Publications by authors named "E Shyong Tai"

598 Publications

Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes.

Nat Commun 2021 06 9;12(1):3505. Epub 2021 Jun 9.

Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias.
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http://dx.doi.org/10.1038/s41467-021-23556-4DOI Listing
June 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 Jun 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Decreased GLUT2 and glucose uptake contribute to insulin secretion defects in MODY3/HNF1A hiPSC-derived mutant β cells.

Nat Commun 2021 05 25;12(1):3133. Epub 2021 May 25.

Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.

Heterozygous HNF1A gene mutations can cause maturity onset diabetes of the young 3 (MODY3), characterized by insulin secretion defects. However, specific mechanisms of MODY3 in humans remain unclear due to lack of access to diseased human pancreatic cells. Here, we utilize MODY3 patient-derived human induced pluripotent stem cells (hiPSCs) to study the effect(s) of a causal HNF1A mutation on pancreatic function. Molecular dynamics simulations predict that the H126D mutation could compromise DNA binding and gene target transcription. Genome-wide RNA-Seq and ChIP-Seq analyses on MODY3 hiPSC-derived endocrine progenitors reveal numerous HNF1A gene targets affected by the mutation. We find decreased glucose transporter GLUT2 expression, which is associated with reduced glucose uptake and ATP production in the MODY3 hiPSC-derived β-like cells. Overall, our findings reveal the importance of HNF1A in regulating GLUT2 and several genes involved in insulin secretion that can account for the insulin secretory defect clinically observed in MODY3 patients.
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http://dx.doi.org/10.1038/s41467-021-22843-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149827PMC
May 2021

Emergency department visits among people with cancer: Frequency, symptoms, and characteristics.

J Am Coll Emerg Physicians Open 2021 Jun 1;2(3):e12438. Epub 2021 May 1.

Division of Cancer Prevention and Control National Center for Chronic Disease Prevention and Health Promotion Centers for Disease Control and Prevention Atlanta Georgia USA.

Objective: People with cancer are increasingly more likely to visit an emergency department for acute care than the general population. They often have long wait times and more exposure to infection and receive treatment from staff less experienced with cancer-related problems. Our objective was to examine emergency department (ED) visits among people with cancer to understand how often and why they seek care.

Methods: We conducted a retrospective study of ED visits using the National Syndromic Surveillance Program BioSense Platform. Cancer reported during an ED visit was identified using codes for any cancer type, including bladder, breast, cervical, colorectal, kidney, liver, lung, ovary, pancreas, prostate, or uterine cancers. Symptoms prompting the visit were identified for people with cancer who visited EDs in the United States from June 2017 to May 2018 in ≈4500 facilities, including 3000 EDs in 46 states and the District of Columbia (66% of all ED visits during a 1-year period).

Results: Of 97 million ED visits examined, 710,297 (0.8%) were among people with cancer. Percentages were higher among women (50.1%) than men (49.5%) and among adults aged ≥65 years (53.6%) than among those ≤64 years (45.7%). The most common presenting symptoms were pain (19.1%); gastrointestinal (13.8%), respiratory (11.5%), and neurologic (5.3%) complaints; fever (4.9%); injury (4.1%); and bleeding (2.4%). Symptom prevalence differed significantly by cancer type.

Conclusions: The Centers for Medicare & Medicaid Services encourages efforts to reduce acute care visits among people with cancer. We characterized almost 70% of ED visits among this population.
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http://dx.doi.org/10.1002/emp2.12438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087934PMC
June 2021

Plasma Metabolome and Lipidome Associations with Type 2 Diabetes and Diabetic Nephropathy.

Metabolites 2021 Apr 8;11(4). Epub 2021 Apr 8.

Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.

We conducted untargeted metabolomics analysis of plasma samples from a cross-sectional case-control study with 30 healthy controls, 30 patients with diabetes mellitus and normal renal function (DM-N), and 30 early diabetic nephropathy (DKD) patients using liquid chromatography-mass spectrometry (LC-MS). We employed two different modes of MS acquisition on a high-resolution MS instrument for identification and semi-quantification, and analyzed data using an advanced multivariate method for prioritizing differentially abundant metabolites. We obtained semi-quantification data for 1088 unique compounds (~55% lipids), excluding compounds that may be either exogenous compounds or treated as medication. Supervised classification analysis over a confounding-free partial correlation network shows that prostaglandins, phospholipids, nucleotides, sugars, and glycans are elevated in the DM-N and DKD patients, whereas glutamine, phenylacetylglutamine, 3-indoxyl sulfate, acetylphenylalanine, xanthine, dimethyluric acid, and asymmetric dimethylarginine are increased in DKD compared to DM-N. The data recapitulate the well-established plasma metabolome changes associated with DM-N and suggest uremic solutes and oxidative stress markers as the compounds indicating early renal function decline in DM patients.
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http://dx.doi.org/10.3390/metabo11040228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069978PMC
April 2021