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1. Association of the gut microbiome with kidney function and damage in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL)

Author

Peters, Brandilyn A, Qi, Qibin, Usyk, Mykhaylo, Daviglus, Martha L, Cai, Jianwen, Franceschini, Nora, Lash, James P, Gellman, Marc D, Yu, Bing, Boerwinkle, Eric, Knight, Rob, Burk, Robert D, and Kaplan, Robert C

Subjects
Microbiology, Biological Sciences, Clinical Research, Diabetes, Nutrition, Kidney Disease, Renal and urogenital, Good Health and Well Being, Humans, Cross-Sectional Studies, Gastrointestinal Microbiome, Hispanic or Latino, Kidney, Public Health, Renal Insufficiency, Chronic, Gut microbiome, chronic kidney disease, glomerular filtration rate, metabolites
Abstract

BackgroundThe gut microbiome is altered in chronic kidney disease (CKD), potentially contributing to CKD progression and co-morbidities, but population-based studies of the gut microbiome across a wide range of kidney function and damage are lacking.MethodsIn the Hispanic Community Health Study/Study of Latinos, gut microbiome was assessed by shotgun sequencing of stool (n = 2,438; 292 with suspected CKD). We examined cross-sectional associations of estimated glomerular filtration rate (eGFR), urinary albumin:creatinine (UAC) ratio, and CKD with gut microbiome features. Kidney trait-related microbiome features were interrogated for correlation with serum metabolites (n = 700), and associations of microbiome-related serum metabolites with kidney trait progression were examined in a prospective analysis (n = 3,635).ResultsHigher eGFR was associated with overall gut microbiome composition, greater abundance of species from Prevotella, Faecalibacterium, Roseburia, and Eubacterium, and microbial functions related to synthesis of long-chain fatty acids and carbamoyl-phosphate. Higher UAC ratio and CKD were related to lower gut microbiome diversity and altered overall microbiome composition only in participants without diabetes. Microbiome features related to better kidney health were associated with many serum metabolites (e.g., higher indolepropionate, beta-cryptoxanthin; lower imidazole propionate, deoxycholic acids, p-cresol glucuronide). Imidazole propionate, deoxycholic acid metabolites, and p-cresol glucuronide were associated with prospective reductions in eGFR and/or increases in UAC ratio over ~6 y.ConclusionsKidney function is a significant correlate of the gut microbiome, while the relationship of kidney damage with the gut microbiome depends on diabetes status. Gut microbiome metabolites may contribute to CKD progression.

Published
2023

2. Circulating metabolites may illustrate relationship of alcohol consumption with cardiovascular disease

Author

Li, Yi, Wang, Mengyao, Liu, Xue, Rong, Jian, Miller, Patricia Emogene, Joehanes, Roby, Huan, Tianxiao, Guo, Xiuqing, Rotter, Jerome I, Smith, Jennifer A, Yu, Bing, Nayor, Matthew, Levy, Daniel, Liu, Chunyu, and Ma, Jiantao

Subjects
Biomedical and Clinical Sciences, Public Health, Health Sciences, Prevention, Clinical Research, Heart Disease, Aging, Cardiovascular, Heart Disease - Coronary Heart Disease, Alcoholism, Alcohol Use and Health, Substance Misuse, 3.1 Primary prevention interventions to modify behaviours or promote wellbeing, Stroke, Cancer, Oral and gastrointestinal, Good Health and Well Being, Humans, Female, Middle Aged, Male, Cardiovascular Diseases, Prospective Studies, Alcohol Drinking, Coronary Disease, Diet, Risk Factors, Alcohol consumption, Cardiovascular disease, Metabolites, Medical and Health Sciences, General & Internal Medicine, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundMetabolite signatures of long-term alcohol consumption are lacking. To better understand the molecular basis linking alcohol drinking and cardiovascular disease (CVD), we investigated circulating metabolites associated with long-term alcohol consumption and examined whether these metabolites were associated with incident CVD.MethodsCumulative average alcohol consumption (g/day) was derived from the total consumption of beer, wine, and liquor on average of 19 years in 2428 Framingham Heart Study Offspring participants (mean age 56 years, 52% women). We used linear mixed models to investigate the associations of alcohol consumption with 211 log-transformed plasma metabolites, adjusting for age, sex, batch, smoking, diet, physical activity, BMI, and familial relationship. Cox models were used to test the association of alcohol-related metabolite scores with fatal and nonfatal incident CVD (myocardial infarction, coronary heart disease, stroke, and heart failure).ResultsWe identified 60 metabolites associated with cumulative average alcohol consumption (p

Published
2023

3. Whole-Genome Sequencing Analysis of Human Metabolome in Multi-Ethnic Populations

Author

Feofanova, Elena V, Brown, Michael R, Alkis, Taryn, Manuel, Astrid M, Li, Xihao, Tahir, Usman A, Li, Zilin, Mendez, Kevin M, Kelly, Rachel S, Qi, Qibin, Chen, Han, Larson, Martin G, Lemaitre, Rozenn N, Morrison, Alanna C, Grieser, Charles, Wong, Kari E, Gersztern, Robert E, Zhao, Zhongming, Lasky-Su, Jessica, and Yu, Bing

Subjects
Genetics, Human Genome, Biotechnology, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Good Health and Well Being, Humans, Quantitative Trait Loci, Ethnicity, Metabolome, Genome-Wide Association Study, Polymorphism, Single Nucleotide, NHLBI Trans-Omics for Precision Medicine
Abstract

Circulating metabolite levels may reflect the state of the human organism in health and disease, however, the genetic architecture of metabolites is not fully understood. We have performed a whole-genome sequencing association analysis of both common and rare variants in up to 11,840 multi-ethnic participants from five studies with up to 1666 circulating metabolites. We have discovered 1985 novel variant-metabolite associations, and validated 761 locus-metabolite associations reported previously. Seventy-nine novel variant-metabolite associations have been replicated, including three genetic loci located on the X chromosome that have demonstrated its involvement in metabolic regulation. Gene-based analysis have provided further support for seven metabolite-replicated loci pairs and their biologically plausible genes. Among those novel replicated variant-metabolite pairs, follow-up analyses have revealed that 26 metabolites have colocalized with 21 tissues, seven metabolite-disease outcome associations have been putatively causal, and 7 metabolites might be regulated by plasma protein levels. Our results have depicted the genetic contribution to circulating metabolite levels, providing additional insights into understanding human disease.

Published
2023

4. Plasma metabolites associated with cognitive function across race/ethnicities affirming the importance of healthy nutrition

Author

Granot‐Hershkovitz, Einat, He, Shan, Bressler, Jan, Yu, Bing, Tarraf, Wassim, Rebholz, Casey M, Cai, Jianwen, Chan, Queenie, Garcia, Tanya P, Mosley, Thomas, Kristal, Bruce S, DeCarli, Charles, Fornage, Myriam, Chen, Guo‐Chong, Qi, Qibin, Kaplan, Robert, González, Hector M, and Sofer, Tamar

Subjects
Medical Biochemistry and Metabolomics, Biomedical and Clinical Sciences, Minority Health, Behavioral and Social Science, Nutrition, Atherosclerosis, Health Disparities, Basic Behavioral and Social Science, 2.1 Biological and endogenous factors, Metabolic and endocrine, Good Health and Well Being, Humans, Cognition, Diet, Healthy, Diet, Mediterranean, Hispanic or Latino, Ribitol, United States, White, Black or African American, Global cognitive function, Mediterranean diet, Metabolites, Puerto Rican, Race/ethnicitie, US Hispanics/Latinos, Race/ethnicities, U.S. Hispanics/Latinos, Clinical Sciences, Neurosciences, Geriatrics, Clinical sciences, Biological psychology
Abstract

IntroductionWe studied the replication and generalization of previously identified metabolites potentially associated with global cognitive function in multiple race/ethnicities and assessed the contribution of diet to these associations.MethodsWe tested metabolite-cognitive function associations in U.S.A. Hispanic/Latino adults (n = 2222) from the Community Health Study/ Study of Latinos (HCHS/SOL) and in European (n = 1365) and African (n = 478) Americans from the Atherosclerosis Risk In Communities (ARIC) Study. We applied Mendelian Randomization (MR) analyses to assess causal associations between the metabolites and cognitive function and between Mediterranean diet and cognitive function.ResultsSix metabolites were consistently associated with lower global cognitive function across all studies. Of these, four were sugar-related (e.g., ribitol). MR analyses provided weak evidence for a potential causal effect of ribitol on cognitive function and bi-directional effects of cognitive performance on diet.DiscussionSeveral diet-related metabolites were associated with global cognitive function across studies with different race/ethnicities.HighlightsMetabolites associated with cognitive function in Puerto Rican adults were recently identified. We demonstrate the generalizability of these associations across diverse race/ethnicities. Most identified metabolites are related to sugars. Mendelian Randomization (MR) provides weak evidence for a causal effect of ribitol on cognitive function. Beta-cryptoxanthin and other metabolites highlight the importance of a healthy diet.

Published
2023

5. Genetic loci of beta-aminoisobutyric acid are associated with aging-related mild cognitive impairment

Author

Granot-Hershkovitz, Einat, Spitzer, Brian, Yang, Yunju, Tarraf, Wassim, Yu, Bing, Boerwinkle, Eric, Fornage, Myriam, Mosley, Thomas H, DeCarli, Charles, Kristal, Bruce S, González, Hector M, and Sofer, Tamar

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Aging, Human Genome, Acquired Cognitive Impairment, Alzheimer's Disease, Health Disparities, Neurodegenerative, Brain Disorders, Dementia, Prevention, Clinical Research, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Minority Health, Genetics, 2.1 Biological and endogenous factors, Humans, Genome-Wide Association Study, Genetic Loci, Polymorphism, Single Nucleotide, Aminoisobutyric Acids, Amino Acid Metabolism, Inborn Errors, Public Health and Health Services, Clinical sciences, Biological psychology
Abstract

We studied the genetic associations of a previously developed Metabolomic Risk Score (MRS) for Mild Cognitive Impairment (MCI) and beta-aminoisobutyric acid metabolite (BAIBA)-the metabolite highlighted by results from a genome-wide association study (GWAS) of the MCI-MRS, and assessed their association with MCI in datasets of diverse race/ethnicities. We first performed a GWAS for the MCI-MRS and BAIBA, in Hispanic/Latino adults (n = 3890) from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We identified ten independent genome-wide significant (p value

Published
2023

6. Evaluating the use of blood pressure polygenic risk scores across race/ethnic background groups

Author

Kurniansyah, Nuzulul, Goodman, Matthew O, Khan, Alyna T, Wang, Jiongming, Feofanova, Elena, Bis, Joshua C, Wiggins, Kerri L, Huffman, Jennifer E, Kelly, Tanika, Elfassy, Tali, Guo, Xiuqing, Palmas, Walter, Lin, Henry J, Hwang, Shih-Jen, Gao, Yan, Young, Kendra, Kinney, Gregory L, Smith, Jennifer A, Yu, Bing, Liu, Simin, Wassertheil-Smoller, Sylvia, Manson, JoAnn E, Zhu, Xiaofeng, Chen, Yii-Der Ida, Lee, I-Te, Gu, C Charles, Lloyd-Jones, Donald M, Zöllner, Sebastian, Fornage, Myriam, Kooperberg, Charles, Correa, Adolfo, Psaty, Bruce M, Arnett, Donna K, Isasi, Carmen R, Rich, Stephen S, Kaplan, Robert C, Redline, Susan, Mitchell, Braxton D, Franceschini, Nora, Levy, Daniel, Rotter, Jerome I, Morrison, Alanna C, and Sofer, Tamar

Subjects
Human Genome, Genetics, Clinical Research, Cardiovascular, Good Health and Well Being, Male, Female, Humans, Blood Pressure, Population Health, Risk Factors, Multifactorial Inheritance, Ethnicity, Genome-Wide Association Study, Genetic Predisposition to Disease
Abstract

We assess performance and limitations of polygenic risk scores (PRSs) for multiple blood pressure (BP) phenotypes in diverse population groups. We compare "clumping-and-thresholding" (PRSice2) and LD-based (LDPred2) methods to construct PRSs from each of multiple GWAS, as well as multi-PRS approaches that sum PRSs with and without weights, including PRS-CSx. We use datasets from the MGB Biobank, TOPMed study, UK biobank, and from All of Us to train, assess, and validate PRSs in groups defined by self-reported race/ethnic background (Asian, Black, Hispanic/Latino, and White). For both SBP and DBP, the PRS-CSx based PRS, constructed as a weighted sum of PRSs developed from multiple independent GWAS, perform best across all race/ethnic backgrounds. Stratified analysis in All of Us shows that PRSs are better predictive of BP in females compared to males, individuals without obesity, and middle-aged (40-60 years) compared to older and younger individuals.

