Publications by authors named "Yongmei Liu"

401 Publications

Application of tetrahedral -deoxyribonucleic acid electrochemistry platform coupling aptazymes and hybridized hairpin reactions for the measurement of extracellular adenosine triphosphate in plants.

Anal Chim Acta 2021 Aug 24;1172:338681. Epub 2021 May 24.

Key Laboratory of Bioelectrochemistry & Environmental Analysis of Gansu Province, Northwest Normal University, Lanzhou, 730070, Gansu, China. Electronic address:

Extracellular ATP (eATP) is an important biological signal transduction molecule. Although a variety of detection methods have been extensively used in ATP sensing and analysis, accurate detection of eATP remains difficult due to its extremely low concentration and spatiotemporal distribution. Here, an eATP measurement strategy based on tetrahedral DNA (T-DNA)-modified electrode sensing platform and hybridization chain reaction (HCR) combined with G-quadruplex/Hemin (G4/Hemin) DNAzyme dual signal amplification is proposed. In this strategy, ATP aptamer and RNA-cleaving DNAzyme were combined to form a split aptazyme. In the presence of ATP, this aptazyme hydrolyzes the cleaving substrate strand with high selectivity, releasing cleaved ssDNA, which are captured by the T-DNA assembled on the electrode surface, triggering an HCR on the electrode surface to form numerous linker sequences of the HCR dsDNA product. When [email protected] (G4) spherical nucleic acid enzymes (SNAzymes) with other linkers are used as nanocatalyst tags, they are captured by HCR dsDNA through sticky linkers present on the electrode surface. An amplified electrochemical redox current signal is generated through SNAzyme-mediated catalysis of HO, enabling easy detection of picomole amounts of ATP. Using this strategy, eATP levels released by tobacco suspension cells were accurately measured and the distribution and concentration of eATP released on the surface of an Arabidopsis leaf was determined.
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http://dx.doi.org/10.1016/j.aca.2021.338681DOI Listing
August 2021

Clonal hematopoiesis associated with epigenetic aging and clinical outcomes.

Aging Cell 2021 Jun 29;20(6):e13366. Epub 2021 May 29.

Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA.

Clonal hematopoiesis of indeterminate potential (CHIP) is a common precursor state for blood cancers that most frequently occurs due to mutations in the DNA-methylation modifying enzymes DNMT3A or TET2. We used DNA-methylation array and whole-genome sequencing data from four cohorts together comprising 5522 persons to study the association between CHIP, epigenetic clocks, and health outcomes. CHIP was strongly associated with epigenetic age acceleration, defined as the residual after regressing epigenetic clock age on chronological age, in several clocks, ranging from 1.31 years (GrimAge, p < 8.6 × 10 ) to 3.08 years (EEAA, p < 3.7 × 10 ). Mutations in most CHIP genes except DNA-damage response genes were associated with increases in several measures of age acceleration. CHIP carriers with mutations in multiple genes had the largest increases in age acceleration and decrease in estimated telomere length. Finally, we found that ~40% of CHIP carriers had acceleration >0 in both Hannum and GrimAge (referred to as AgeAccelHG+). This group was at high risk of all-cause mortality (hazard ratio 2.90, p < 4.1 × 10 ) and coronary heart disease (CHD) (hazard ratio 3.24, p < 9.3 × 10 ) compared to those who were CHIP-/AgeAccelHG-. In contrast, the other ~60% of CHIP carriers who were AgeAccelHG- were not at increased risk of these outcomes. In summary, CHIP is strongly linked to age acceleration in multiple clocks, and the combination of CHIP and epigenetic aging may be used to identify a population at high risk for adverse outcomes and who may be a target for clinical interventions.
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http://dx.doi.org/10.1111/acel.13366DOI Listing
June 2021

The SUN1-SPDYA interaction plays an essential role in meiosis prophase I.

Nat Commun 2021 05 26;12(1):3176. Epub 2021 May 26.

Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Chromosomes pair and synapse with their homologous partners to segregate correctly at the first meiotic division. Association of telomeres with the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex composed of SUN1 and KASH5 enables telomere-led chromosome movements and telomere bouquet formation, facilitating precise pairwise alignment of homologs. Here, we identify a direct interaction between SUN1 and Speedy A (SPDYA) and determine the crystal structure of human SUN1-SPDYA-CDK2 ternary complex. Analysis of meiosis prophase I process in SPDYA-binding-deficient SUN1 mutant mice reveals that the SUN1-SPDYA interaction is required for the telomere-LINC complex connection and the assembly of a ring-shaped telomere supramolecular architecture at the nuclear envelope, which is critical for efficient homologous pairing and synapsis. Overall, our results provide structural insights into meiotic telomere structure that is essential for meiotic prophase I progression.
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http://dx.doi.org/10.1038/s41467-021-23550-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155084PMC
May 2021

Benchmarking association analyses of continuous exposures with RNA-seq in observational studies.

Brief Bioinform 2021 May 20. Epub 2021 May 20.

Harbor-UCLA Medical Center at the Lundquist Institute, USA.

