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1.
BMC Genomics ; 20(1): 842, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31718558

RESUMO

BACKGROUND: Recent advances in genomic technologies have facilitated genome-wide investigation of human genetic variations. However, most efforts have focused on the major populations, yet trio genomes of indigenous populations from Southeast Asia have been under-investigated. RESULTS: We analyzed the whole-genome deep sequencing data (~ 30×) of five native trios from Peninsular Malaysia and North Borneo, and characterized the genomic variants, including single nucleotide variants (SNVs), small insertions and deletions (indels) and copy number variants (CNVs). We discovered approximately 6.9 million SNVs, 1.2 million indels, and 9000 CNVs in the 15 samples, of which 2.7% SNVs, 2.3% indels and 22% CNVs were novel, implying the insufficient coverage of population diversity in existing databases. We identified a higher proportion of novel variants in the Orang Asli (OA) samples, i.e., the indigenous people from Peninsular Malaysia, than that of the North Bornean (NB) samples, likely due to more complex demographic history and long-time isolation of the OA groups. We used the pedigree information to identify de novo variants and estimated the autosomal mutation rates to be 0.81 × 10- 8 - 1.33 × 10- 8, 1.0 × 10- 9 - 2.9 × 10- 9, and ~ 0.001 per site per generation for SNVs, indels, and CNVs, respectively. The trio-genomes also allowed for haplotype phasing with high accuracy, which serves as references to the future genomic studies of OA and NB populations. In addition, high-frequency inherited CNVs specific to OA or NB were identified. One example is a 50-kb duplication in DEFA1B detected only in the Negrito trios, implying plausible effects on host defense against the exposure of diverse microbial in tropical rainforest environment of these hunter-gatherers. The CNVs shared between OA and NB groups were much fewer than those specific to each group. Nevertheless, we identified a 142-kb duplication in AMY1A in all the 15 samples, and this gene is associated with the high-starch diet. Moreover, novel insertions shared with archaic hominids were identified in our samples. CONCLUSION: Our study presents a full catalogue of the genome variants of the native Malaysian populations, which is a complement of the genome diversity in Southeast Asians. It implies specific population history of the native inhabitants, and demonstrated the necessity of more genome sequencing efforts on the multi-ethnic native groups of Malaysia and Southeast Asia.

2.
Value Health Reg Issues ; 21: 66-68, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31655465

RESUMO

There has been continuous development in the field of health technology assessment (HTA) owing to the added value of HTA in supporting healthcare reimbursement decisions. Collaboration and engagement among countries in Asia has been carried out to share experiences and learning on the barriers and factors facilitating the implementation and use of HTA in policy making. A symposium on the topic of Health Technology Assessment (HTA): Selecting the Highest Value Care was held on January 10, 2019 at the National University of Singapore, during which 3 major challenges confronting HTA development in Asia were identified. The symposium also offered possible ways to overcome the challenges.

3.
BMJ Open ; 9(10): e032198, 2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31630110

RESUMO

BACKGROUND: Since the Singapore Mental Health Study in 2010 which reported a 16.0% prevalence rate for current smokers and 4.5% for nicotine dependence, new anti-smoking strategies have been implemented. The aim of this study was to compare smoking trends from the 2010 study with the second Singapore Mental Health Study in 2016 (SMHS 2016). METHODS: A survey of 6126 individuals aged 18 years and above randomly selected among Singapore residents was conducted using the same methodology as the 2010 study. The measures used in this analysis were sociodemographic questions, the Composite International Diagnostic Interview which assessed for psychiatric disorders, the Fagerstrom Test for Nicotine Dependence and a list of chronic physical conditions that were prevalent in Singapore. Logistic regression analyses were used to test for associations between smoking/nicotine-dependence and other measures. RESULTS: In the SMHS 2016, 16.1% were current smokers and 3.3% were nicotine-dependent. As compared with non-smokers, current smokers were more likely to be younger, male gender, of ethnic minority and had lower/vocational education level. Younger age, male gender, lower/vocational education and psychiatric disorders (major depression, bipolar disorder and alcohol use disorders) predicted nicotine dependence. No associations were found between nicotine dependence and any of the chronic conditions. CONCLUSION: The prevalence of current smokers in the population has plateaued while that of nicotine dependence has decreased from 2010. However, the study did not investigate the use of e-cigarettes. Inequalities in smoking and nicotine dependence continue to pervade the population particularly among those of ethnic minority, lower/vocational education and the mentally ill.