Published
2023

7. Large scale proteomic studies create novel privacy considerations

Author

Hill, Andrew C, Guo, Claire, Litkowski, Elizabeth M, Manichaikul, Ani W, Yu, Bing, Konigsberg, Iain R, Gorbet, Betty A, Lange, Leslie A, Pratte, Katherine A, Kechris, Katerina J, DeCamp, Matthew, Coors, Marilyn, Ortega, Victor E, Rich, Stephen S, Rotter, Jerome I, Gerzsten, Robert E, Clish, Clary B, Curtis, Jeffrey L, Hu, Xiaowei, Obeidat, Ma-en, Morris, Melody, Loureiro, Joseph, Ngo, Debby, O’Neal, Wanda K, Meyers, Deborah A, Bleecker, Eugene R, Hobbs, Brian D, Cho, Michael H, Banaei-Kashani, Farnoush, and Bowler, Russell P

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Atherosclerosis, Cardiovascular, Minority Health, Health Disparities, Human Genome, Biotechnology, Generic health relevance, Humans, Proteome, Bayes Theorem, Privacy, Genome-Wide Association Study, Polymorphism, Single Nucleotide
Abstract

Privacy protection is a core principle of genomic but not proteomic research. We identified independent single nucleotide polymorphism (SNP) quantitative trait loci (pQTL) from COPDGene and Jackson Heart Study (JHS), calculated continuous protein level genotype probabilities, and then applied a naïve Bayesian approach to link SomaScan 1.3K proteomes to genomes for 2812 independent subjects from COPDGene, JHS, SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) and Multi-Ethnic Study of Atherosclerosis (MESA). We correctly linked 90-95% of proteomes to their correct genome and for 95-99% we identify the 1% most likely links. The linking accuracy in subjects with African ancestry was lower (~ 60%) unless training included diverse subjects. With larger profiling (SomaScan 5K) in the Atherosclerosis Risk Communities (ARIC) correct identification was > 99% even in mixed ancestry populations. We also linked proteomes-to-proteomes and used the proteome only to determine features such as sex, ancestry, and first-degree relatives. When serial proteomes are available, the linking algorithm can be used to identify and correct mislabeled samples. This work also demonstrates the importance of including diverse populations in omics research and that large proteomic datasets (> 1000 proteins) can be accurately linked to a specific genome through pQTL knowledge and should not be considered unidentifiable.

Published
2023

8. An integrated multi-omics analysis of sleep-disordered breathing traits implicates P2XR4 purinergic signaling

Author

Kurniansyah, Nuzulul, Wallace, Danielle A, Zhang, Ying, Yu, Bing, Cade, Brian, Wang, Heming, Ochs-Balcom, Heather M, Reiner, Alexander P, Ramos, Alberto R, Smith, Joshua D, Cai, Jianwen, Daviglus, Martha, Zee, Phyllis C, Kaplan, Robert, Kooperberg, Charles, Rich, Stephen S, Rotter, Jerome I, Gharib, Sina A, Redline, Susan, and Sofer, Tamar

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Genetics, Lung, Atherosclerosis, Cardiovascular, Neurosciences, Aging, Sleep Research, 2.1 Biological and endogenous factors, Good Health and Well Being, Humans, Hispanic or Latino, Multiomics, Sleep, Sleep Apnea Syndromes, Oxyhemoglobins, Receptors, Purinergic P2X7, Multifactorial Inheritance, Biological sciences, Biomedical and clinical sciences
Abstract

Sleep Disordered Breathing (SDB) is a common disease associated with increased risk for cardiometabolic, cardiovascular, and cognitive diseases. How SDB affects the molecular environment is still poorly understood. We study the association of three SDB measures with gene expression measured using RNA-seq in multiple blood tissues from the Multi-Ethnic Study of Atherosclerosis. We develop genetic instrumental variables for the associated transcripts as polygenic risk scores (tPRS), then generalize and validate the tPRS in the Women's Health Initiative. We measure the associations of the validated tPRS with SDB and serum metabolites in Hispanic Community Health Study/Study of Latinos. Here we find differential gene expression by blood cell type in relation to SDB traits and link P2XR4 expression to average oxyhemoglobin saturation during sleep and butyrylcarnitine (C4) levels. These findings can be used to develop interventions to alleviate the effect of SDB on the human molecular environment.

Published
2023

9. Assessing the contribution of rare genetic variants to phenotypes of chronic obstructive pulmonary disease using whole-genome sequence data

Author

Kim, Wonji, Hecker, Julian, Barr, R Graham, Boerwinkle, Eric, Cade, Brian, Correa, Adolfo, Dupuis, Josée, Gharib, Sina A, Lange, Leslie, London, Stephanie J, Morrison, Alanna C, O'Connor, George T, Oelsner, Elizabeth C, Psaty, Bruce M, Vasan, Ramachandran S, Redline, Susan, Rich, Stephen S, Rotter, Jerome I, Yu, Bing, Lange, Christoph, Manichaikul, Ani, Zhou, Jin J, Sofer, Tamar, Silverman, Edwin K, Qiao, Dandi, Cho, Michael H, and Group, NHLBI Trans-Omics in Precision Medicine Consortium and TOPMed Lung Working

Subjects
Biological Sciences, Genetics, Chronic Obstructive Pulmonary Disease, Lung, Human Genome, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Generic health relevance, Respiratory, Humans, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Pulmonary Disease, Chronic Obstructive, Genome-Wide Association Study, Phenotype, NHLBI Trans-Omics in Precision Medicine (TOPMed) Consortium and TOPMed Lung Working Group, Medical and Health Sciences, Genetics & Heredity
Abstract

RationaleGenetic variation has a substantial contribution to chronic obstructive pulmonary disease (COPD) and lung function measurements. Heritability estimates using genome-wide genotyping data can be biased if analyses do not appropriately account for the nonuniform distribution of genetic effects across the allele frequency and linkage disequilibrium (LD) spectrum. In addition, the contribution of rare variants has been unclear.ObjectivesWe sought to assess the heritability of COPD and lung function using whole-genome sequence data from the Trans-Omics for Precision Medicine program.MethodsUsing the genome-based restricted maximum likelihood method, we partitioned the genome into bins based on minor allele frequency and LD scores and estimated heritability of COPD, FEV1% predicted and FEV1/FVC ratio in 11 051 European ancestry and 5853 African-American participants.Measurements and main resultsIn European ancestry participants, the estimated heritability of COPD, FEV1% predicted and FEV1/FVC ratio were 35.5%, 55.6% and 32.5%, of which 18.8%, 19.7%, 17.8% were from common variants, and 16.6%, 35.8%, and 14.6% were from rare variants. These estimates had wide confidence intervals, with common variants and some sets of rare variants showing a statistically significant contribution (P-value

Published
2022

10. Clonal hematopoiesis of indeterminate potential, DNA methylation, and risk for coronary artery disease

Author

Uddin, MD Mesbah, Nguyen, Ngoc Quynh H, Yu, Bing, Brody, Jennifer A, Pampana, Akhil, Nakao, Tetsushi, Fornage, Myriam, Bressler, Jan, Sotoodehnia, Nona, Weinstock, Joshua S, Honigberg, Michael C, Nachun, Daniel, Bhattacharya, Romit, Griffin, Gabriel K, Chander, Varuna, Gibbs, Richard A, Rotter, Jerome I, Liu, Chunyu, Baccarelli, Andrea A, Chasman, Daniel I, Whitsel, Eric A, Kiel, Douglas P, Murabito, Joanne M, Boerwinkle, Eric, Ebert, Benjamin L, Jaiswal, Siddhartha, Floyd, James S, Bick, Alexander G, Ballantyne, Christie M, Psaty, Bruce M, Natarajan, Pradeep, and Conneely, Karen N

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Atherosclerosis, Heart Disease, Cardiovascular, Cancer, Stem Cell Research, Aging, Human Genome, Heart Disease - Coronary Heart Disease, Regenerative Medicine, Hematology, Prevention, 2.1 Biological and endogenous factors, Good Health and Well Being, Clonal Hematopoiesis, Coronary Artery Disease, DNA Methylation, Hematopoiesis, Hematopoietic Stem Cells, Humans
Abstract

Age-related changes to the genome-wide DNA methylation (DNAm) pattern observed in blood are well-documented. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by the age-related acquisition and expansion of leukemogenic mutations in hematopoietic stem cells (HSCs), is associated with blood cancer and coronary artery disease (CAD). Epigenetic regulators DNMT3A and TET2 are the two most frequently mutated CHIP genes. Here, we present results from an epigenome-wide association study for CHIP in 582 Cardiovascular Health Study (CHS) participants, with replication in 2655 Atherosclerosis Risk in Communities (ARIC) Study participants. We show that DNMT3A and TET2 CHIP have distinct and directionally opposing genome-wide DNAm association patterns consistent with their regulatory roles, albeit both promoting self-renewal of HSCs. Mendelian randomization analyses indicate that a subset of DNAm alterations associated with these two leading CHIP genes may promote the risk for CAD.

Published
2022

11. Host and gut microbial tryptophan metabolism and type 2 diabetes: an integrative analysis of host genetics, diet, gut microbiome and circulating metabolites in cohort studies

Author

Qi, Qibin, Li, Jun, Yu, Bing, Moon, Jee-Young, Chai, Jin C, Merino, Jordi, Hu, Jie, Ruiz-Canela, Miguel, Rebholz, Casey, Wang, Zheng, Usyk, Mykhaylo, Chen, Guo-Chong, Porneala, Bianca C, Wang, Wenshuang, Nguyen, Ngoc Quynh, Feofanova, Elena V, Grove, Megan L, Wang, Thomas J, Gerszten, Robert E, Dupuis, Josée, Salas-Salvadó, Jordi, Bao, Wei, Perkins, David L, Daviglus, Martha L, Thyagarajan, Bharat, Cai, Jianwen, Wang, Tao, Manson, JoAnn E, Martínez-González, Miguel A, Selvin, Elizabeth, Rexrode, Kathryn M, Clish, Clary B, Hu, Frank B, Meigs, James B, Knight, Rob, Burk, Robert D, Boerwinkle, Eric, and Kaplan, Robert C

Subjects
Obesity, Human Genome, Prevention, Genetics, Nutrition, Diabetes, 2.2 Factors relating to the physical environment, Aetiology, Metabolic and endocrine, Oral and gastrointestinal, Bacteria, Cohort Studies, Diabetes Mellitus, Type 2, Diet, Gastrointestinal Microbiome, Humans, Kynurenine, Lactase, Tryptophan, diabetes mellitus, dietary factors, genetics, Clinical Sciences, Paediatrics and Reproductive Medicine, Gastroenterology & Hepatology
Abstract

ObjectiveTryptophan can be catabolised to various metabolites through host kynurenine and microbial indole pathways. We aimed to examine relationships of host and microbial tryptophan metabolites with incident type 2 diabetes (T2D), host genetics, diet and gut microbiota.MethodWe analysed associations between circulating levels of 11 tryptophan metabolites and incident T2D in 9180 participants of diverse racial/ethnic backgrounds from five cohorts. We examined host genome-wide variants, dietary intake and gut microbiome associated with these metabolites.ResultsTryptophan, four kynurenine-pathway metabolites (kynurenine, kynurenate, xanthurenate and quinolinate) and indolelactate were positively associated with T2D risk, while indolepropionate was inversely associated with T2D risk. We identified multiple host genetic variants, dietary factors, gut bacteria and their potential interplay associated with these T2D-relaetd metabolites. Intakes of fibre-rich foods, but not protein/tryptophan-rich foods, were the dietary factors most strongly associated with tryptophan metabolites. The fibre-indolepropionate association was partially explained by indolepropionate-associated gut bacteria, mostly fibre-using Firmicutes. We identified a novel association between a host functional LCT variant (determining lactase persistence) and serum indolepropionate, which might be related to a host gene-diet interaction on gut Bifidobacterium, a probiotic bacterium significantly associated with indolepropionate independent of other fibre-related bacteria. Higher milk intake was associated with higher levels of gut Bifidobacterium and serum indolepropionate only among genetically lactase non-persistent individuals.ConclusionHigher milk intake among lactase non-persistent individuals, and higher fibre intake were associated with a favourable profile of circulating tryptophan metabolites for T2D, potentially through the host-microbial cross-talk shifting tryptophan metabolism toward gut microbial indolepropionate production.