Large datasets of hundreds to thousands of individuals measuring RNA-seq in observational studies are becoming available. Many popular software packages for analysis of RNA-seq data were constructed to study differences in expression signatures in an experimental design with well-defined conditions (exposures). In contrast, observational studies may have varying levels of confounding transcript-exposure associations; further, exposure measures may vary from discrete (exposed, yes/no) to continuous (levels of exposure), with non-normal distributions of exposure. We compare popular software for gene expression-DESeq2, edgeR and limma-as well as linear regression-based analyses for studying the association of continuous exposures with RNA-seq. We developed a computation pipeline that includes transformation, filtering and generation of empirical null distribution of association P-values, and we apply the pipeline to compute empirical P-values with multiple testing correction. We employ a resampling approach that allows for assessment of false positive detection across methods, power comparison and the computation of quantile empirical P-values. The results suggest that linear regression methods are substantially faster with better control of false detections than other methods, even with the resampling method to compute empirical P-values. We provide the proposed pipeline with fast algorithms in an R package Olivia, and implemented it to study the associations of measures of sleep disordered breathing with RNA-seq in peripheral blood mononuclear cells in participants from the Multi-Ethnic Study of Atherosclerosis.
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http://dx.doi.org/10.1093/bib/bbab194DOI Listing
May 2021

Influence Mechanism of the Affordances of Chronic Disease Management Apps on Continuance Intention: Questionnaire Study.

JMIR Mhealth Uhealth 2021 05 13;9(5):e21831. Epub 2021 May 13.

Business School of Central South University, Changsha City, China.

Background: Mobile health apps are becoming increasingly popular, and they provide opportunities for effective health management. Existing chronic disease management (CDM) apps cannot meet users' practical and urgent needs, and user adhesion is poor. Few studies, however, have investigated the factors that influence the continuance intention of CDM app users.

Objective: Starting from the affordances of CDM apps, this study aimed to analyze how such apps can influence continuance intention through the role of health empowerment.

Methods: Adopting a stimulus-organism-response framework, an antecedent model was established for continuance intention from the perspective of perceived affordances, uses and gratifications theory, and health empowerment. Perceived affordances were used as the "stimulus," users' gratifications and health empowerment were used as the "organism," and continuance intention was used as the "response." Data were collected online through a well-known questionnaire survey platform in China, and 323 valid questionnaires were obtained. The theoretical model was tested using structural equation modeling.

Results: Perceived connection affordances were found to have significant positive effects on social interactivity gratification (t=6.201, P<.001) and informativeness gratification (t=5.068, P<.001). Perceived utilitarian affordances had significant positive effects on informativeness gratification (t=7.029, P<.001), technology gratification (t=8.404, P<.001), and function gratification (t=9.812, P<.001). Perceived hedonic affordances had significant positive effects on function gratification (t=5.305, P<.001) and enjoyment gratification (t=13.768, P<.001). Five gratifications (t=2.767, P=.005; t=4.632, P<.001; t=7.608, P<.001; t=2.496, P=.012; t=5.088, P<.001) had significant positive effects on health empowerment. Social interactivity gratification, informativeness gratification, and function gratification had significant positive effects on continuance intention. Technology gratification and enjoyment gratification did not have a significant effect on continuance intention. Health empowerment had a significant positive effect on continuance intention. Health empowerment and gratifications play mediating roles in the influence of affordances on continuance intention.

Conclusions: Health empowerment and gratifications of users' needs are effective ways to promote continuance intention. The gratifications of users' needs can realize health empowerment and then inspire continuance intention. Affordances are key antecedents that affect gratifications of users' needs, health empowerment, and continuance intention.
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http://dx.doi.org/10.2196/21831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160810PMC
May 2021

Transcriptome prediction performance across machine learning models and diverse ancestries.

HGG Adv 2021 Apr 5;2(2). Epub 2021 Jan 5.

Program in Bioinformatics, Loyola University Chicago, Chicago, IL, USA.

Transcriptome prediction methods such as PrediXcan and FUSION have become popular in complex trait mapping. Most transcriptome prediction models have been trained in European populations using methods that make parametric linear assumptions like the elastic net (EN). To potentially further optimize imputation performance of gene expression across global populations, we built transcriptome prediction models using both linear and non-linear machine learning (ML) algorithms and evaluated their performance in comparison to EN. We trained models using genotype and blood monocyte transcriptome data from the Multi-Ethnic Study of Atherosclerosis (MESA) comprising individuals of African, Hispanic, and European ancestries and tested them using genotype and whole-blood transcriptome data from the Modeling the Epidemiology Transition Study (METS) comprising individuals of African ancestries. We show that the prediction performance is highest when the training and the testing population share similar ancestries regardless of the prediction algorithm used. While EN generally outperformed random forest (RF), support vector regression (SVR), and K nearest neighbor (KNN), we found that RF outperformed EN for some genes, particularly between disparate ancestries, suggesting potential robustness and reduced variability of RF imputation performance across global populations. When applied to a high-density lipoprotein (HDL) phenotype, we show including RF prediction models in PrediXcan revealed potential gene associations missed by EN models. Therefore, by integrating other ML modeling into PrediXcan and diversifying our training populations to include more global ancestries, we may uncover new genes associated with complex traits.
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http://dx.doi.org/10.1016/j.xhgg.2020.100019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087249PMC
April 2021

Epigenome-wide association study of kidney function identifies trans-ethnic and ethnic-specific loci.