4.
Hum Mol Genet ; 28(19): 3327-3338, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31504550

RESUMO

Although hundreds of genome-wide association studies-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of 30 studies consisting of up to 13 005 cases (≥95th percentile of body mass index (BMI) achieved 2-18 years old) and 15 599 controls (consistently <50th percentile of BMI) of European, African, North/South American and East Asian ancestry. Suggestive loci were taken forward for replication in a sample of 1888 cases and 4689 controls from seven cohorts of European and North/South American ancestry. In addition to observing 18 previously implicated BMI or obesity loci, for both early and late onset, we uncovered one completely novel locus in this trans-ancestral analysis (nearest gene, METTL15). The variant was nominally associated with only the European subgroup analysis but had a consistent direction of effect in other ethnicities. We then utilized trans-ancestral Bayesian analysis to narrow down the location of the probable causal variant at each genome-wide significant signal. Of all the fine-mapped loci, we were able to narrow down the causative variant at four known loci to fewer than 10 single nucleotide polymorphisms (SNPs) (FAIM2, GNPDA2, MC4R and SEC16B loci). In conclusion, an ethnically diverse setting has enabled us to both identify an additional pediatric obesity locus and further fine-map existing loci.

5.
Int J Antimicrob Agents ; 54(2): 109-116, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30981926

RESUMO

Drug-resistant tuberculosis (TB) is a major public health problem. There is little information regarding the genotypic-phenotypic association of anti-TB drugs, especially for second-line drugs. This study compared phenotypic drug susceptibility testing (DST) with predictions based on whole-genome sequencing (WGS) data for 266 Mycobacterium tuberculosis isolates. Phenotypic DST used the standard proportional method. Clinical isolates of M. tuberculosis collected in Thailand between 1998 and 2013 comprised 51 drug-sensitive strains, six mono-resistant strains, two multiple-resistant strains, 88 multi-drug-resistant strains, 95 pre-extensively drug-resistant strains and 24 extensively drug-resistant strains. WGS analysis was performed using the computer programs PhyResSE and TB-Profiler. TB-Profiler had higher average concordance with phenotypic DST than PhyResSE for both first-line (91.96% vs. 91.4%) and second-line (79.67% vs. 78.20%) anti-TB drugs. The average sensitivity for all anti-TB drugs was also higher (83.13% vs. 72.08%) with slightly lower specificity (83.50% vs. 86.68%). Regardless of the program used, isoniazid, rifampicin and amikacin had the highest concordance with phenotypic DST (96.2%, 93.5% and 95.6%, respectively). Ethambutol, ethionamide and fluoroquinolones had the lowest concordance (87.34%, 81.44% and 73.85%, respectively). Concordance rates of ofloxacin (a second-generation fluoroquinolone), levofloxacin, moxifloxacin and gatifloxacin (third- and fourth-generation fluoroquinolones) were 91.79%, 76.62%, 72.64% and 57.35%, respectively. Discordance between phenotypic and WGS-based DSTs may be due, in part, to the choice of critical concentration and variable reproducibility of the phenotypic tests. It may also be due to limitations of the mutation databases (especially for the second-line drugs) and the analysis program used. Mutations related to fluoroquinolone resistance, especially the later generations, need to be identified.