Published
2022

12. Polygenic transcriptome risk scores for COPD and lung function improve cross-ethnic portability of prediction in the NHLBI TOPMed program

Author

Hu, Xiaowei, Qiao, Dandi, Kim, Wonji, Moll, Matthew, Balte, Pallavi P, Lange, Leslie A, Bartz, Traci M, Kumar, Rajesh, Li, Xingnan, Yu, Bing, Cade, Brian E, Laurie, Cecelia A, Sofer, Tamar, Ruczinski, Ingo, Nickerson, Deborah A, Muzny, Donna M, Metcalf, Ginger A, Doddapaneni, Harshavardhan, Gabriel, Stacy, Gupta, Namrata, Dugan-Perez, Shannon, Cupples, L Adrienne, Loehr, Laura R, Jain, Deepti, Rotter, Jerome I, Wilson, James G, Psaty, Bruce M, Fornage, Myriam, Morrison, Alanna C, Vasan, Ramachandran S, Washko, George, Rich, Stephen S, O’Connor, George T, Bleecker, Eugene, Kaplan, Robert C, Kalhan, Ravi, Redline, Susan, Gharib, Sina A, Meyers, Deborah, Ortega, Victor, Dupuis, Josée, London, Stephanie J, Lappalainen, Tuuli, Oelsner, Elizabeth C, Silverman, Edwin K, Barr, R Graham, Thornton, Timothy A, Wheeler, Heather E, Group, TOPMed Lung Working, Cho, Michael H, Im, Hae Kyung, and Manichaikul, Ani

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Clinical Research, Lung, Prevention, Tobacco, Chronic Obstructive Pulmonary Disease, Tobacco Smoke and Health, Respiratory, Good Health and Well Being, Humans, National Heart, Lung, and Blood Institute (U.S.), Pulmonary Disease, Chronic Obstructive, Risk Factors, Transcriptome, United States, TOPMed Lung Working Group, cross-ethnic portability, gene expression, integrative analysis, polygenic transcriptome risk score, pulmonary disease, risk prediction, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

While polygenic risk scores (PRSs) enable early identification of genetic risk for chronic obstructive pulmonary disease (COPD), predictive performance is limited when the discovery and target populations are not well matched. Hypothesizing that the biological mechanisms of disease are shared across ancestry groups, we introduce a PrediXcan-derived polygenic transcriptome risk score (PTRS) to improve cross-ethnic portability of risk prediction. We constructed the PTRS using summary statistics from application of PrediXcan on large-scale GWASs of lung function (forced expiratory volume in 1 s [FEV1] and its ratio to forced vital capacity [FEV1/FVC]) in the UK Biobank. We examined prediction performance and cross-ethnic portability of PTRS through smoking-stratified analyses both on 29,381 multi-ethnic participants from TOPMed population/family-based cohorts and on 11,771 multi-ethnic participants from TOPMed COPD-enriched studies. Analyses were carried out for two dichotomous COPD traits (moderate-to-severe and severe COPD) and two quantitative lung function traits (FEV1 and FEV1/FVC). While the proposed PTRS showed weaker associations with disease than PRS for European ancestry, the PTRS showed stronger association with COPD than PRS for African Americans (e.g., odds ratio [OR] = 1.24 [95% confidence interval [CI]: 1.08-1.43] for PTRS versus 1.10 [0.96-1.26] for PRS among heavy smokers with ≥ 40 pack-years of smoking) for moderate-to-severe COPD. Cross-ethnic portability of the PTRS was significantly higher than the PRS (paired t test p

Published
2022

13. Clonal Hematopoiesis Is Associated With Higher Risk of Stroke

Author

Bhattacharya, Romit, Zekavat, Seyedeh M, Haessler, Jeffrey, Fornage, Myriam, Raffield, Laura, Uddin, Mesbah, Bick, Alexander G, Niroula, Abhishek, Yu, Bing, Gibson, Christopher, Griffin, Gabriel, Morrison, Alanna C, Psaty, Bruce M, Longstreth, William T, Bis, Joshua C, Rich, Stephen S, Rotter, Jerome I, Tracy, Russell P, Correa, Adolfo, Seshadri, Sudha, Johnson, Andrew, Collins, Jason M, Hayden, Kathleen M, Madsen, Tracy E, Ballantyne, Christie M, Jaiswal, Siddhartha, Ebert, Benjamin L, Kooperberg, Charles, Manson, JoAnn E, Whitsel, Eric A, Program, NHLBI Trans-Omics for Precision Medicine, Natarajan, Pradeep, and Reiner, Alexander P

Subjects
Epidemiology, Health Sciences, Prevention, Genetics, Stroke, Neurosciences, Aging, Hematology, Brain Disorders, Cerebrovascular, Good Health and Well Being, Adult, Aged, Aged, 80 and over, Clonal Hematopoiesis, DNA Methyltransferase 3A, DNA-Binding Proteins, Dioxygenases, Female, Hemorrhagic Stroke, Humans, Incidence, Ischemic Stroke, Male, Middle Aged, Prevalence, Repressor Proteins, Risk, brain ischemia, cardiovascular diseases, clonal hematopoiesis, humans, prospective studies, NHLBI Trans-Omics for Precision Medicine Program, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Neurology & Neurosurgery, Clinical sciences, Allied health and rehabilitation science
Abstract

Background and purposeClonal hematopoiesis of indeterminate potential (CHIP) is a novel age-related risk factor for cardiovascular disease-related morbidity and mortality. The association of CHIP with risk of incident ischemic stroke was reported previously in an exploratory analysis including a small number of incident stroke cases without replication and lack of stroke subphenotyping. The purpose of this study was to discover whether CHIP is a risk factor for ischemic or hemorrhagic stroke.MethodsWe utilized plasma genome sequence data of blood DNA to identify CHIP in 78 752 individuals from 8 prospective cohorts and biobanks. We then assessed the association of CHIP and commonly mutated individual CHIP driver genes (DNMT3A, TET2, and ASXL1) with any stroke, ischemic stroke, and hemorrhagic stroke.ResultsCHIP was associated with an increased risk of total stroke (hazard ratio, 1.14 [95% CI, 1.03-1.27]; P=0.01) after adjustment for age, sex, and race. We observed associations with CHIP with risk of hemorrhagic stroke (hazard ratio, 1.24 [95% CI, 1.01-1.51]; P=0.04) and with small vessel ischemic stroke subtypes. In gene-specific association results, TET2 showed the strongest association with total stroke and ischemic stroke, whereas DMNT3A and TET2 were each associated with increased risk of hemorrhagic stroke.ConclusionsCHIP is associated with an increased risk of stroke, particularly with hemorrhagic and small vessel ischemic stroke. Future studies clarifying the relationship between CHIP and subtypes of stroke are needed.

Published
2022

14. Associations of Pulmonary Function with MRI Brain Volumes: A Coordinated Multi-Study Analysis

Author

Frenzel, Stefan, Bis, Joshua C, Gudmundsson, Elias F, O’Donnell, Adrienne, Simino, Jeannette, Yaqub, Amber, Bartz, Traci M, Brusselle, Guy GO, Bülow, Robin, DeCarli, Charles S, Ewert, Ralf, Gharib, Sina A, Ghosh, Saptaparni, Gireud-Goss, Monica, Gottesman, Rebecca F, Ikram, M Arfan, Knopman, David S, Launer, Lenore J, London, Stephanie J, Longstreth, WT, Lopez, Oscar L, van Lent, Debora Melo, O’Connor, George, Satizabal, Claudia L, Shrestha, Srishti, Sigurdsson, Sigurdur, Stubbe, Beate, Talluri, Rajesh, Vasan, Ramachandran S, Vernooij, Meike W, Völzke, Henry, Wiggins, Kerri L, Yu, Bing, Beiser, Alexa S, Gudnason, Vilmundur, Mosley, Thomas, Psaty, Bruce M, Wolters, Frank J, Grabe, Hans J, and Seshadri, Sudha

Subjects
Brain Disorders, Lung, Neurosciences, Clinical Research, Aging, Humans, Aged, Forced Expiratory Volume, Cross-Sectional Studies, Magnetic Resonance Imaging, Brain, Dementia, epidemiology, magnetic resonance imaging, respiratory function tests, Clinical Sciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract

BackgroundPrevious studies suggest poor pulmonary function is associated with increased burden of cerebral white matter hyperintensities and brain atrophy among elderly individuals, but the results are inconsistent.ObjectiveTo study the cross-sectional associations of pulmonary function with structural brain variables.MethodsData from six large community-based samples (N = 11,091) were analyzed. Spirometric measurements were standardized with respect to age, sex, height, and ethnicity using reference equations of the Global Lung Function Initiative. Associations of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and their ratio FEV1/FVC with brain volume, gray matter volume, hippocampal volume, and volume of white matter hyperintensities were investigated using multivariable linear regressions for each study separately and then combined using random-effect meta-analyses.ResultsFEV1 and FVC were positively associated with brain volume, gray matter volume, and hippocampal volume, and negatively associated with white matter hyperintensities volume after multiple testing correction, with little heterogeneity present between the studies. For instance, an increase of FVC by one unit was associated with 3.5 ml higher brain volume (95% CI: [2.2, 4.9]). In contrast, results for FEV1/FVC were more heterogeneous across studies, with significant positive associations with brain volume, gray matter volume, and hippocampal volume, but not white matter hyperintensities volume. Associations of brain variables with both FEV1 and FVC were consistently stronger than with FEV1/FVC, specifically with brain volume and white matter hyperintensities volume.ConclusionIn cross-sectional analyses, worse pulmonary function is associated with smaller brain volumes and higher white matter hyperintensities burden.

Published
2022

15. Body Fat Distribution, Cardiometabolic Traits, and Risk of Major Lower-Extremity Arterial Disease in Postmenopausal Women.