Genome Med 2021 Apr 30;13(1):74. Epub 2021 Apr 30.

Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.

Background: DNA methylation (DNAm) is associated with gene regulation and estimated glomerular filtration rate (eGFR), a measure of kidney function. Decreased eGFR is more common among US Hispanics and African Americans. The causes for this are poorly understood. We aimed to identify trans-ethnic and ethnic-specific differentially methylated positions (DMPs) associated with eGFR using an agnostic, genome-wide approach.

Methods: The study included up to 5428 participants from multi-ethnic studies for discovery and 8109 participants for replication. We tested the associations between whole blood DNAm and eGFR using beta values from Illumina 450K or EPIC arrays. Ethnicity-stratified analyses were performed using linear mixed models adjusting for age, sex, smoking, and study-specific and technical variables. Summary results were meta-analyzed within and across ethnicities. Findings were assessed using integrative epigenomics methods and pathway analyses.

Results: We identified 93 DMPs associated with eGFR at an FDR of 0.05 and replicated 13 and 1 DMPs across independent samples in trans-ethnic and African American meta-analyses, respectively. The study also validated 6 previously published DMPs. Identified DMPs showed significant overlap enrichment with DNase I hypersensitive sites in kidney tissue, sites associated with the expression of proximal genes, and transcription factor motifs and pathways associated with kidney tissue and kidney development.

Conclusions: We uncovered trans-ethnic and ethnic-specific DMPs associated with eGFR, including DMPs enriched in regulatory elements in kidney tissue and pathways related to kidney development. These findings shed light on epigenetic mechanisms associated with kidney function, bridging the gap between population-specific eGFR-associated DNAm and tissue-specific regulatory context.
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http://dx.doi.org/10.1186/s13073-021-00877-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088054PMC
April 2021

Development and validation of a nomogram for assessing survival in extensive-stage small-cell lung cancer patients with superior vena cava syndrome referred for thoracic radiotherapy: a comparison of upfront vs. consolidative approaches.

Strahlenther Onkol 2021 Apr 28. Epub 2021 Apr 28.

Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 610041, Chengdu, China.

Purpose: This study sought to design and validate a nomogram capable of predicting outcomes in extensive-stage small-cell lung cancer (ES-SCLC) patients with superior vena cava syndrome (SVCS) based upon the timing of their radiotherapy treatment.

Methods: We retrospectively analyzed data from 175 ES-SCLC patients with SCVS, comparing outcomes between those that underwent upfront thoracic radiotherapy (initial radiotherapy with simultaneous chemotherapy) and those that underwent consolidative thoracic radiotherapy (following 4-6 cycles of chemotherapy). Significant predictors of patient outcomes were identified using a Cox proportional hazard model and were used to construct our nomogram. This model was subsequently validated using receiver operating characteristic (ROC) curves, concordance index (C-index) values, and a risk classification system in order to evaluate its discriminative and predictive accuracy.

Results: The overall survival (OS) of ES-SCLC patients with SVCS that underwent chemotherapy (CT), consolidative thoracic radiotherapy (cc-TRT), and upfront thoracic radiotherapy (cu-TRT) was 8.2, 11.7, and 14.9 months, respectively (p < 0.001), with respective progression-free survival (PFS) durations of 3.3, 5.0, and 7.3 months (p < 0.001). A multivariate regression analysis revealed age, gender, ECOG performance status, sites of tumor metastasis, and treatment approach to all be independent predictors of survival outcomes. A nomogram was therefore developed incorporating these factors. C‑index values upon internal and external validation of this nomogram were 0.7625 and 0.7959, respectively, and ROC and calibration curves revealed this model to be accurate and consistent.

Conclusions: We found that upfront thoracic radiotherapy in combination with chemotherapy may be associated with a positive impact on outcomes in ES-SCLC patients with SVCS.
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http://dx.doi.org/10.1007/s00066-021-01783-4DOI Listing
April 2021

Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure.

Mol Psychiatry 2021 Apr 15. Epub 2021 Apr 15.

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

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P < 5 × 10), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P < 5 × 10). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P = 2 × 10). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (P < 10). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.
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http://dx.doi.org/10.1038/s41380-021-01087-0DOI Listing
April 2021

Epigenome-wide analysis of long-term air pollution exposure and DNA methylation in monocytes: results from the Multi-Ethnic Study of Atherosclerosis.

Epigenetics 2021 Apr 5:1-17. Epub 2021 Apr 5.

Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington, USA.