6.
BMC Bioinformatics ; 20(1): 68, 2019 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-30736750

RESUMO

BACKGROUND: It is possible to predict whether a tuberculosis (TB) patient will fail to respond to specific antibiotics by sequencing the genome of the infecting Mycobacterium tuberculosis (Mtb) and observing whether the pathogen carries specific mutations at drug-resistance sites. This advancement has led to the collation of TB databases such as PATRIC and ReSeqTB that possess both whole genome sequences and drug resistance phenotypes of infecting Mtb isolates. Bioinformatics tools have also been developed to predict drug resistance from whole genome sequencing (WGS) data. Here, we evaluate the performance of four popular tools (TBProfiler, MyKrobe, KvarQ, PhyResSE) with 6746 isolates compiled from publicly available databases, and subsequently identify highly probable phenotyping errors in the databases by genetically predicting the drug phenotypes using all four software. RESULTS: Our results show that these bioinformatics tools generally perform well in predicting the resistance status for two key first-line agents (isoniazid, rifampicin), but the accuracy is lower for second-line injectables and fluoroquinolones. The error rates in the databases are also non-trivial, reaching as high as 31.1% for prothionamide, and that phenotypes from ReSeqTB are more susceptible to errors. CONCLUSIONS: The good performance of the automated software for drug resistance prediction from TB WGS data shown in this study further substantiates the usefulness and promise of utilising genetic data to accurately profile TB drug resistance, thereby reducing misdiagnoses arising from error-prone culture-based drug susceptibility testing.


Assuntos
Algoritmos , Antituberculosos/farmacologia , Benchmarking , Bases de Dados Genéticas , Farmacorresistência Bacteriana/genética , Genômica/métodos , Tuberculose/genética , Calibragem , Humanos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/isolamento & purificação , Sensibilidade e Especificidade , Software , Tuberculose/microbiologia
8.
Nat Genet ; 50(6): 849-856, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29785015

RESUMO

To examine the transmission dynamics of Mycobacterium tuberculosis (Mtb) isolated from tuberculosis patients in Ho Chi Minh City, Vietnam, we sequenced the whole genomes of 1,635 isolates and compared these with 3,144 isolates from elsewhere. The data identify an underlying burden of disease caused by the endemic Mtb lineage 1 associated with the activation of long-term latent infection, and a threefold higher burden associated with the more recently introduced Beijing lineage and lineage 4 Mtb strains. We find that Beijing lineage Mtb is frequently transferred between Vietnam and other countries, and detect higher levels of transmission of Beijing lineage strains within this host population than the endemic lineage 1 Mtb. Screening for parallel evolution of Beijing lineage-associated SNPs in other Mtb lineages as a signal of positive selection, we identify an alteration in the ESX-5 type VII-secreted protein EsxW, which could potentially contribute to the enhanced transmission of Beijing lineage Mtb in Vietnamese and other host populations.

9.
Nat Genet ; 50(6): 834-848, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29808027

RESUMO

Refractive errors, including myopia, are the most frequent eye disorders worldwide and an increasingly common cause of blindness. This genome-wide association meta-analysis in 160,420 participants and replication in 95,505 participants increased the number of established independent signals from 37 to 161 and showed high genetic correlation between Europeans and Asians (>0.78). Expression experiments and comprehensive in silico analyses identified retinal cell physiology and light processing as prominent mechanisms, and also identified functional contributions to refractive-error development in all cell types of the neurosensory retina, retinal pigment epithelium, vascular endothelium and extracellular matrix. Newly identified genes implicate novel mechanisms such as rod-and-cone bipolar synaptic neurotransmission, anterior-segment morphology and angiogenesis. Thirty-one loci resided in or near regions transcribing small RNAs, thus suggesting a role for post-transcriptional regulation. Our results support the notion that refractive errors are caused by a light-dependent retina-to-sclera signaling cascade and delineate potential pathobiological molecular drivers.

10.
Sci Rep ; 8(1): 4910, 2018 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-29559684

RESUMO

Tuberculous meningitis (TBM) is a severe form of tuberculosis with a high mortality rate. The factors associated with TBM pathogenesis are still unclear. Using comparative whole-genome sequence analysis we compared Mycobacterium tuberculosis (Mtb) isolates from cerebrospinal fluid of TBM cases (n = 73) with those from sputum of pulmonary tuberculosis (PulTB) patients (n = 220) from Thailand. The aim of this study was to seek genetic variants of Mtb associated with TBM. Regardless of Mtb lineage, we found 242 variants that were common to all TBM isolates. Among these variants, 28 were missense SNPs occurring mainly in the pks genes (involving polyketide synthesis) and the PE/PPE gene. Six lineage-independent SNPs were commonly found in TBM isolates, two of which were missense SNPs in Rv0532 (PE_PGRS6). Structural variant analysis revealed that PulTB isolates had 14 genomic regions containing 2-3-fold greater read depth, indicating higher copy number variants and half of these genes belonged to the PE/PPE gene family. Phylogenetic analysis revealed only two small clusters of TBM clonal isolates without support from epidemiological data. This study reported genetic variants of Mtb commonly found in TBM patients compared to PulTB patients. Variants associated with TBM disease warrant further investigation.