Author

Chen, Guo-Chong, Arthur, Rhonda, Kamensky, Victor, Chai, Jin Choul, Yu, Bing, Shadyab, Aladdin H, Allison, Matthew, Sun, Yangbo, Saquib, Nazmus, Wild, Robert A, Bao, Wei, Dannenberg, Andrew J, Rohan, Thomas E, Kaplan, Robert C, Wassertheil-Smoller, Sylvia, and Qi, Qibin

Subjects
Diabetes, Clinical Research, Aging, Cardiovascular, Patient Safety, Nutrition, Prevention, Metabolic and endocrine, Body Fat Distribution, Body Mass Index, Cardiovascular Diseases, Extremities, Female, Humans, Postmenopause, Risk Factors
Abstract

ObjectiveTo assess the relationship between body fat distribution and incident lower-extremity arterial disease (LEAD).Research design and methodsWe included 155,925 postmenopausal women with anthropometric measures from the Women's Health Initiative who had no known LEAD at recruitment. A subset of 10,894 participants had body composition data quantified by DXA. Incident cases of symptomatic LEAD were ascertained and adjudicated through medical record review.ResultsWe identified 1,152 incident cases of LEAD during a median 18.8 years follow-up. After multivariable adjustment and mutual adjustment, waist and hip circumferences were positively and inversely associated with risk of LEAD, respectively (both P-trend < 0.0001). In a subset (n = 22,561) where various cardiometabolic biomarkers were quantified, a similar positive association of waist circumference with risk of LEAD was eliminated after adjustment for diabetes and HOMA of insulin resistance (P-trend = 0.89), whereas hip circumference remained inversely associated with the risk after adjustment for major cardiometabolic traits (P-trend = 0.0031). In the DXA subset, higher trunk fat (P-trend = 0.0081) and higher leg fat (P-trend < 0.0001) were associated with higher and lower risk of LEAD, respectively. Further adjustment for diabetes, dyslipidemia, and blood pressure diminished the association for trunk fat (P-trend = 0.49), yet the inverse association for leg fat persisted (P-trend = 0.0082).ConclusionsAmong U.S. postmenopausal women, a positive association of upper-body fat with risk of LEAD appeared to be attributable to traditional risk factors, especially insulin resistance. Lower-body fat was inversely associated with risk of LEAD beyond known risk factors.

Published
2022

16. A multi-ethnic polygenic risk score is associated with hypertension prevalence and progression throughout adulthood

Author

Kurniansyah, Nuzulul, Goodman, Matthew O, Kelly, Tanika N, Elfassy, Tali, Wiggins, Kerri L, Bis, Joshua C, Guo, Xiuqing, Palmas, Walter, Taylor, Kent D, Lin, Henry J, Haessler, Jeffrey, Gao, Yan, Shimbo, Daichi, Smith, Jennifer A, Yu, Bing, Feofanova, Elena V, Smit, Roelof AJ, Wang, Zhe, Hwang, Shih-Jen, Liu, Simin, Wassertheil-Smoller, Sylvia, Manson, JoAnn E, Lloyd-Jones, Donald M, Rich, Stephen S, Loos, Ruth JF, Redline, Susan, Correa, Adolfo, Kooperberg, Charles, Fornage, Myriam, Kaplan, Robert C, Psaty, Bruce M, Rotter, Jerome I, Arnett, Donna K, Morrison, Alanna C, Franceschini, Nora, Levy, Daniel, and Sofer, Tamar

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Hypertension, Human Genome, Prevention, Cardiovascular, Aging, Aetiology, 2.1 Biological and endogenous factors, Adult, Diabetes Mellitus, Type 2, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Multifactorial Inheritance, Prevalence, Risk Factors, NHLBI Trans-Omics in Precision Medicine (TOPMed) Consortium
Abstract

In a multi-stage analysis of 52,436 individuals aged 17-90 across diverse cohorts and biobanks, we train, test, and evaluate a polygenic risk score (PRS) for hypertension risk and progression. The PRS is trained using genome-wide association studies (GWAS) for systolic, diastolic blood pressure, and hypertension, respectively. For each trait, PRS is selected by optimizing the coefficient of variation (CV) across estimated effect sizes from multiple potential PRS using the same GWAS, after which the 3 trait-specific PRSs are combined via an unweighted sum called "PRSsum", forming the HTN-PRS. The HTN-PRS is associated with both prevalent and incident hypertension at 4-6 years of follow up. This association is further confirmed in age-stratified analysis. In an independent biobank of 40,201 individuals, the HTN-PRS is confirmed to be predictive of increased risk for coronary artery disease, ischemic stroke, type 2 diabetes, and chronic kidney disease.

Published
2022

17. Identification of Functional Genetic Determinants of Cardiac Troponin T and I in a Multiethnic Population and Causal Associations With Atrial Fibrillation

Author

Yang, Yunju, Bartz, Traci M, Brown, Michael R, Guo, Xiuqing, Zilhão, Nuno R, Trompet, Stella, Weiss, Stefan, Yao, Jie, Brody, Jennifer A, Defilippi, Christopher R, Hoogeveen, Ron C, Lin, Henry J, Gudnason, Vilmundur, Ballantyne, Christie M, Dörr, Marcus, Jukema, J Wouter, Petersmann, Astrid, Psaty, Bruce M, Rotter, Jerome I, Boerwinkle, Eric, Fornage, Myriam, Jun, Goo, and Yu, Bing

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Genetics, Heart Disease - Coronary Heart Disease, Cardiovascular, Human Genome, Heart Disease, 2.1 Biological and endogenous factors, Good Health and Well Being, Adaptor Proteins, Signal Transducing, Anoctamins, Apoptosis Regulatory Proteins, Atrial Fibrillation, Biomarkers, Genome-Wide Association Study, Humans, Troponin I, Troponin T, cardiovascular diseases, genome-wide association study, heart failure, Mendelian randomization analysis, troponin I, troponin T, Medical Biotechnology, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology
Abstract

BackgroundElevated cardiac troponin levels in blood are associated with increased risk of cardiovascular diseases and mortality. Cardiac troponin levels are heritable, but their genetic architecture remains elusive.MethodsWe conducted a transethnic genome-wide association analysis on high-sensitivity cTnT (cardiac troponin T; hs-cTnT) and high-sensitivity cTnI (cardiac troponin I; hs-cTnI) levels in 24 617 and 14 336 participants free of coronary heart disease and heart failure from 6 population-based cohorts, followed by a series of bioinformatic analyses to decipher the genetic architecture of hs-cTnT and hs-cTnI.ResultsWe identified 4 genome-wide significant loci for hs-cTnT including a novel locus rs3737882 in PPFIA4 and 3 previously reported loci at NCOA2, TRAM1, and BCL2. One known locus at VCL was replicated for hs-cTnI. One copy of C allele for rs3737882 was associated with a 6% increase in hs-cTnT levels (minor allele frequency, 0.18; P=2.80×10-9). We observed pleiotropic loci located at BAG3 and ANO5. The proportions of variances explained by single-nucleotide polymorphisms were 10.15% and 7.74% for hs-cTnT and hs-cTnI, respectively. Single-nucleotide polymorphisms were colocalized with BCL2 expression in heart tissues and hs-cTnT and with ANO5 expression in artery, heart tissues, and whole blood and both troponins. Mendelian randomization analyses showed that genetically increased hs-cTnT and hs-cTnI levels were associated with higher odds of atrial fibrillation (odds ratio, 1.38 [95% CI, 1.25-1.54] for hs-cTnT and 1.21 [95% CI, 1.06-1.37] for hs-cTnI).ConclusionsWe identified a novel genetic locus associated with hs-cTnT in a multiethnic population and found that genetically regulated troponin levels were associated with atrial fibrillation.

Published
2021

18. Dietary factors, gut microbiota, and serum trimethylamine-N-oxide associated with cardiovascular disease in the Hispanic Community Health Study/Study of Latinos

Author

Mei, Zhendong, Chen, Guo-Chong, Wang, Zheng, Usyk, Mykhaylo, Yu, Bing, Baeza, Yoshiki Vazquez, Humphrey, Greg, Benitez, Rodolfo Salido, Li, Jun, Williams-Nguyen, Jessica S, Daviglus, Martha L, Hou, Lifang, Cai, Jianwen, Zheng, Yan, Knight, Rob, Burk, Robert D, Boerwinkle, Eric, Kaplan, Robert C, and Qi, Qibin

Subjects
Biomedical and Clinical Sciences, Nutrition and Dietetics, Clinical Research, Cardiovascular, Prevention, Nutrition, Good Health and Well Being, Adult, Aged, Biomarkers, Cardiovascular Diseases, Cross-Sectional Studies, Diet, Female, Gastrointestinal Microbiome, Hispanic or Latino, Humans, Male, Methylamines, Middle Aged, Public Health, cardiovascular disease, diet, gut microbiota, trimethylamine-N-oxide, Hispanic Americans, Engineering, Medical and Health Sciences, Nutrition & Dietetics, Clinical sciences, Nutrition and dietetics
Abstract

BackgroundTrimethylamine-N-oxide (TMAO), a diet-derived and gut microbiota-related metabolite, is associated with cardiovascular disease (CVD). However, major dietary determinants and specific gut bacterial taxa related to TMAO remain to be identified in humans.ObjectivesWe aimed to identify dietary and gut microbial factors associated with circulating TMAO.MethodsThis cross-sectional study included 3972 participants (57.3% women) aged 18-74 y from the Hispanic Community Health Study/Study of Latinos in the United States. Dietary information was collected by 24-h dietary recalls at baseline interview (2008-2011), and baseline serum TMAO and its precursors were measured by an untargeted approach. Gut microbiome was profiled by shotgun metagenomic sequencing in a subset of participants (n = 626) during a follow-up visit (2016-2018). Logistic and linear regression were used to examine associations of inverse-normalized metabolites with prevalent CVD, dietary intake, and bacterial species, respectively, after adjustment for sociodemographic, behavioral, and clinical factors.ResultsTMAO was positively associated with prevalent CVD (case number = 279; OR = 1.34; 95% CI: 1.17, 1.54, per 1-SD). Fish (P = 1.26 × 10-17), red meat (P = 3.33 × 10-16), and egg (P = 3.89 × 10-5) intakes were top dietary factors positively associated with TMAO. We identified 9 gut bacterial species significantly associated with TMAO (false discovery rate

Published
2021

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

Author

Zhao, Xutong, Qiao, Dandi, Yang, Chaojie, Kasela, Silva, Kim, Wonji, Ma, Yanlin, Shrine, Nick, Batini, Chiara, Sofer, Tamar, Taliun, Sarah A Gagliano, Sakornsakolpat, Phuwanat, Balte, Pallavi P, Prokopenko, Dmitry, Yu, Bing, Lange, Leslie A, Dupuis, Josée, Cade, Brian E, Lee, Jiwon, Gharib, Sina A, Daya, Michelle, Laurie, Cecelia A, Ruczinski, Ingo, Cupples, L Adrienne, Loehr, Laura R, Bartz, Traci M, Morrison, Alanna C, Psaty, Bruce M, Vasan, Ramachandran S, Wilson, James G, Taylor, Kent D, Durda, Peter, Johnson, W Craig, Cornell, Elaine, Guo, Xiuqing, Liu, Yongmei, Tracy, Russell P, Ardlie, Kristin G, Aguet, François, VanDenBerg, David J, Papanicolaou, George J, Rotter, Jerome I, Barnes, Kathleen C, Jain, Deepti, Nickerson, Deborah A, Muzny, Donna M, Metcalf, Ginger A, Doddapaneni, Harshavardhan, Dugan-Perez, Shannon, Gupta, Namrata, Gabriel, Stacey, Rich, Stephen S, O'Connor, George T, Redline, Susan, Reed, Robert M, Laurie, Cathy C, Daviglus, Martha L, Preudhomme, Liana K, Burkart, Kristin M, Kaplan, Robert C, Wain, Louise V, Tobin, Martin D, London, Stephanie J, Lappalainen, Tuuli, Oelsner, Elizabeth C, Abecasis, Goncalo R, Silverman, Edwin K, Barr, R Graham, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Lung Working Group, Cho, Michael H, and Manichaikul, Ani

Subjects
NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Lung Working Group, Lung, Humans, Pulmonary Disease, Chronic Obstructive, Genetic Predisposition to Disease, Intracellular Signaling Peptides and Proteins, Calcium-Binding Proteins, Small Ubiquitin-Related Modifier Proteins, Follow-Up Studies, Feasibility Studies, Polymorphism, Single Nucleotide, Adult, Aged, Aged, 80 and over, Middle Aged, African Americans, Female, Male, Protein Inhibitors of Activated STAT, Respiratory Physiological Phenomena, Genome-Wide Association Study, Genetic Loci, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Whole Genome Sequencing, and over, Polymorphism, Single Nucleotide, Pulmonary Disease, Chronic Obstructive
Abstract

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.