Air pollution might affect atherosclerosis through DNA methylation changes in cells crucial to atherosclerosis, such as monocytes. We conducted an epigenome-wide study of DNA methylation in CD14+ monocytes and long-term ambient air pollution exposure in adults participating in the Multi-Ethnic Study of Atherosclerosis (MESA). We also assessed the association between differentially methylated signals and -gene expression. Using spatiotemporal models, one-year average concentrations of outdoor fine particulate matter (PM) and oxides of nitrogen (NO) were estimated at participants' homes. We assessed DNA methylation and gene expression using Illumina 450k and HumanHT-12 v4 Expression BeadChips, respectively (n = 1,207). We used bump hunting and site-specific approaches to identify differentially methylated signals (false discovery rate of 0.05) and used linear models to assess associations between differentially methylated signals and -gene expression. Four differentially methylated regions (DMRs) located on chromosomes 5, 6, 7, and 16 (within or near , and , respectively) were associated with PM. The DMRs on chromosomes 5 and 6 also associated with NO. The DMR on chromosome 5 had the smallest p-value for both PM (p = 1.4×10) and NO (p = 7.7×10). Three differentially methylated CpGs were identified for PM, and cg05926640 (near ) had the smallest p-value (p = 5.6×10). NO significantly associated with cg11756214 within (p = 5.6×10). Several differentially methylated signals were also associated with -gene expression. The DMR located on chromosome 7 was associated with the expression of , and . The DMRs located on chromosomes 5 and 16 were associated with expression of and , respectively. The CpG cg05926640 was associated with expression of , and . We identified differential DNA methylation in monocytes associated with long-term air pollution exposure. Methylation signals associated with gene expression might help explain how air pollution contributes to cardiovascular disease.
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http://dx.doi.org/10.1080/15592294.2021.1900028DOI Listing
April 2021

Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.

Am J Hum Genet 2021 04 12;108(4):564-582. Epub 2021 Mar 12.

The Charles R. Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.
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http://dx.doi.org/10.1016/j.ajhg.2021.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059339PMC
April 2021

Integrative proteomic and lipidomic analysis of Kaili Sour Soup-mediated attenuation of high-fat diet-induced nonalcoholic fatty liver disease in a rat model.

Nutr Metab (Lond) 2021 Mar 10;18(1):26. Epub 2021 Mar 10.

Department of Infectious Diseases, Affiliated Hospital of Guizhou Medical University, 28 Guiyi Street, Guiyang City, 550004, Guizhou Province, China.

Background: Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease and is characterized by excessive fat accumulation. Kaili Sour Soup, a food typical of Guizhou Province, is believed to have significant health benefits. Thus, we aimed to identify and assess the impact of Kaili Sour Soup on NAFLD and its underlying mechanism using integrative proteomic and lipidomic analysis.

Methods: A high-fat diet and male Wistar rats were used to construct a NAFLD rat model. Haematoxylin and eosin (HE) and Oil Red O staining analyses were used to perform the histologic examination. Proteomic analysis was utilized to systematically identify the global protein profile in NAFLD with and without Kaili Sour Soup treatment. Western blot assays were used to verify the expression of proteins screened by proteomic analysis. Lipidomic analysis was performed to screen lipid metabolism in NAFLD with and without Kaili Sour Soup treatment.

Results: Kaili Sour Soup alleviated high-fat diet (HFD)-induced fatty liver and had a normalizing effect on physiological and biochemical indicators of NAFLD, including body weight, liver weight, liver index, total cholesterol (TC), triglyceride (TG), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and insulin resistance level of homeostasis model assessment (HOMA-IR). Kaili Sour Soup decreased the levels of 13 proteins (Tmem44, Rnaseh2b, Gstm6l, LOC100910877, Rufy4, Slc12a2, Pcif1, P4503A1, Sult1e1, Nop53, AABR07065656.4, AABR07065789.3) that were upregulated by HFD and increased the levels of 3 proteins (Sult1c2, Sult1c2a, Snrnp48) that were downregulated by HFD. Kaili Sour Soup attenuated the HFD-induced increase in acyl carnitine (AcCa) and enhanced the HFD-induced decreases in gangliosides (GM3) and lysophosphatidylserine (LPS) in the NAFLD rat model.

Conclusions: Altogether, this study revealed that Kaili Sour Soup attenuated HFD-induced fatty liver and systematically identified abnormal proteins and lipids involved in the role of Kaili Sour Soup in a NAFLD rat model.
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http://dx.doi.org/10.1186/s12986-021-00553-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7945315PMC
March 2021

End to end intussusception anastomosis decreases the risk of anastomotic leakage after neoadjvant chemoradiation and McKeown oesophagectomy.

Radiother Oncol 2021 05 1;158:285-292. Epub 2021 Mar 1.

Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, PR China. Electronic address:

Background And Purpose: To investigate the relationship between the radiation dose to the anastomotic region and postoperative anastomotic leakage rates after McKeown oesophagectomy with cervical anastomosis.

Materials And Methods: Between January 2017 and December 2019, 164 consecutive patients undergoing trimodal therapy including neoadjuvant chemoradiotherapy and sequential McKeown oesophagectomy were included. The demographic and clinical patient data were collected. Additionally, the radiation dose to the regions including the mediastinum, airway, gastric fundus and anastomotic region was recalculated.

Results: Twelve patients presented with anastomotic leakage, accounting for 7.3% (12/164) of the cohort. The anastomoses were located in the radiation field for all patients with anastomotic leakage (12/12, 100%), and for 61.8% (94/152) of those without (P = 0.009). Higher radiation doses, including the D50 and the mean, maximal and minimal doses to the oesophageal anastomotic region were found in the anastomotic leak group. Subgroup analysis between patients with end to end (ETE) anastomosis and ETE intussusception anastomosis revealed a lower anastomotic leakage rate in the latter after 1:1 ratio propensity score-matching (10.4% vs. 1.3%, P = 0.034).