11.
Ann Hum Genet ; 82(4): 216-226, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29521412

RESUMO

The region of northern Borneo is home to the current state of Sabah, Malaysia. It is located closest to the southern Philippine islands and may have served as a viaduct for ancient human migration onto or off of Borneo Island. In this study, five indigenous ethnic groups from Sabah were subjected to genome-wide SNP genotyping. These individuals represent the "North Borneo"-speaking group of the great Austronesian family. They have traditionally resided in the inland region of Sabah. The dataset was merged with public datasets, and the genetic relatedness of these groups to neighboring populations from the islands of Southeast Asia, mainland Southeast Asia and southern China was inferred. Genetic structure analysis revealed that these groups formed a genetic cluster that was independent of the clusters of neighboring populations. Additionally, these groups exhibited near-absolute proportions of a genetic component that is also common among Austronesians from Taiwan and the Philippines. They showed no genetic admixture with Austro-Melanesian populations. Furthermore, phylogenetic analysis showed that they are closely related to non-Austro-Melansian Filipinos as well as to Taiwan natives but are distantly related to populations from mainland Southeast Asia. Relatively lower heterozygosity and higher pairwise genetic differentiation index (FST ) values than those of nearby populations indicate that these groups might have experienced genetic drift in the past, resulting in their differentiation from other Austronesians. Subsequent formal testing suggested that these populations have received no gene flow from neighboring populations. Taken together, these results imply that the indigenous ethnic groups of northern Borneo shared a common ancestor with Taiwan natives and non-Austro-Melanesian Filipinos and then isolated themselves on the inland of Sabah. This isolation presumably led to no admixture with other populations, and these individuals therefore underwent strong genetic differentiation. This report contributes to addressing the paucity of genetic data on representatives from this strategic region of ancient human migration event(s).

12.
Mol Vis ; 24: 127-142, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29422769

RESUMO

Purpose: To identify genes and genetic markers associated with corneal astigmatism. Methods: A meta-analysis of genome-wide association studies (GWASs) of corneal astigmatism undertaken for 14 European ancestry (n=22,250) and 8 Asian ancestry (n=9,120) cohorts was performed by the Consortium for Refractive Error and Myopia. Cases were defined as having >0.75 diopters of corneal astigmatism. Subsequent gene-based and gene-set analyses of the meta-analyzed results of European ancestry cohorts were performed using VEGAS2 and MAGMA software. Additionally, estimates of single nucleotide polymorphism (SNP)-based heritability for corneal and refractive astigmatism and the spherical equivalent were calculated for Europeans using LD score regression. Results: The meta-analysis of all cohorts identified a genome-wide significant locus near the platelet-derived growth factor receptor alpha (PDGFRA) gene: top SNP: rs7673984, odds ratio=1.12 (95% CI:1.08-1.16), p=5.55×10-9. No other genome-wide significant loci were identified in the combined analysis or European/Asian ancestry-specific analyses. Gene-based analysis identified three novel candidate genes for corneal astigmatism in Europeans-claudin-7 (CLDN7), acid phosphatase 2, lysosomal (ACP2), and TNF alpha-induced protein 8 like 3 (TNFAIP8L3). Conclusions: In addition to replicating a previously identified genome-wide significant locus for corneal astigmatism near the PDGFRA gene, gene-based analysis identified three novel candidate genes, CLDN7, ACP2, and TNFAIP8L3, that warrant further investigation to understand their role in the pathogenesis of corneal astigmatism. The much lower number of genetic variants and genes demonstrating an association with corneal astigmatism compared to published spherical equivalent GWAS analyses suggest a greater influence of rare genetic variants, non-additive genetic effects, or environmental factors in the development of astigmatism.