Published
2020

20. Unraveling the functional role of the orphan solute carrier, SLC22A24 in the transport of steroid conjugates through metabolomic and genome-wide association studies.

Author

Yee, Sook Wah, Stecula, Adrian, Chien, Huan-Chieh, Zou, Ling, Feofanova, Elena V, van Borselen, Marjolein, Cheung, Kit Wun Kathy, Yousri, Noha A, Suhre, Karsten, Kinchen, Jason M, Boerwinkle, Eric, Irannejad, Roshanak, Yu, Bing, and Giacomini, Kathleen M

Subjects
Animals, Humans, Steroids, Androsterone, Organic Cation Transport Proteins, Symporters, Phylogeny, Biological Transport, Polymorphism, Single Nucleotide, Models, Molecular, Genome-Wide Association Study, Metabolomics, HEK293 Cells, Polymorphism, Single Nucleotide, Models, Molecular, Genetics, Developmental Biology
Abstract

Variation in steroid hormone levels has wide implications for health and disease. The genes encoding the proteins involved in steroid disposition represent key determinants of interindividual variation in steroid levels and ultimately, their effects. Beginning with metabolomic data from genome-wide association studies (GWAS), we observed that genetic variants in the orphan transporter, SLC22A24 were significantly associated with levels of androsterone glucuronide and etiocholanolone glucuronide (sentinel SNPs p-value

Published
2019

21. New alcohol-related genes suggest shared genetic mechanisms with neuropsychiatric disorders

Author

Evangelou, Evangelos, Gao, He, Chu, Congying, Ntritsos, Georgios, Blakeley, Paul, Butts, Andrew R, Pazoki, Raha, Suzuki, Hideaki, Koskeridis, Fotios, Yiorkas, Andrianos M, Karaman, Ibrahim, Elliott, Joshua, Luo, Qiang, Aeschbacher, Stefanie, Bartz, Traci M, Baumeister, Sebastian E, Braund, Peter S, Brown, Michael R, Brody, Jennifer A, Clarke, Toni-Kim, Dimou, Niki, Faul, Jessica D, Homuth, Georg, Jackson, Anne U, Kentistou, Katherine A, Joshi, Peter K, Lemaitre, Rozenn N, Lind, Penelope A, Lyytikäinen, Leo-Pekka, Mangino, Massimo, Milaneschi, Yuri, Nelson, Christopher P, Nolte, Ilja M, Perälä, Mia-Maria, Polasek, Ozren, Porteous, David, Ratliff, Scott M, Smith, Jennifer A, Stančáková, Alena, Teumer, Alexander, Tuominen, Samuli, Thériault, Sébastien, Vangipurapu, Jagadish, Whitfield, John B, Wood, Alexis, Yao, Jie, Yu, Bing, Zhao, Wei, Arking, Dan E, Auvinen, Juha, Liu, Chunyu, Männikkö, Minna, Risch, Lorenz, Rotter, Jerome I, Snieder, Harold, Veijola, Juha, Blakemore, Alexandra I, Boehnke, Michael, Campbell, Harry, Conen, David, Eriksson, Johan G, Grabe, Hans J, Guo, Xiuqing, van der Harst, Pim, Hartman, Catharina A, Hayward, Caroline, Heath, Andrew C, Jarvelin, Marjo-Riitta, Kähönen, Mika, Kardia, Sharon LR, Kühne, Michael, Kuusisto, Johanna, Laakso, Markku, Lahti, Jari, Lehtimäki, Terho, McIntosh, Andrew M, Mohlke, Karen L, Morrison, Alanna C, Martin, Nicholas G, Oldehinkel, Albertine J, Penninx, Brenda WJH, Psaty, Bruce M, Raitakari, Olli T, Rudan, Igor, Samani, Nilesh J, Scott, Laura J, Spector, Tim D, Verweij, Niek, Weir, David R, Wilson, James F, Levy, Daniel, Tzoulaki, Ioanna, Bell, Jimmy D, Matthews, Paul M, Rothenfluh, Adrian, Desrivières, Sylvane, Schumann, Gunter, and Elliott, Paul

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Epidemiology, Health Sciences, Psychology, Pharmacology and Pharmaceutical Sciences, Biotechnology, Substance Misuse, Brain Disorders, Mental Health, Neurosciences, Serious Mental Illness, Alcoholism, Alcohol Use and Health, Schizophrenia, Genetics, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Cardiovascular, Mental health, Stroke, Cancer, Oral and gastrointestinal, Good Health and Well Being, Adult, Aged, Alcohol Drinking, Alcoholism, Brain, Female, Genes, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Magnetic Resonance Imaging, Male, Mental Disorders, Middle Aged, Neuroimaging, Polymorphism, Single Nucleotide, Quantitative Trait Loci, White People, Biomedical and clinical sciences, Health sciences
Abstract

Excessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. Here we conducted a meta-analysis of genome-wide association studies of alcohol consumption (g d-1) from the UK Biobank, the Alcohol Genome-Wide Consortium and the Cohorts for Heart and Aging Research in Genomic Epidemiology Plus consortia, collecting data from 480,842 people of European descent to decipher the genetic architecture of alcohol intake. We identified 46 new common loci and investigated their potential functional importance using magnetic resonance imaging data and gene expression studies. We identify genetic pathways associated with alcohol consumption and suggest genetic mechanisms that are shared with neuropsychiatric disorders such as schizophrenia.

Published
2019

22. Reproducibility and Variability of Protein Analytes Measured Using a Multiplexed Modified Aptamer Assay.

Author

Tin, Adrienne, Yu, Bing, Ma, Jianzhong, Masushita, Kunihiro, Daya, Natalie, Hoogeveen, Ron C, Ballantyne, Christie M, Couper, David, Rebholz, Casey M, Grams, Morgan E, Alonso, Alvaro, Mosley, Thomas, Heiss, Gerardo, Ganz, Peter, Selvin, Elizabeth, Boerwinkle, Eric, and Coresh, Josef

Subjects
Aging, Prevention, Good Health and Well Being, Aged, Atherosclerosis, Blood Proteins, Equipment Design, Female, Glomerular Filtration Rate, Humans, Male, Middle Aged, Prospective Studies, Proteomics, Reproducibility of Results
Abstract

BACKGROUND:There is growing interest in the use of multiplexed aptamer-based assays for large-scale proteomic studies. However, the analytic, short- and long-term variation of the measured proteins is largely uncharacterized. METHODS:We quantified 4001 plasma protein analytes from 42 participants in the Atherosclerosis Risk in Communities (ARIC) Study in split samples and at multiple visits using a multiplexed modified aptamer assay. We calculated the CV, Spearman correlation, and intraclass correlation (ICC) between split samples and evaluated the short-term (4-9 weeks) and long-term (approximately 20 years) variability using paired t-tests with log-transformed protein concentrations and Bonferroni-corrected significance thresholds. We performed principal component (PC) analysis of protein analyte concentrations and evaluated their associations with age, sex, race, and estimated glomerular filtration rate (eGFR). RESULTS:The mean baseline age was 57 years at the first visit, 43% of participants were male and 57% were white. Among 3693 protein analytes that passed quality control, half (n = 1846) had CVs < 5.0%, Spearman correlations > 0.89, and ICCs > 0.96 among the split samples. Over the short term, only 1 analyte had a statistically significant difference between the 2 time points, whereas, over approximately 20 years, 866 analytes (23.4%) had statistically significant differences (P < 1.4 × 10-5, 681 increased, 185 decreased). PC1 had high correlations with age (-0.73) and eGFR (0.60). PC2 had moderate correlation with male sex (0.18) and white race (0.31). CONCLUSIONS:Multiplexed modified aptamer technology can assay thousands of proteins with excellent precision. Our results support the potential for large-scale studies of the plasma proteome over the lifespan.

Published
2019

23. Associations between SLC16A11 variants and diabetes in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL)

Author

Hidalgo, Bertha A, Sofer, Tamar, Qi, Qibin, Schneiderman, Neil, Chen, Y-D Ida, Kaplan, Robert C, Avilés-Santa, M Larissa, North, Kari E, Arnett, Donna K, Szpiro, Adam, Cai, Jianwen, Yu, Bing, Boerwinkle, Eric, Papanicolaou, George, Laurie, Cathy C, Rotter, Jerome I, and Stilp, Adrienne M

Subjects
Biological Sciences, Genetics, Clinical Research, Minority Health, Health Disparities, Diabetes, Metabolic and endocrine, Diabetes Mellitus, Type 2, Genetic Association Studies, Genetic Predisposition to Disease, Haplotypes, Hispanic or Latino, Humans, Monocarboxylic Acid Transporters, Polymorphism, Single Nucleotide, United States
Abstract

Five sequence variants in SLC16A11 (rs117767867, rs13342692, rs13342232, rs75418188, and rs75493593), which occur in two non-reference haplotypes, were recently shown to be associated with diabetes in Mexicans from the SIGMA consortium. We aimed to determine whether these previous findings would replicate in the HCHS/SOL Mexican origin group and whether genotypic effects were similar in other HCHS/SOL groups. We analyzed these five variants in 2492 diabetes cases and 5236 controls from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), which includes U.S. participants from six diverse background groups (Mainland groups: Mexican, Central American, and South American; and Caribbean groups: Puerto Rican, Cuban, and Dominican). We estimated the SNP-diabetes association in the six groups and in the combined sample. We found that the risk alleles occur in two non-reference haplotypes in HCHS/SOL, as in the SIGMA Mexicans. The haplotype frequencies were very similar between SIGMA Mexicans and the HCHS/SOL Mainland groups, but different in the Caribbean groups. The SLC16A11 sequence variants were significantly associated with risk for diabetes in the Mexican origin group (P = 0.025), replicating the SIGMA findings. However, these variants were not significantly associated with diabetes in a combined analysis of all groups, although the power to detect such effects was 85% (assuming homogeneity of effects among the groups). Additional analyses performed separately in each of the five non-Mexican origin groups were not significant. We also analyzed (1) exclusion of young controls and, (2) SNP by BMI interactions, but neither was significant in the HCHS/SOL data. The previously reported effects of SLC16A11 variants on diabetes in Mexican samples was replicated in a large Mexican-American sample, but these effects were not significant in five non-Mexican Hispanic/Latino groups sampled from U.S. populations. Lack of replication in the HCHS/SOL non-Mexicans, and in the entire HCHS/SOL sample combined may represent underlying genetic heterogeneity. These results indicate a need for future genetic research to consider heterogeneity of the Hispanic/Latino population in the assessment of disease risk, but add to the evidence suggesting SLC16A11 as a potential therapeutic target for type 2 diabetes.