Conclusion: Anastomosis location in the radiation field and a higher radiation dose to the oesophageal anastomotic region were associated with the occurrence of anastomotic leakage after trimodal therapy. Compared with ETE anastomosis, ETE intussusception anastomosis might reduce the occurrence of anastomotic leakage after neoadjuvant chemoradiation and subsequent McKeown oesophagectomy.
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http://dx.doi.org/10.1016/j.radonc.2021.02.030DOI Listing
May 2021

Exosomal circRNAs as novel cancer biomarkers: Challenges and opportunities.

Int J Biol Sci 2021 14;17(2):562-573. Epub 2021 Jan 14.

Department of Inspection, The medical faculty of Qingdao University, Qingdao 266003, China.

Identifying high specificity and sensitivity biomarkers has always been the focus of research in the field of non-invasive cancer diagnosis. Exosomes are extracellular vesicles with a lipid bilayer membrane that can be released by all types of cells, which contain a variety of proteins, lipids, and a variety of non-coding RNAs. Increasing research has shown that the lipid bilayer can effectively protect the nucleic acid in exosomes. In cancers, tumor cell-derived exosomal circRNAs can act on target cells or organs through the transport of exosomes, and then participate in the regulation of tumor development and metastasis. Since exosomes exist in various body fluids and circRNAs in exosomes exhibit high stability, exosomal circRNAs have the potential as biomarkers for early and minimally invasive cancer diagnosis and prognosis judgment. In this review, we summarized circRNAs and their biological roles in cancers, with the emerging value biomarkers in cancer diagnosis, disease judgment, and prognosis observation. In addition, we briefly compared the advantages of exosomal circRNAs as biomarkers and the current obstacles in the exosome isolation technology, shed light to the future development of this technology.
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http://dx.doi.org/10.7150/ijbs.48782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893596PMC
January 2021

Genome-wide association study of circulating interleukin 6 levels identifies novel loci.

Hum Mol Genet 2021 Apr;30(5):393-409

Institute of Cardiovascular Science, University College London, London WC1E 6BT, UK.

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.
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http://dx.doi.org/10.1093/hmg/ddab023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098112PMC
April 2021

Changes of Brain Structure in Patients With Metastatic Non-Small Cell Lung Cancer After Long-Term Target Therapy With EGFR-TKI.

Front Oncol 2020 6;10:573512. Epub 2021 Jan 6.

Department of Thoracic Oncology and State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.

Purpose: Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy is the routine treatment for patients with metastatic non-small cell lung cancer (NSCLC) harboring positive EGFR mutations. Patients who undergo such treatment have reported cognitive decline during follow-up. This study, therefore, aimed to evaluate brain structural changes in patients receiving EGFR-TKI to increase understanding of this potential symptom.

Method: The medical records of 75 patients with metastatic NSCLC (without brain metastasis or other co-morbidities) who received EGFR-TKI therapy from 2010 to 2017 were reviewed. The modified Scheltens Visual Scale and voxel-based morphometry were used to evaluate changes in white matter lesions (WML) and gray matter volume (GMV), respectively.

Results: The WML scores were higher at the 12-month [8.65 ± 3.86; 95% confidence interval (CI), 1.60-2.35; p < 0.001] and 24-month follow-ups (10.11 ± 3.85; 95% CI, 2.98-3.87; p < 0.001) compared to baseline (6.68 ± 3.64). At the 24-month follow-up, the visual scores were also significantly higher in younger patients (3.89 ± 2.04) than in older patients (3.00 ± 1.78; p = 0.047) and higher in female patients (3.80 ± 2.04) than in male patients (2.73 ± 1.56; p = 0.023). Additionally, significant GMV loss was observed in sub-regions of the right occipital lobe (76.71 voxels; 95% CI, 40.740-112.69 voxels), left occipital lobe (93.48 voxels; 95% CI, 37.48-149.47 voxels), and left basal ganglia (37.57 voxels; 95% CI, 21.58-53.57 voxels) (all p < 0.005; cluster-level false discovery rate < 0.05).

Conclusions: An increase in WMLs and loss of GMV were observed in patients with metastatic NSCLC undergoing long-term EGFR-TKI treatment. This might reflect an unknown side-effect of EGFR-TKI treatment. Further prospective studies are necessary to confirm our findings.
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http://dx.doi.org/10.3389/fonc.2020.573512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815525PMC
January 2021

Fecal transplantation alleviates acute liver injury in mice through regulating Treg/Th17 cytokines balance.

Sci Rep 2021 Jan 15;11(1):1611. Epub 2021 Jan 15.

Department of Infectious Diseases, The Affiliated Hospital of Guizhou Medical University, No. 28 Guiyang Street, Guiyang, 550002, Guizhou, China.