Assuntos
Fosfatase Ácida/genética , Astigmatismo/genética , Claudinas/genética , Doenças da Córnea/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Grupo com Ancestrais do Continente Asiático , Astigmatismo/diagnóstico , Astigmatismo/etnologia , Astigmatismo/patologia , Estudos de Coortes , Córnea/metabolismo , Córnea/patologia , Doenças da Córnea/diagnóstico , Doenças da Córnea/etnologia , Doenças da Córnea/patologia , Grupo com Ancestrais do Continente Europeu , Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Razão de Chances , Polimorfismo de Nucleotídeo Único , Software
13.
Hum Genet ; 137(2): 161-173, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29383489

RESUMO

Southeast Asia (SEA) is enriched with a complex history of peopling. Malaysia, which is located at the crossroads of SEA, has been recognized as one of the hubs for early human migration. To unravel the genomic complexity of the native inhabitants of Malaysia, we sequenced 12 samples from 3 indigenous populations from Peninsular Malaysia and 4 native populations from North Borneo to a high coverage of 28-37×. We showed that the Negritos from Peninsular Malaysia shared a common ancestor with the East Asians, but exhibited some level of gene flow from South Asia, while the North Borneo populations exhibited closer genetic affinity towards East Asians than the Malays. The analysis of time of divergence suggested that ancestors of Negrito were the earliest settlers in the Malay Peninsula, whom first separated from the Papuans ~ 50-33 thousand years ago (kya), followed by East Asian (~ 40-15 kya), while the divergence time frame between North Borneo and East Asia populations predates the Austronesian expansion period implies a possible pre-Neolithic colonization. Substantial Neanderthal ancestry was confirmed in our genomes, as was observed in other East Asians. However, no significant difference was observed, in terms of the proportion of Denisovan gene flow into these native inhabitants from Malaysia. Judging from the similar amount of introgression in the Southeast Asians and East Asians, our findings suggest that the Denisovan gene flow may have occurred before the divergence of these populations and that the shared similarities are likely an ancestral component.

14.
Proc Natl Acad Sci U S A ; 115(2): 379-384, 2018 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-29279374

RESUMO

A major challenge in evaluating the contribution of rare variants to complex disease is identifying enough copies of the rare alleles to permit informative statistical analysis. To investigate the contribution of rare variants to the risk of type 2 diabetes (T2D) and related traits, we performed deep whole-genome analysis of 1,034 members of 20 large Mexican-American families with high prevalence of T2D. If rare variants of large effect accounted for much of the diabetes risk in these families, our experiment was powered to detect association. Using gene expression data on 21,677 transcripts for 643 pedigree members, we identified evidence for large-effect rare-variant cis-expression quantitative trait loci that could not be detected in population studies, validating our approach. However, we did not identify any rare variants of large effect associated with T2D, or the related traits of fasting glucose and insulin, suggesting that large-effect rare variants account for only a modest fraction of the genetic risk of these traits in this sample of families. Reliable identification of large-effect rare variants will require larger samples of extended pedigrees or different study designs that further enrich for such variants.


Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença/genética , Variação Genética , Americanos Mexicanos/genética , Diabetes Mellitus Tipo 2/etnologia , Diabetes Mellitus Tipo 2/patologia , Saúde da Família , Feminino , Frequência do Gene , Predisposição Genética para Doença/etnologia , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Linhagem , Fenótipo , Locos de Características Quantitativas/genética , Sequenciamento Completo do Genoma/métodos
15.
J Med Genet ; 55(3): 181-188, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29079706