Published
2019

24. KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference

Author

Schumann, Gunter, Liu, Chunyu, O'Reilly, Paul, Gao, He, Song, Parkyong, Xu, Bing, Ruggeri, Barbara, Amin, Najaf, Jia, Tianye, Preis, Sarah, Segura Lepe, Marcelo, Akira, Shizuo, Barbieri, Caterina, Baumeister, Sebastian, Cauchi, Stephane, Clarke, Toni-Kim, Enroth, Stefan, Fischer, Krista, Hällfors, Jenni, Harris, Sarah E, Hieber, Saskia, Hofer, Edith, Hottenga, Jouke-Jan, Johansson, Åsa, Joshi, Peter K, Kaartinen, Niina, Laitinen, Jaana, Lemaitre, Rozenn, Loukola, Anu, Luan, Jian'an, Lyytikäinen, Leo-Pekka, Mangino, Massimo, Manichaikul, Ani, Mbarek, Hamdi, Milaneschi, Yuri, Moayyeri, Alireza, Mukamal, Kenneth, Nelson, Christopher, Nettleton, Jennifer, Partinen, Eemil, Rawal, Rajesh, Robino, Antonietta, Rose, Lynda, Sala, Cinzia, Satoh, Takashi, Schmidt, Reinhold, Schraut, Katharina, Scott, Robert, Smith, Albert Vernon, Starr, John M, Teumer, Alexander, Trompet, Stella, Uitterlinden, André G, Venturini, Cristina, Vergnaud, Anne-Claire, Verweij, Niek, Vitart, Veronique, Vuckovic, Dragana, Wedenoja, Juho, Yengo, Loic, Yu, Bing, Zhang, Weihua, Zhao, Jing Hua, Boomsma, Dorret I, Chambers, John, Chasman, Daniel I, Daniela, Toniolo, de Geus, Eco, Deary, Ian, Eriksson, Johan G, Esko, Tõnu, Eulenburg, Volker, Franco, Oscar H, Froguel, Philippe, Gieger, Christian, Grabe, Hans J, Gudnason, Vilmundur, Gyllensten, Ulf, Harris, Tamara B, Hartikainen, Anna-Liisa, Heath, Andrew C, Hocking, Lynne, Hofman, Albert, Huth, Cornelia, Jarvelin, Marjo-Riitta, Jukema, J Wouter, Kaprio, Jaakko, Kooner, Jaspal S, Kutalik, Zoltan, Lahti, Jari, Langenberg, Claudia, Lehtimäki, Terho, Liu, Yongmei, Madden, Pamela AF, Martin, Nicholas, Morrison, Alanna, Penninx, Brenda, Pirastu, Nicola, Psaty, Bruce, and Raitakari, Olli

Subjects
Biological Psychology, Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Psychology, Alcoholism, Alcohol Use and Health, Genetics, Basic Behavioral and Social Science, Substance Misuse, Liver Disease, Behavioral and Social Science, Digestive Diseases, Neurosciences, Cardiovascular, Cancer, Oral and gastrointestinal, Stroke, Good Health and Well Being, Alcohol Drinking, Animals, Behavior, Animal, Brain, Emotions, Female, Fibroblast Growth Factors, Genome-Wide Association Study, Humans, Klotho Proteins, Liver, Male, Membrane Proteins, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Polymorphism, Single Nucleotide, alcohol consumption, human, beta-Klotho, FGF21, mouse model, β-Klotho
Abstract

Excessive alcohol consumption is a major public health problem worldwide. Although drinking habits are known to be inherited, few genes have been identified that are robustly linked to alcohol drinking. We conducted a genome-wide association metaanalysis and replication study among >105,000 individuals of European ancestry and identified β-Klotho (KLB) as a locus associated with alcohol consumption (rs11940694; P = 9.2 × 10-12). β-Klotho is an obligate coreceptor for the hormone FGF21, which is secreted from the liver and implicated in macronutrient preference in humans. We show that brain-specific β-Klotho KO mice have an increased alcohol preference and that FGF21 inhibits alcohol drinking by acting on the brain. These data suggest that a liver-brain endocrine axis may play an important role in the regulation of alcohol drinking behavior and provide a unique pharmacologic target for reducing alcohol consumption.

Published
2016

25. Rare Exome Sequence Variants in CLCN6 Reduce Blood Pressure Levels and Hypertension Risk.

Author

Yu, Bing, Pulit, Sara L, Hwang, Shih-Jen, Brody, Jennifer A, Amin, Najaf, Auer, Paul L, Bis, Joshua C, Boerwinkle, Eric, Burke, Gregory L, Chakravarti, Aravinda, Correa, Adolfo, Dreisbach, Albert W, Franco, Oscar H, Ehret, Georg B, Franceschini, Nora, Hofman, Albert, Lin, Dan-Yu, Metcalf, Ginger A, Musani, Solomon K, Muzny, Donna, Palmas, Walter, Raffel, Leslie, Reiner, Alex, Rice, Ken, Rotter, Jerome I, Veeraraghavan, Narayanan, Fox, Ervin, Guo, Xiuqing, North, Kari E, Gibbs, Richard A, van Duijn, Cornelia M, Psaty, Bruce M, Levy, Daniel, Newton-Cheh, Christopher, Morrison, Alanna C, and CHARGE Consortium and the National Heart, Lung, and Blood Institute GO ESP*

Subjects
CHARGE Consortium and the National Heart, Lung, and Blood Institute GO ESP*, Humans, Hypertension, Chloride Channels, Risk Factors, Blood Pressure, Gene Frequency, Alleles, African Continental Ancestry Group, European Continental Ancestry Group, Female, Male, Exome, blood pressure, exome, genetic variation, genome-wide association study, hypertension, CHARGE Consortium and the National Heart, Lung, and Blood Institute GO ESP*, Cardiovascular System & Hematology, Genetics, Cardiorespiratory Medicine and Haematology, Medical Biotechnology
Abstract

BackgroundRare genetic variants influence blood pressure (BP).Methods and resultsWhole-exome sequencing was performed on DNA samples from 17 956 individuals of European ancestry and African ancestry (14 497, first-stage discovery and 3459, second-stage discovery) to examine the effect of rare variants on hypertension and 4 BP traits: systolic BP, diastolic BP, pulse pressure, and mean arterial pressure. Tests of ≈170 000 common variants (minor allele frequency, ≥1%; statistical significance, P≤2.9×10(-7)) and gene-based tests of rare variants (minor allele frequency,

Published
2016

26. Genome-Wide Association Study of Cardiac Structure and Systolic Function in African Americans

Author

Fox, Ervin R, Musani, Solomon K, Barbalic, Maja, Lin, Honghuang, Yu, Bing, Ogunyankin, Kofo O, Smith, Nicholas L, Kutlar, Abdullah, Glazer, Nicole L, Post, Wendy S, Paltoo, Dina N, Dries, Daniel L, Farlow, Deborah N, Duarte, Christine W, Kardia, Sharon L, Meyers, Kristin J, Sun, Yan V, Arnett, Donna K, Patki, Amit A, Sha, Jin, Cui, Xiangqui, Samdarshi, Tandaw E, Penman, Alan D, Bibbins-Domingo, Kirsten, Bková, Petra, Benjamin, Emelia J, Bluemke, David A, Morrison, Alanna C, Heiss, Gerardo, Carr, J Jeffrey, Tracy, Russell P, Mosley, Thomas H, Taylor, Herman A, Psaty, Bruce M, Heckbert, Susan R, Cappola, Thomas P, and Vasan, Ramachandran S

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Human Genome, Genetics, Minority Health, Clinical Research, Heart Disease, Cardiovascular, Black or African American, Aged, Cohort Studies, Diastole, Echocardiography, Female, Genome-Wide Association Study, Genotype, Heart, Humans, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Systole, White People, echocardiography, ethnic, genome-wide association studies, left atrium genetics, left ventricular mass genetics, Medical Biotechnology, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology
Abstract

BackgroundUsing data from 4 community-based cohorts of African Americans, we tested the association between genome-wide markers (single-nucleotide polymorphisms) and cardiac phenotypes in the Candidate-gene Association Resource study.Methods and resultsAmong 6765 African Americans, we related age, sex, height, and weight-adjusted residuals for 9 cardiac phenotypes (assessed by echocardiogram or magnetic resonance imaging) to 2.5 million single-nucleotide polymorphisms genotyped using Genome-wide Affymetrix Human SNP Array 6.0 (Affy6.0) and the remainder imputed. Within the cohort, genome-wide association analysis was conducted, followed by meta-analysis across cohorts using inverse variance weights (genome-wide significance threshold=4.0 ×10(-7)). Supplementary pathway analysis was performed. We attempted replication in 3 smaller cohorts of African ancestry and tested lookups in 1 consortium of European ancestry (EchoGEN). Across the 9 phenotypes, variants in 4 genetic loci reached genome-wide significance: rs4552931 in UBE2V2 (P=1.43×10(-7)) for left ventricular mass, rs7213314 in WIPI1 (P=1.68×10(-7)) for left ventricular internal diastolic diameter, rs1571099 in PPAPDC1A (P=2.57×10(-8)) for interventricular septal wall thickness, and rs9530176 in KLF5 (P=4.02×10(-7)) for ejection fraction. Associated variants were enriched in 3 signaling pathways involved in cardiac remodeling. None of the 4 loci replicated in cohorts of African ancestry was confirmed in lookups in EchoGEN.ConclusionsIn the largest genome-wide association study of cardiac structure and function to date in African Americans, we identified 4 genetic loci related to left ventricular mass, interventricular septal wall thickness, left ventricular internal diastolic diameter, and ejection fraction, which reached genome-wide significance. Replication results suggest that these loci may be unique to individuals of African ancestry. Additional large-scale studies are warranted for these complex phenotypes.

Published
2013

27. Plasma proteome analyses in individuals of European and African ancestry identify cis-pQTLs and models for proteome-wide association studies

Author

Zhang, Jingning, Dutta, Diptavo, Köttgen, Anna, Tin, Adrienne, Schlosser, Pascal, Grams, Morgan E., Harvey, Benjamin, Yu, Bing, Boerwinkle, Eric, Coresh, Josef, and Chatterjee, Nilanjan

Subjects
Gout, Proteome, Genetics, Humans, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Article, Genome-Wide Association Study
Abstract

Improved understanding of genetic regulation of the proteome can facilitate identification of the causal mechanisms for complex traits. We analyzed data on 4,657 plasma proteins from 7,213 European American (EA) and 1,871 African American (AA) individuals from the Atherosclerosis Risk in Communities study, and further replicated findings on 467 AA individuals from the African American Study of Kidney Disease and Hypertension study. Here, we identified 2,004 proteins in EA and 1,618 in AA, with most overlapping, which showed associations with common variants in cis-regions. Availability of AA samples led to smaller credible sets and notable number of population-specific cis-protein quantitative trait loci. Elastic Net produced powerful models for protein prediction in both populations. An application of proteome-wide association studies to serum urate and gout implicated several proteins, including IL1RN, revealing the promise of the drug anakinra to treat acute gout flares. Our study demonstrates the value of large and diverse ancestry study to investigate the genetic mechanisms of molecular phenotypes and their relationship with complex traits.

Published
2022
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28. The small molecule chemical compound cinobufotalin attenuates resistance to DDP by inducing ENKUR expression to suppress MYH9-mediated c-Myc deubiquitination in lung adenocarcinoma

Author

Jia-Hao, Liu, Hui-Ling, Yang, Shu-Ting, Deng, Zhe, Hu, Wei-Feng, Chen, Wei-Wei, Yan, Ren-Tao, Hou, Yong-Hao, Li, Rui-Ting, Xian, Ying-Ying, Xie, Yun, Su, Li-Yang, Wu, Ping, Xu, Zhi-Bo, Zhu, Xiong, Liu, Yu-Ling, Deng, Yu-Bing, Wang, Zhen, Liu, and Wei-Yi, Fang

Subjects
Pharmacology, Lung Neoplasms, Myosin Heavy Chains, Adenocarcinoma of Lung, Antineoplastic Agents, Nasopharyngeal Neoplasms, General Medicine, Myosins, Bufanolides, Gene Expression Regulation, Neoplastic, Ubiquitin-Specific Peptidase 7, Phosphatidylinositol 3-Kinases, Drug Resistance, Neoplasm, Cell Line, Tumor, Humans, Calmodulin-Binding Proteins, Pharmacology (medical), Cisplatin, Proto-Oncogene Proteins c-akt, beta Catenin, Adaptor Proteins, Signal Transducing, Transcription Factors
Abstract

The small molecule chemical compound cinobufotalin (CB) is reported to be a potential antitumour drug that increases cisplatin (DDP) sensitivity in nasopharyngeal carcinoma. In this study, we first found that CB decreased DDP resistance, migration and invasion in lung adenocarcinoma (LUAD). Mechanistic studies showed that CB induced ENKUR expression by suppressing PI3K/AKT signalling to downregulate c-Jun, a negative transcription factor of ENKUR. Furthermore, ENKUR was shown to function as a tumour suppressor by binding to β-catenin to decrease c-Jun expression, thus suppressing MYH9 transcription. Interestingly, MYH9 is a binding protein of ENKUR. The Enkurin domain of ENKUR binds to MYH9, and the Myosin_tail of MYH9 binds to ENKUR. Downregulation of MYH9 reduced the recruitment of the deubiquitinase USP7, leading to increased c-Myc ubiquitination and degradation, decreased c-Myc nuclear translocation, and inactivation of epithelial-mesenchymal transition (EMT) signalling, thus attenuating DDP resistance. Our data demonstrated that CB is a promising antitumour drug and may be a candidate chemotherapeutic drug for LUAD patients.