Changes in intestinal microecology during acute liver failure (ALF) directly affect the occurrence and development of the disease. The study aimed to investigate the relationship between the intestinal microbiota and the key immune cells. Fecal microbiota transplantation (FMT) was used to determine whether ALF can balance Th17/Treg cytokines. The relationship between gut microbiota and clinical indicators was analyzed. BALB/c mice were treated with D-galactosamine (D-GalN) to induce a murine ALF model. FMT to D-GalN mice was conducted to test for liver function indicators. Results showed that the proportions of Lachnospiraceae, Prevotella, S24-7, Odoribacter and Rikenellaceae in D-GalN mice with intestinal microbiota disorder were restored after FMT. Further, CIA analysis showed that bacteria had a covariant relationship with clinical indicators. Microbiota could account for changes in 49.9% of the overall clinical indicators. Adonis analysis showed that Ruminococcus, and Enterococcus have a greater impact on clinical indicators. FMT down-regulated the expression of IL-17A, TNF-α, and TGF-β, while up-regulated IL-10 and IL-22. Transplantation of feces from Saccharomyces boulardii donor mice improved GalN-induced liver damage. These findings indicate that FMT attenuates D-GalN-induced liver damage in mice, and a clinical trial is required to validate the relevance of our findings in humans, and to test whether this therapeutic approach is effective for patients with ALF.
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http://dx.doi.org/10.1038/s41598-021-81263-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810881PMC
January 2021

Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.

Nat Commun 2021 01 5;12(1):24. Epub 2021 Jan 5.

Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA.

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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http://dx.doi.org/10.1038/s41467-020-19366-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785747PMC
January 2021

Effects of Danlou tablet for the treatment of stable angina pectoris: A study protocol of a randomized, double-blind, and placebo-controlled clinical trial.

Medicine (Baltimore) 2020 Dec;99(49):e23416

Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences.

Introduction: Stable angina pectoris has a high prevalence and causes serious harm. Revascularization therapy can relieve angina pectoris to some extent, but it is not widely accepted in China due to the cost and secondary events. The Chinese proprietary medicine Danlou tablet has been widely used to treat angina pectoris, but previous trials had inadequate methodologies. In this study, we aim to conduct a randomized controlled trial to evaluate its efficacy and safety on stable angina.

Methods And Analysis: This study is a WeChat-based randomized, double-blind, and placebo-controlled clinical trial in China. Eligible participants are adults (aged 30-75 years) with CT-confirmed stable angina and traditional Chinese medicine-diagnosed intermingled phlegm and blood stasis syndrome. A total of 76 participants will be randomly allocated in a 1:1 ratio to the oral Danlou tablet group (1.5 mg a time, 3 times daily for 28 days) or the placebo group. Patients are permitted concomitant use of routine medications during these 28 days. The primary outcome is angina frequency per week. The secondary outcomes include angina severity, angina duration, traditional Chinese medicine efficacy, the withdrawal rate of emergency medications, blood lipids, and electrocardiograph efficacy. The WeChat app will be used to remind patients to take their medicines and fill out the forms. All data will be recorded in case report forms and analyzed by Statistical Analysis System software.

Ethics And Dissemination: This study has been approved by the Ethics Committee of Guang'anmen Hospital, China Academy of Chinese Medical Sciences in Beijing, China (No. 2019-225-KY).

Trial Registration Number: ClinicalTrials.gov, ID: ChiCTR1900028068.
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http://dx.doi.org/10.1097/MD.0000000000023416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717752PMC
December 2020

Risk factors for symptomatic radiation pneumonitis after stereotactic body radiation therapy (SBRT) in patients with non-small cell lung cancer.

Radiother Oncol 2021 03 21;156:231-238. Epub 2020 Oct 21.

Department of Radiation Oncology, University Hospitals/Seidman Cancer Center and Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, USA; Department of Clinical Oncology, Hong Kong University Shenzhen Hospital, and Hong Kong University, Hong Kong, China. Electronic address:

Background And Purpose: Radiation pneumonitis (RP) can be a potential fatal toxicity of stereotactic body radiation therapy (SBRT) for medically inoperable non-small cell lung cancer (NSCLC). This study aimed to examine the risk factors that predict RP and explore dosimetric tolerance for safe practice in a large institutional series of NSCLC patients.

Materials And Methods: Patients with early-stage and locally recurrent NSCLC who received lung SBRT between 2002 and 2015 formed the study population. The primary endpoint was grade 2 or above radiation pneumonitis (RP2). Lungs were re-contoured consistently by one radiation oncologist according to the RTOG atlas for organs at risk. Dosimetric factors were computed consistently with exclusion of gross tumor volume of either ipsilateral, contralateral, or total lungs.

Results: A total of 339 patients were eligible. With a median follow-up of 47 months, RP2 was recorded in 10% patients. History of respiratory comorbidity, previous thoracic radiation, right lung location, mean lung doses of total or ipsilateral lung, and total lung volume receiving 20 Gy were all significantly associated with the risk of RP2. The dosimetric parameters of contralateral lung, including mean dose and volume receiving more than 5, 10, and 20 Gy, were not significantly associated with RP2 (ps > 0.05). A model of combining significant clinical and dosimetric factors had a predictive accuracy AUC of 0.76. According to this model, RP2 can be limited to <10% should the patient have no previous lung radiation and the mean dose of total and ipsilateral lungs be kept less than 6 Gy and 20 Gy, respectively.