RESUMO

BACKGROUND: Multiple single nucleotide polymorphisms (SNPs) have been associated with colorectal cancer (CRC) risk. The role of structural or copy number variants (CNV) in CRC, however, remained unclear. We investigated the role of CNVs in patients with sporadic CRC. METHODS: A genome-wide association study (GWAS) was performed on 1000 Singapore Chinese patients aged 50 years or more with no family history of CRC and 1000 ethnicity-matched, age-matched and gender-matched healthy controls using the Affymetrix SNP 6 platform. After 16 principal component corrections, univariate and multivariate segmentations followed by association testing were performed on 1830 samples that passed quality assurance tests. RESULTS: A rare CNV region (CNVR) at chromosome 14q11 (OR=1.92 (95% CI 1.59 to 2.32), p=2.7e-12) encompassing CHD8, and common CNVR at chromosomes 3q13.12 (OR=1.54 (95% CI 1.33 to 1.77), p=2.9e-9) and 12p12.3 (OR=1.69 (95% CI 1.41 to 2.01), p=2.8e-9) encompassing CD47 and RERG/ARHGDIB, respectively, were significantly associated with CRC risk. CNV loci were validated in an independent replication panel using an optimised copy number assay. Whole-genome expression data in matched tumours of a subset of cases demonstrated that copy number loss at CHD8 was significantly associated with dysregulation of several genes that perturb the Wnt, TP53 and inflammatory pathways. CONCLUSIONS: A rare CNVR at 14q11 encompassing the chromatin modifier CHD8 was significantly associated with sporadic CRC risk. Copy number loss at CHD8 altered expressions of genes implicated in colorectal tumourigenesis.

16.
PLoS One ; 12(11): e0185487, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29091727

RESUMO

The contemporary Japanese populations largely consist of three genetically distinct groups-Hondo, Ryukyu and Ainu. By principal-component analysis, while the three groups can be clearly separated, the Hondo people, comprising 99% of the Japanese, form one almost indistinguishable cluster. To understand fine-scale genetic structure, we applied powerful haplotype-based statistical methods to genome-wide single nucleotide polymorphism data from 1600 Japanese individuals, sampled from eight distinct regions in Japan. We then combined the Japanese data with 26 other Asian populations data to analyze the shared ancestry and genetic differentiation. We found that the Japanese could be separated into nine genetic clusters in our dataset, showing a marked concordance with geography; and that major components of ancestry profile of Japanese were from the Korean and Han Chinese clusters. We also detected and dated admixture in the Japanese. While genetic differentiation between Ryukyu and Hondo was suggested to be caused in part by positive selection, genetic differentiation among the Hondo clusters appeared to result principally from genetic drift. Notably, in Asians, we found the possibility that positive selection accentuated genetic differentiation among distant populations but attenuated genetic differentiation among close populations. These findings are significant for studies of human evolution and medical genetics.


Assuntos
Grupo com Ancestrais do Continente Asiático , Polimorfismo de Nucleotídeo Único , Estudo de Associação Genômica Ampla , Humanos , Japão , Família Multigênica
17.
Int J Epidemiol ; 46(6): 1891-1902, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29025108

RESUMO

Background: Dyslipidemia, particularly high-density lipoprotein cholesterol (HDL-C), has recently been implicated in the pathogenesis of age-related macular degeneration (AMD), the leading cause of vision loss. However, epidemiological studies have yielded conflicting results. Methods: We investigated the causal role of plasma lipid levels in AMD in multiethnic populations comprising 16 144 advanced AMD cases and 17 832 controls of European descent, together with 2219 cases and 5275 controls of Asian descent, using Mendelian randomization in three models. Model 1 is a conventional meta-analysis which does not account for pleiotropy of instrumental variable (IV) effects. Model 2 is a univariate, inverse variance weighted regression analysis that accounts for potential unbalanced pleiotropy using MR-Egger method. Finally, Model 3 is a multivariate regression analysis that addresses pleiotropy by MR-Egger method and by adjusting for effects on other lipid traits. Results: A 1 standard deviation (SD) higher HDL-cholesterol level was associated with an odds ratio (OR) for AMD of 1.17 (95% confidence interval: 1.07-1.29) in Europeans (P = 6.88 × 10-4) and of 1.58 (1.24-2.00) in Asians (P = 2.92 × 10-4) in Model 3. The corresponding OR estimates were 1.30 (1.09-1.55) in Europeans (P = 3.18 × 10-3) and 1.42 (1.11-1.80) in Asians (P = 4.42 × 10-3) in Model 1, and 1.21 (1.11-1.31) in Europeans (P = 3.12 × 10-5) and 1.51 (1.20-1.91) in Asians (P = 7.61 × 10-4) in Model 2. Conversely, neither LDL-C (Europeans: OR = 0.96, P = 0.272; Asians: OR = 1.02, P = 0.874; Model 3) nor triglyceride levels (Europeans: OR = 0.91, P = 0.102; Asians: OR = 1.06, P = 0.613) were associated with AMD. We also assessed the association between lipid levels and polypoidal choroidal vasculopathy (PCV) in Asians, a subtype of AMD, and found a similar trend for association of PCV with HDL-C levels. Conclusions: Our study shows that high levels of plasma HDL-C are causally associated with an increased risk for advanced AMD in European and Asian populations, implying that strategies reducing HDL-C levels may be useful to prevent and treat AMD.


