronesians, Tai-Kadai-speaking populations. The data described in this study will assist in understanding of the history of Han, Tai-Kadai-speaking, and Austronesian-speaking populations from ethnology, archeology, and linguistic perspectives in the future.

Genome-wide identification of cis DNA methylation quantitative trait loci in three Southeast Asian Populations.

DNA methylation (DNAm) is an epigenetic modification that acts to regulate gene transcription, is essential for cellular processes and plays an important role in complex traits and disease. Variation in DNAm levels is influenced by both genetic and environmental factors. Several studies have examined the extent to which common genetic variation influences DNAm (i.e. mQTLs), however, an improved understanding of mQTLs across diverse human populations is needed to increase their utility in integrative genomic studies in order to further our understanding of complex trait and disease biology. Here, we systematically examine cis-mQTLs in three Southeast Asian populations in the Singapore Integrative Omics (iOmics) Study, comprised of Chinese (n= 93), Indians (n= 83) and Malays (n= 78). A total of 24 851 cis-mQTL probes were associated with at least one SNP in meta- and ethnicity-specific analyses at a stringent significance level. These cis-mQTL probes show significant differences in local SNP heritability between the ethnicities, enrichment in functionally relevant regions using data from the Roadmap Epigenomics Mapping Consortium and are associated with nearby genes and complex traits due to pleiotropy. Importantly, DNAm prediction performance and the replication of cis-mQTLs both within iOmics and between two independent mQTL studies in European and Bangladeshi individuals is best when the genetic distance between the ethnicities is small, with differences in cis-mQTLs likely due to differences in allele frequency and linkage disequilibrium. This study highlights the importance of, and opportunities from, extending investigation of the genetic control of DNAm to Southeast Asian populations.

Prevalence of pharmacogenomic variants in 100 pharmacogenes among Southeast Asian populations under the collaboration of the Southeast Asian Pharmacogenomics Research Network (SEAPharm)

Pharmacogenomics can enhance the outcome of treatment by adopting pharmacogenomic testing to maximize drug efficacy and lower the risk of serious adverse events. Next-generation sequencing (NGS) is a cost-effective technology for genotyping several pharmacogenomic loci at once, thereby increasing publicly available data. A panel of 100 pharmacogenes among Southeast Asian (SEA) populations was resequenced using the NGS platform under the collaboration of the Southeast Asian Pharmacogenomics Research Network (SEAPharm). Here, we present the frequencies of pharmacogenomic variants and the comparison of these pharmacogenomic variants among different SEA populations and other populations used as controls. We investigated the different types of pharmacogenomic variants, especially those that may have a functional impact. Our results provide substantial genetic variations at 100 pharmacogenomic loci among SEA populations that may contribute to interpopulation variability in drug response phenotypes. Correspondingly, this study provides basic information for further pharmacogenomic investigations in SEA populations.