Conclusion: Dosimetric factors of total or ipsilateral lung together with important clinical factors were significant risk factors for symptomatic radiation pneumonitis after SBRT. Constraining mean lung dose can limit clinically significant lung toxicity.
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http://dx.doi.org/10.1016/j.radonc.2020.10.015DOI Listing
March 2021

Role of Antiangiogenic Agents Combined With EGFR Tyrosine Kinase Inhibitors in Treatment-naive Lung Cancer: A Meta-Analysis.

Clin Lung Cancer 2021 Jan 18;22(1):e70-e83. Epub 2020 Sep 18.

Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.

Background: Antiangiogenic agents combined with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are considered potentially effective biologically synergistic drug combinations for EGFR-mutant advanced non-small-cell lung cancer (NSCLC), although some controversy remains. The European Commission has approved the use of bevacizumab plus erlotinib as first-line treatment of EGFR-mutated NSCLC; however, it has not yet been approved by the U.S. Food and Drug Administration. Recently, several phase III, randomized controlled trials of combinations of antiangiogenic agents and EGFR-TKIs have been reported. These studies have not yet been included in any previous meta-analysis.

Materials And Methods: We performed a meta-analysis to compare antiangiogenic agents plus EGFR-TKIs versus EGFR-TKIs alone for treatment of EGFR-mutant NSCLC. The main outcomes were progression-free survival (PFS), overall survival (OS), the objective response rate (ORR), and adverse events (AEs).

Results: We identified 9 previous reports of 6 randomized controlled trials and 1 prospective cohort study, involving 1295 patients. Compared with EGFR-TKIs alone, antiangiogenic agents plus EGFR-TKIs resulted in a higher PFS (hazard ratio, 0.58; 95% confidence interval [CI], 0.50-0.67; P < .001). However, no significant differences in OS (hazard ratio, 0.79; 95% CI, 0.53-1.18; P = .26) and ORR (risk ratio, 1.03; 95% CI, 0.97-1.10; P = .30) were found between the 2 groups. An increased risk of serious AEs (risk ratio, 1.41; 95% CI, 1.11-1.79; P = .005) was found in the combination drug therapy group.

Conclusions: Antiangiogenic agents plus EGFR-TKIs enhanced PFS for patients with EGFR-mutant NSCLC but with a greater risk of serious AEs. No significant benefits for OS and ORR were found between the 2 groups.
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http://dx.doi.org/10.1016/j.cllc.2020.08.005DOI Listing
January 2021

Inherited causes of clonal haematopoiesis in 97,691 whole genomes.

Nature 2020 10 14;586(7831):763-768. Epub 2020 Oct 14.

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.
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http://dx.doi.org/10.1038/s41586-020-2819-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944936PMC
October 2020

Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants.

Nat Commun 2020 10 14;11(1):5182. Epub 2020 Oct 14.

The Institute for Translational Genomics and Population Sciences, The Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA.

Chronic obstructive pulmonary disease (COPD), diagnosed by reduced lung function, is a leading cause of morbidity and mortality. We performed whole genome sequence (WGS) analysis of lung function and COPD in a multi-ethnic sample of 11,497 participants from population- and family-based studies, and 8499 individuals from COPD-enriched studies in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We identify at genome-wide significance 10 known GWAS loci and 22 distinct, previously unreported loci, including two common variant signals from stratified analysis of African Americans. Four novel common variants within the regions of PIAS1, RGN (two variants) and FTO show evidence of replication in the UK Biobank (European ancestry n ~ 320,000), while colocalization analyses leveraging multi-omic data from GTEx and TOPMed identify potential molecular mechanisms underlying four of the 22 novel loci. Our study demonstrates the value of performing WGS analyses and multi-omic follow-up in cohorts of diverse ancestry.
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http://dx.doi.org/10.1038/s41467-020-18334-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598941PMC
October 2020

Applicability of the adjusted graded prognostic assessment for lung cancer with brain metastases using molecular markers (Lung-molGPA) in a Chinese cohort: A retrospective study of multiple institutions.

Cancer Med 2020 12 7;9(23):8772-8781. Epub 2020 Oct 7.

Department of Thoracic Oncology, Cancer Centre, Sichuan University West China Hospital, Chengdu, Sichuan, P.R. China.

Background: In this era of precision medicine, prognostic heterogeneity is an important feature of patients with non-small cell lung cancer (NSCLC) with brain metastases (BM). This multi-institutional study is aimed to verify the applicability of the adjusted Lung-molGPA model for NSCLC with BM in a Chinese cohort.

Methods: This retrospective study included 1903 patients at three hospitals in Southwest China. The performance of the Lung-molGPA model was compared with that of the adjusted DS-GPA model in terms of estimating the survival of NSCLC with BM.

Results: The median OS of this patient cohort was 27.0 months, and the adenocarcinoma survived longer than the non-adenocarcinoma (28.0 months vs 18.7 months, p < 0.001). The adjusted Lung-molGPA model was more accurate in predicting survival of adenocarcinoma patients than the adjusted DS-GPA model (C-index: 0.615 vs 0.571), and it was not suitable for predicting survival of non-adenocarcinoma patients (p = 0.286, 1.5-2.0 vs 2.5-3.0; p = 0.410, 2.5-3.0 vs 3.5-4.0).