Assuntos
HDL-Colesterol/sangue , Degeneração Macular/sangue , Degeneração Macular/genética , Análise da Randomização Mendeliana , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Fatores de Risco
18.
Nat Commun ; 8(1): 653, 2017 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-28935855

RESUMO

The Singapore Integrative Omics Study provides valuable insights on establishing population reference measurement in 364 Chinese, Malay, and Indian individuals. These measurements include > 2.5 millions genetic variants, 21,649 transcripts expression, 282 lipid species quantification, and 284 clinical, lifestyle, and dietary variables. This concept paper introduces the depth of the data resource, and investigates the extent of ethnic variation at these omics and non-omics biomarkers. It is evident that there are specific biomarkers in each of these platforms to differentiate between the ethnicities, and intra-population analyses suggest that Chinese and Indians are the most biologically homogeneous and heterogeneous, respectively, of the three groups. Consistent patterns of correlations between lipid species also suggest the possibility of lipid tagging to simplify future lipidomics assays. The Singapore Integrative Omics Study is expected to allow the characterization of intra-omic and inter-omic correlations within and across all three ethnic groups through a systems biology approach.The Singapore Genome Variation projects characterized the genetics of Singapore's Chinese, Malay, and Indian populations. The Singapore Integrative Omics Study introduced here goes further in providing multi-omic measurements in individuals from these populations, including genetic, transcriptome, lipidome, and lifestyle data, and will facilitate the study of common diseases in Asian communities.


Assuntos
Metabolismo dos Lipídeos , Metagenômica/normas , Polimorfismo de Nucleotídeo Único , Grupo com Ancestrais do Continente Asiático/genética , Dieta , Variação Genética , Humanos , Estilo de Vida , MicroRNAs , Variantes Farmacogenômicos , Análise de Componente Principal , Controle de Qualidade , Padrões de Referência , Singapura/etnologia
19.
J Hum Genet ; 62(12): 1049-1055, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28835638

RESUMO

Polypoidal choroidal vasculopathy (PCV), a subtype of age-related macular degeneration (AMD) more frequently seen in East Asians, has both common and distinct clinical manifestations with typical neovascular AMD (tAMD). We aim to examine the extent to which common genetic variants are shared between these two subtypes. We performed the meta-analysis of association in a total of 1062 PCV patients, 1157 tAMD patients and 5275 controls of East Asian descent from the Genetics of AMD in Asians Consortium at the 34 known AMD loci. A total of eight loci were significantly associated with PCV, including age-related maculopathy susceptibility 2 (ARMS2)-HtrA serine peptidase 1 (HTRA1), complement factor H (CFH), C2-CFB-SKIV2L, CETP, VEGFA, ADAMTS9-AS2 and TGFBR1 (P<5 × 10-4) from the single-nucleotide polymorphism-based test and COL4A3 from the gene-based tests (Pgene=2.02 × 10-4). PCV and tAMD are genetically highly correlated (rg=0.69, P=4.68 × 10-3), with AMD known loci accounting for up to 36% variation. Weaker association for PCV was observed at ARMS2-HTRA1 (Pdif=4.39 × 10-4) and KMT2E-SRPK2(Pdif=4.43 × 10-3), compared with tAMD. Variants at CFH, CETP and VEGFA exhibited different association signals in East Asians, in contrast to those in European individuals. Our data suggest a substantially shared genetic susceptibility for PCV and tAMD, while also highlight the unique associations for PCV, which is useful in understanding the pathogenesis of PCV.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Predisposição Genética para Doença , Variação Genética , Degeneração Macular/genética , Polimorfismo de Nucleotídeo Único/genética , Fator H do Complemento/genética , Loci Gênicos/genética , Humanos
20.
Clin Infect Dis ; 64(suppl_2): S68-S75, 2017 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-28475792