Published
2022
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29. Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk

Author

Shrine, Nick, Izquierdo, Abril G, Chen, Jing, Packer, Richard, Hall, Robert J, Guyatt, Anna L, Batini, Chiara, Thompson, Rebecca J, Pavuluri, Chandan, Malik, Vidhi, Hobbs, Brian D, Moll, Matthew, Kim, Wonji, Tal-Singer, Ruth, Bakke, Per, Fawcett, Katherine A, John, Catherine, Coley, Kayesha, Piga, Noemi Nicole, Pozarickij, Alfred, Lin, Kuang, Millwood, Iona Y, Chen, Zhengming, Li, Liming, China Kadoorie Biobank Collaborative Group, Wijnant, Sara RA, Lahousse, Lies, Brusselle, Guy, Uitterlinden, Andre G, Manichaikul, Ani, Oelsner, Elizabeth C, Rich, Stephen S, Barr, R Graham, Kerr, Shona M, Vitart, Veronique, Brown, Michael R, Wielscher, Matthias, Imboden, Medea, Jeong, Ayoung, Bartz, Traci M, Gharib, Sina A, Flexeder, Claudia, Karrasch, Stefan, Gieger, Christian, Peters, Annette, Stubbe, Beate, Hu, Xiaowei, Ortega, Victor E, Meyers, Deborah A, Bleecker, Eugene R, Gabriel, Stacey B, Gupta, Namrata, Smith, Albert Vernon, Luan, Jian'an, Zhao, Jing-Hua, Hansen, Ailin F, Langhammer, Arnulf, Willer, Cristen, Bhatta, Laxmi, Porteous, David, Smith, Blair H, Campbell, Archie, Sofer, Tamar, Lee, Jiwon, Daviglus, Martha L, Yu, Bing, Lim, Elise, Xu, Hanfei, O'Connor, George T, Thareja, Gaurav, Albagha, Omar ME, Qatar Genome Program Research (QGPR) Consortium, Suhre, Karsten, Granell, Raquel, Faquih, Tariq O, Hiemstra, Pieter S, Slats, Annelies M, Mullin, Benjamin H, Hui, Jennie, James, Alan, Beilby, John, Patasova, Karina, Hysi, Pirro, Koskela, Jukka T, Wyss, Annah B, Jin, Jianping, Sikdar, Sinjini, Lee, Mikyeong, May-Wilson, Sebastian, Pirastu, Nicola, Kentistou, Katherine A, Joshi, Peter K, Timmers, Paul RHJ, Williams, Alexander T, Free, Robert C, Wang, Xueyang, Morrison, John L, Gilliland, Frank D, Chen, Zhanghua, Wang, Carol A, Foong, Rachel E, Harris, Sarah E, Taylor, Adele, Redmond, Paul, Cook, James P, Mahajan, Anubha, Lind, Lars, Palviainen, Teemu, Lehtimäki, Terho, Raitakari, Olli T, Kaprio, Jaakko, Rantanen, Taina, Pietiläinen, Kirsi H, Cox, Simon R, Pennell, Craig E, Hall, Graham L, Gauderman, W James, Brightling, Chris, Wilson, James F, Vasankari, Tuula, Laitinen, Tarja, Salomaa, Veikko, Mook-Kanamori, Dennis O, Timpson, Nicholas J, Zeggini, Eleftheria, Dupuis, Josée, Hayward, Caroline, Brumpton, Ben, Langenberg, Claudia, Weiss, Stefan, Homuth, Georg, Schmidt, Carsten Oliver, Probst-Hensch, Nicole, Jarvelin, Marjo-Riitta, Morrison, Alanna C, Polasek, Ozren, Rudan, Igor, Lee, Joo-Hyeon, Sayers, Ian, Rawlins, Emma L, Dudbridge, Frank, Silverman, Edwin K, Strachan, David P, Walters, Robin G, Morris, Andrew P, London, Stephanie J, Cho, Michael H, Wain, Louise V, Hall, Ian P, Tobin, Martin D, Shrine, Nick [0000-0003-3641-4371], Chen, Jing [0000-0003-1287-1930], Guyatt, Anna L. [0000-0003-1860-6337], Hobbs, Brian D. [0000-0001-9564-0745], Kim, Wonji [0000-0002-1249-797X], Coley, Kayesha [0000-0003-4951-6799], Chen, Zhengming [0000-0001-6423-105X], Li, Liming [0000-0001-5873-7089], Lahousse, Lies [0000-0002-3494-4363], Uitterlinden, Andre G. [0000-0002-7276-3387], Oelsner, Elizabeth C. [0000-0002-7481-9671], Rich, Stephen S. [0000-0003-3872-7793], Kerr, Shona M. [0000-0002-4137-1495], Vitart, Veronique [0000-0002-4991-3797], Jeong, Ayoung [0000-0003-1542-0756], Gharib, Sina A. [0000-0002-2480-4367], Gieger, Christian [0000-0001-6986-9554], Peters, Annette [0000-0001-6645-0985], Hu, Xiaowei [0000-0001-7804-7392], Smith, Albert Vernon [0000-0003-1942-5845], Luan, Jian’an [0000-0003-3137-6337], Langhammer, Arnulf [0000-0001-5296-6673], Willer, Cristen [0000-0001-5645-4966], Porteous, David [0000-0003-1249-6106], Smith, Blair H. [0000-0002-5362-9430], Campbell, Archie [0000-0003-0198-5078], Sofer, Tamar [0000-0001-8520-8860], Lee, Jiwon [0000-0002-4079-7494], Lim, Elise [0000-0001-8967-8464], Thareja, Gaurav [0000-0003-2277-6400], Albagha, Omar M. E. [0000-0001-5916-5983], Suhre, Karsten [0000-0001-9638-3912], Granell, Raquel [0000-0002-4890-4012], Faquih, Tariq O. [0000-0001-8026-2251], Hiemstra, Pieter S. [0000-0002-0238-5982], Hysi, Pirro [0000-0001-5752-2510], Koskela, Jukka T. [0000-0002-0154-7222], Jin, Jianping [0000-0002-3774-1609], Sikdar, Sinjini [0000-0003-1230-5162], Lee, Mikyeong [0000-0002-3036-3684], May-Wilson, Sebastian [0000-0003-2668-5717], Joshi, Peter K. [0000-0002-6361-5059], Timmers, Paul R. H. J. [0000-0002-5197-1267], Gilliland, Frank D. [0000-0002-9033-7269], Wang, Carol A. [0000-0002-4301-3974], Harris, Sarah E. [0000-0002-4941-5106], Mahajan, Anubha [0000-0001-5585-3420], Palviainen, Teemu [0000-0002-7847-8384], Kaprio, Jaakko [0000-0002-3716-2455], Pietiläinen, Kirsi H. [0000-0002-8522-1288], Cox, Simon R. [0000-0003-4036-3642], Pennell, Craig E. [0000-0002-0937-6165], Wilson, James F. [0000-0001-5751-9178], Vasankari, Tuula [0000-0002-1413-8970], Salomaa, Veikko [0000-0001-7563-5324], Timpson, Nicholas J. [0000-0002-7141-9189], Dupuis, Josée [0000-0003-2871-3603], Brumpton, Ben [0000-0002-3058-1059], Langenberg, Claudia [0000-0002-5017-7344], Weiss, Stefan [0000-0002-3553-4315], Homuth, Georg [0000-0001-6839-0605], Jarvelin, Marjo-Riitta [0000-0002-2149-0630], Morrison, Alanna C. [0000-0001-6381-4296], Rudan, Igor [0000-0001-6993-6884], Lee, Joo-Hyeon [0000-0002-7364-6422], Sayers, Ian [0000-0001-5601-5410], Rawlins, Emma L. [0000-0001-7426-3792], Dudbridge, Frank [0000-0002-8817-8908], Strachan, David P. [0000-0001-7854-1366], Walters, Robin G. [0000-0002-9179-0321], Morris, Andrew P. [0000-0002-6805-6014], London, Stephanie J. [0000-0003-4911-5290], Cho, Michael H. [0000-0002-4907-1657], Wain, Louise V. [0000-0003-4951-1867], Hall, Ian P. [0000-0001-9933-3216], Tobin, Martin D. [0000-0002-3596-7874], Apollo - University of Cambridge Repository, Tampere University, Department of Clinical Chemistry, Clinical Medicine, Department of General Administration, Guyatt, Anna L [0000-0003-1860-6337], Hobbs, Brian D [0000-0001-9564-0745], Uitterlinden, Andre G [0000-0002-7276-3387], Oelsner, Elizabeth C [0000-0002-7481-9671], Rich, Stephen S [0000-0003-3872-7793], Kerr, Shona M [0000-0002-4137-1495], Gharib, Sina A [0000-0002-2480-4367], Luan, Jian'an [0000-0003-3137-6337], Smith, Blair H [0000-0002-5362-9430], Albagha, Omar ME [0000-0001-5916-5983], Faquih, Tariq O [0000-0001-8026-2251], Hiemstra, Pieter S [0000-0002-0238-5982], Koskela, Jukka T [0000-0002-0154-7222], Joshi, Peter K [0000-0002-6361-5059], Timmers, Paul RHJ [0000-0002-5197-1267], Gilliland, Frank D [0000-0002-9033-7269], Wang, Carol A [0000-0002-4301-3974], Harris, Sarah E [0000-0002-4941-5106], Pietiläinen, Kirsi H [0000-0002-8522-1288], Cox, Simon R [0000-0003-4036-3642], Pennell, Craig E [0000-0002-0937-6165], Wilson, James F [0000-0001-5751-9178], Timpson, Nicholas J [0000-0002-7141-9189], Morrison, Alanna C [0000-0001-6381-4296], Rawlins, Emma L [0000-0001-7426-3792], Strachan, David P [0000-0001-7854-1366], Walters, Robin G [0000-0002-9179-0321], Morris, Andrew P [0000-0002-6805-6014], London, Stephanie J [0000-0003-4911-5290], Cho, Michael H [0000-0002-4907-1657], Wain, Louise V [0000-0003-4951-1867], Hall, Ian P [0000-0001-9933-3216], Tobin, Martin D [0000-0002-3596-7874], Epidemiology, and Internal Medicine

Subjects
Smoking, 631/208/205/2138, 45/43, article, 692/699/1785, Polymorphism, Single Nucleotide, 3142 Public health care science, environmental and occupational health, Pulmonary Disease, Chronic Obstructive, Genetics, Humans, 1182 Biochemistry, cell and molecular biology, Genetic Predisposition to Disease, Lung, Genome-Wide Association Study
Abstract

Funder: British Lung Foundation, Funder: National Institute for Health Research (NIHR), Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.