Conclusions: The adjusted Lung-molGPA model is better than the DS-GPA model in predicting the prognosis of adenocarcinoma patients. However, it failed to estimate the prognosis for non-adenocarcinoma patients.
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http://dx.doi.org/10.1002/cam4.3485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724493PMC
December 2020

PD-L1 expression is a promising predictor of survival in patients with advanced lung adenocarcinoma undergoing pemetrexed maintenance therapy.

Sci Rep 2020 09 30;10(1):16150. Epub 2020 Sep 30.

Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China.

This study aimed to identify potential predictive factors for the survival of advanced lung adenocarcinoma patients undergoing pemetrexed maintenance therapy. 122 advanced lung adenocarcinoma patients who received pemetrexed maintenance therapy were retrospectively analyzed. Kaplan-Meier method with Log-rank test was used for survival analysis. Univariate and multivariate Cox regression were performed to evaluate prognostic factors for overall survival (OS) and progression-free survival (PFS). Bivariate correlation analysis was used for exploratory purpose. For the whole cohort of 122 patients, median PFS was 11.97 months (95% CI 10.611-13.329) and estimated median OS was 45.07 months (95% CI 31.690-58.450). The mPFS of ALK-positive patients was superior to negative patients (18.27 vs. 11.90 months; P  = 0.039). Patients with ECOG PS 0 (14.4 vs. 11.1 months; p = 0.040) and patients with single-organ metastasis (19.0 vs. 11.0 months; p = 0.014) had prolonged median PFS. Compared with the low PD-L1 expression group, PFS of high PD-L1 expression group were improved (13.6 vs. 11.1 months, p = 0.104, at 1% cut-off; 17.5 vs. 11.1 months, p = 0.009, at 10% cut-off; and 27.5 vs. 11.4 months, p = 0.005, at 50% cut-off). No differences were found between EGFR positive and negative patients. PD-L1 expression was an independent prognostic factor for both PFS and OS times (PFS: HR, 0.175; P  = 0.001; OS: HR, 0.107; P  = 0.036). Bivariate correlation showed a significant positive correlation between PD-L1 expression and PFS (correlation coefficient R = 0.485, P  < 0.001). High PD-L1 expression could be a potential effective predictor for favorable survival of advanced lung adenocarcinoma patients undergoing pemetrexed maintenance therapy.
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http://dx.doi.org/10.1038/s41598-020-73013-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527332PMC
September 2020

The Polygenic and Monogenic Basis of Blood Traits and Diseases.

Cell 2020 09;182(5):1214-1231.e11

Laboratory of Epidemiology and Population Science, National Institute on Aging/NIH, Baltimore, MD, 21224, USA.

Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation.
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http://dx.doi.org/10.1016/j.cell.2020.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482360PMC
September 2020

Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations.

Cell 2020 09;182(5):1198-1213.e14

Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA 02130, USA; Department of Medicine, Division on Aging, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.

Most loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p < 5 × 10, including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL-7 secretion levels in vitro. Fine-mapping prioritized variants annotated as functional and generated 95% credible sets that were 30% smaller when using the trans-ethnic as opposed to the EUR-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations and compared genetic architecture and the effect of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies.
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http://dx.doi.org/10.1016/j.cell.2020.06.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480402PMC
September 2020

Genome-Wide Association Study Meta-Analysis of Stroke in 22 000 Individuals of African Descent Identifies Novel Associations With Stroke.

Stroke 2020 08 22;51(8):2454-2463. Epub 2020 Jul 22.

Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC (C.D.L., C.L.).

Background And Purpose: Stroke is a complex disease with multiple genetic and environmental risk factors. Blacks endure a nearly 2-fold greater risk of stroke and are 2× to 3× more likely to die from stroke than European Americans.

Methods: The COMPASS (Consortium of Minority Population Genome-Wide Association Studies of Stroke) has conducted a genome-wide association meta-analysis of stroke in >22 000 individuals of African ancestry (3734 cases, 18 317 controls) from 13 cohorts.

Results: In meta-analyses, we identified one single nucleotide polymorphism (rs55931441) near the gene that reached genome-wide significance (=4.62×10) and an additional 29 variants with suggestive evidence of association (<1×10), representing 24 unique loci. For validation, a look-up analysis for a 100 kb region flanking the COMPASS single nucleotide polymorphism was performed in SiGN (Stroke Genetics Network) Europeans, SiGN Hispanics, and METASTROKE (Europeans). Using a stringent Bonferroni correction value of 2.08×10 (0.05/24 unique loci), we were able to validate associations at the locus in both SiGN (=8.18×10) and METASTROKE (=1.72×10) European populations. Overall, 16 of 24 loci showed evidence for validation across multiple populations. Previous studies have reported associations between variants in the gene and lipids, C-reactive protein, and risk of coronary artery disease and stroke. Suggestive associations with variants in the and genes represent potential novel ischemic stroke loci.

Conclusions: These findings represent the most thorough investigation of genetic determinants of stroke in individuals of African descent, to date.
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http://dx.doi.org/10.1161/STROKEAHA.120.029123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387190PMC
August 2020