RESUMO

Background: Since 2010, the incidence of carbapenem-resistant Enterobacteriaceae (CRE) has been increasing in Singapore. We analyzed the clinical and molecular epidemiology of CRE among adult inpatients in Singapore. Methods: Quarterly incidence of unique subjects (per 100000 patient-days) with positive clinical and surveillance cultures for CRE were estimated based on mandatory data submitted to the National Public Health Laboratory by public hospitals between 2010 and 2015. CRE-positive adult inpatients were prospectively recruited from 6 public sector hospitals between December 2013 and April 2015. Subjects answered a standardized epidemiologic questionnaire and provided samples for this study. Further clinical information was extracted from subjects' electronic medical records. Whole-genome sequencing was performed on study isolates to determine transmission clusters. Results: Incidence of CRE clinical cultures among adult inpatients plateaued from 2013 (range: 7.73 to 10.32 per 100000 patient-days) following an initial increase between 2010 and end-2012. We prospectively recruited 249 subjects. Their median age was 65 years, 108 (43%) were female, and 161 (64.7%) had carbapenemase-producing Enterobacteriaceae (CPE). On multivariate analysis, prior carbapenem exposure (OR: 3.23; 95% CI: 1.67-6.25) and hematological malignancies (OR: 2.85; 95% CI: 1.10-7.41) were associated with non-carbapenemase-producing CRE (NCPE) (n = 88) compared with CPE (n = 161) subjects. Among 430 CRE isolates from the 249 subjects, 307(71.3%) were CPE, of which 154(50.2%) were blaKPC-positive, 97(31.6%) blaNDM-positive, and 42 (13.7%) blaOXA-positive. Klebsiella pneumoniae (n = 180, 41.9%), Escherichia coli (n = 129, 30.0%) and Enterobacter cloacae (n = 62, 14.4%) were the main Enterobacteriaceae species. WGS (n = 206) revealed diverse bacterial strain type (STs). The predominant blaKPC-positive plasmid was pHS102707 (n = 62, 55.4%) and the predominant blaNDM-positive plasmid was pNDM-ECS01 (n = 46, 48.9%). Five transmission clusters involving 13 subjects were detected. Conclusions: Clinical CRE trend among adult inpatients showed stabilization following a rapid rise since introduction in 2010 potentially due to infection prevention measures and antimicrobial stewardship. More work is needed on understanding CPE transmission dynamics.


Assuntos
Enterobacteriáceas Resistentes a Carbapenêmicos/genética , Infecção Hospitalar/epidemiologia , Infecções por Enterobacteriaceae/epidemiologia , Pacientes Internados , Adulto , Idoso , Antibacterianos/uso terapêutico , Enterobacteriáceas Resistentes a Carbapenêmicos/efeitos dos fármacos , Enterobacteriáceas Resistentes a Carbapenêmicos/isolamento & purificação , Carbapenêmicos/farmacologia , Carbapenêmicos/uso terapêutico , DNA Bacteriano/genética , Registros Eletrônicos de Saúde , Enterobacter cloacae/genética , Enterobacter cloacae/isolamento & purificação , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/transmissão , Escherichia coli/genética , Escherichia coli/isolamento & purificação , Infecções por Escherichia coli/epidemiologia , Feminino , Genoma Bacteriano , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Incidência , Infecções por Klebsiella/epidemiologia , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/isolamento & purificação , Masculino , Inquéritos e Questionários , Adulto Jovem , Resistência beta-Lactâmica , beta-Lactamases/biossíntese , beta-Lactamases/genética
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