Published
2023
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30. [miRNA-181a-5p inhibits proliferation and migration of osteosarcoma cell line HOS by targeting HOXB4]

Author

Jia-Xi, Li, Xi-Jing, He, Fei, Li, Yu-Tian, Lei, Yu-Bing, Yang, Jing, Li, Gao-Yang, Zong, Min-Chao, Zhao, and Su-E, Chang

Subjects
Homeodomain Proteins, MicroRNAs, Osteosarcoma, Cell Line, Tumor, Humans, Apoptosis, Bone Neoplasms, Cell Proliferation, Transcription Factors
Abstract

To study the effects and mechanisms of miR-181a-5p on the proliferation, cycle and migration of HOS osteosarcoma cells.Real-time quantitative PCR was used to detect the expression of miR-181a-5p and HOXB4 in osteoblast hFOB1.19 cell line and osteosarcoma cell lines (HOS, U2OS, MG63). miR-181a-5p mimics and miR-181a-5p inhibitors were respectively transfected into HOS cells by Lipofectamine 2000, and miR NC group was set as control group. CCK-8 method was used to detect the change in cell proliferation. Flow cytometry was used to detect the changes in cell cycles. Wound healing experiments and Transwell migration experiments were used to detect the changes in cell migration ability. The target gene of miR-181a-5p was predicted by Targetscan website and validated by Dual-luciferase reporter gene system and Western blot.Compared with osteoblast hFOB1.19, miR-181a-5p was low expressed in osteosarcoma cells HOS, U2OS, and MG63(miR-181a-5p is down expressed in osteosarcoma cells, and over-expression miR-181a-5p inhibits the proliferation, cell cycle and migration ability of osteosarcoma cells by targeting HOXB4.

Published
2022

31. The Differential Metabolomes in Cumulus and Mural Granulosa Cells from Human Preovulatory Follicles

Author

Er-Meng Gao, Ri-Cheng Chian, Ling Wang, Rong-Xin Tang, Di Zhang, Bongkoch Turathum, and Yu-Bing Liu

Subjects
medicine.drug_class, medicine.medical_treatment, Andrology, Follicle, Western blot, Tandem Mass Spectrometry, medicine, Humans, Cumulus Cells, Granulosa Cells, In vitro fertilisation, Estradiol, biology, medicine.diagnostic_test, Chemistry, fungi, Obstetrics and Gynecology, Oocyte, PLA2G4A, SCARB1, Cholesterol, Real-time polymerase chain reaction, medicine.anatomical_structure, Estrogen, Metabolome, Oocytes, biology.protein, Female, Chromatography, Liquid
Abstract

This study evaluated the differences in metabolites between cumulus cells (CCs) and mural granulosa cells (MGCs) from human preovulatory follicles to understand the mechanism of oocyte maturation involving CCs and MGCs. CCs and MGCs were collected from women who were undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatment. The differences in morphology were determined by immunofluorescence. The metabolomics of CCs and MGCs was measured by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) followed by quantitative polymerase chain reaction (qPCR) and western blot analysis to further confirm the genes and proteins involved in oocyte maturation. CCs and MGCs were cultured for 48 h in vitro, and the medium was collected for detection of hormone levels. There were minor morphological differences between CCs and MGCs. LC-MS/MS analysis showed that there were differences in 101 metabolites between CCs and MGCs: 7 metabolites were upregulated in CCs, and 94 metabolites were upregulated in MGCs. The metabolites related to cholesterol transport and estradiol production were enriched in CCs, while metabolites related to antiapoptosis were enriched in MGCs. The expression of genes and proteins involved in cholesterol transport (ABCA1, LDLR, and SCARB1) and estradiol production (SULT2B1 and CYP19A1) was significantly higher in CCs, and the expression of genes and proteins involved in antiapoptosis (CRLS1, LPCAT3, and PLA2G4A) was significantly higher in MGCs. The level of estrogen in CCs was significantly higher than that in MGCs, while the progesterone level showed no significant differences. There are differences between the metabolomes of CCs and MGCs. These differences may be involved in the regulation of oocyte maturation.

Published
2021
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32. A Novel Multi-view Bi-clustering method for identifying abnormal Co-occurrence medical visit behaviors

Author

Yu-Bing Guo, Zi-Xin Zheng, Lan-Ju Kong, Wei Guo, Zhong-Min Yan, Li-Zhen Cui, and And Xiao-Fang Wang

Subjects
Humans, Cluster Analysis, Molecular Biology, General Biochemistry, Genetics and Molecular Biology, Algorithms
Abstract

Abnormal co-occurrence medical visit behavior is a form of medical insurance fraud. Specifically, an organized gang of fraudsters hold multiple medical insurance cards and purchase similar drugs frequently at the same time and the same location in order to siphon off medical insurance funds. Conventional identification methods to identify such behaviors rely mainly on manual auditing, making it difficult to satisfy the needs of identifying the small number of fraudulent behaviors in the large-scale medical data. On the other hand, the existing single-view bi-clustering algorithms only consider the features of the time-location dimension while neglecting the similarities in prescriptions and neglecting the fact that fraudsters may belong to multiple gangs. Therefore, in this paper, we present a multi-view bi-clustering method for identifying abnormal co-occurrence medical visit behavioral patterns, which performs cluster analysis simultaneously on the large-scale, complex and diverse visiting record dimension and prescription dimension to identify bi-clusters with similar time-location features. The proposed method constructs a matrix view of patients and visit records as well as a matrix view of patients and prescriptions, while decomposing multiple data matrices into sparse row and column vectors to obtain a consistent patient population across views. Subsequently the proposed method identifies the corresponding abnormal co-occurrence medical visit behavior and may greatly facilitate the safe operations and the sustainability of medical insurance funds. The experimental results show that our proposed method leads to more efficient and more accurate identifications of abnormal co-occurrence medical visit behavior, demonstrating its high efficiency and effectiveness.

Published
2022

33. Dysregulated sphingolipid metabolism and autophagy in granulosa cells of women with endometriosis

Author

Bongkoch, Turathum, Er-Meng, Gao, Khwanthana, Grataitong, Yu-Bing, Liu, Ling, Wang, Xue, Dai, and Ri-Cheng, Chian

Subjects
Male, Sphingolipids, Granulosa Cells, Semen, Tandem Mass Spectrometry, Endocrinology, Diabetes and Metabolism, Autophagy, Endometriosis, Humans, Female, Ceramides, Cells, Cultured, Chromatography, Liquid
Abstract

We evaluated metabolic profiles between cumulus cells (CCs) and mural granulosa cells (MGCs) derived from women with endometriosis to identify their correlations with oocyte quality. CCs and MGCs were collected from women with and without endometriosis undergoing in vitro fertilization/intracytoplasmic sperm injection treatment. The metabolomics of CCs and MGCs were measured by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) followed by a quantitative polymerase chain reaction to further confirm the genes involved in the metabolic results. LC-MS/MS analysis revealed differences in 24 metabolites of CCs and 71 metabolites of MGCs between groups. Among them, five metabolites were upregulated and 19 metabolites were downregulated in CCs with endometriosis, whereas three metabolites were upregulated and 68 metabolites were downregulated in MGCs with endometriosis. Metabolites related to sphingolipid metabolism, which included palmitic acid (PA) and docosahexaenoic acid, increased significantly only in CCs with endometriosis, whereas sphingosine and PA were significantly downregulated in MGCs with endometriosis compared with CCs and MGCs without endometriosis. Gene expression involved in ceramide synthesis (CERS1, SPTL1, and SMPD1) and autophagy (BECN1, LAMP, and PC3) were significantly higher in CCs with endometriosis according to FASN, BECN1, and LAMP protein expressions. However, gene expression involved in ceramide synthesis (SPHK1, ASAH1, and SGPP1) and autophagy (BECN1, LAMP, and PC3) were significantly lower in MGCs with endometriosis, whereas CERS1 and UGCG expression increased. There are differences in sphingolipid metabolites in CCs and MGCs with endometriosis compared with women without endometriosis. These differences seem to be involved in the regulation of autophagic cell death in preovulatory follicles.

Published
2022
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34. Fatigue correlates with sleep disturbances in Parkinson disease

Author

Han-Ying Gu, Cheng-Jie Mao, Yu-Bing Shen, Yu-Lan Cao, Xiang-Yang Cao, Jin-Ru Zhang, Fen Wang, Chun-Feng Liu, and Yun Shen

Subjects
Sleep Wake Disorders, medicine.medical_specialty, Sleep behavior disorder, Hamilton Anxiety Rating Scale, Polysomnography, lcsh:Medicine, REM Sleep Behavior Disorder, REM sleep behavior disorder, 03 medical and health sciences, 0302 clinical medicine, Rating scale, Humans, Medicine, Fatigue, Depression (differential diagnoses), medicine.diagnostic_test, business.industry, lcsh:R, Hamilton Rating Scale for Depression, Chronic fatigue, Original Articles, General Medicine, medicine.disease, Parkinson disease, 030220 oncology & carcinogenesis, Physical therapy, Anxiety, medicine.symptom, Sleep, business, 030217 neurology & neurosurgery
Abstract

Background:. Many Parkinson disease (PD) patients complain about chronic fatigue and sleep disturbances during the night. The objective of this study is to determine the relationship between fatigue and sleep disturbances by using polysomnography (PSG) in PD patients. Methods:. Two hundred and thirty-two PD patients (152 with mild fatigue and 80 with severe fatigue) were recruited in this study. Demographic information and clinical symptoms were collected. Fatigue severity scale (FSS) was applied to evaluate the severity of fatigue, and PSG was conducted in all PD patients. FSS ≥4 was defined as severe fatigue, and FSS

Published
2021
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35. [Nephrotic Syndrome Caused by AA Amyloidosis Secondary to Unicentric Castleman's Disease:Report of One Case]

Author

Rui-Lian, You, Yu-Bing, Wen, Jing, Wang, Jie, Ma, Li-Meng, Chen, and Xue-Mei, Li

Subjects
Serum Amyloid A Protein, Nephrotic Syndrome, Castleman Disease, Humans, Amyloidosis
Abstract

AA amyloidosis is a rare systemic complication caused commonly by chronic inflammatory arthritis,periodic fever disease,vasculitis,tumors,etc.Castleman's disease is an uncommon cause of AA amyloidosis.Here,we reported a case of unicentric Castleman's disease-induced AA amyloidosis with nephrotic syndrome as the main manifestation.The laboratory examination showed elevated levels of inflammatory indicators.We summarized the clinical manifestations,diagnosis,and therapy of this case,aiming to facilitate the management of patients with unknown reasons of renal amyloidosis.

Published
2022

36. Bazedoxifene Plays a Protective Role against Inflammatory Injury of Endothelial Cells by Targeting CD40

Author

Zizhao Tang, Ren Guo, Fangqin Nie, Panhao Huang, Wenmin Song, Qi Pei, and Yu Bing Lv

Subjects
0301 basic medicine, Indoles, Article Subject, THP-1 Cells, Anti-Inflammatory Agents, RM1-950, medicine.disease_cause, Antioxidants, Bazedoxifene, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, Cell Movement, Cell Adhesion, Human Umbilical Vein Endothelial Cells, medicine, Diseases of the circulatory (Cardiovascular) system, Humans, Pharmacology (medical), Viability assay, CD40 Antigens, Inflammation, Pharmacology, CD40, biology, Tumor Necrosis Factor-alpha, business.industry, General Medicine, Glycoprotein 130, Coculture Techniques, Oxidative Stress, 030104 developmental biology, Selective estrogen receptor modulator, RC666-701, 030220 oncology & carcinogenesis, biology.protein, Cancer research, Therapeutics. Pharmacology, Signal transduction, Reactive Oxygen Species, Cardiology and Cardiovascular Medicine, business, Oxidative stress, Signal Transduction, Research Article, medicine.drug
Abstract

The inflammatory response and oxidative stress play key roles in the formation and development of atherosclerosis. Bazedoxifene is a new IL6/GP130 inhibitor recommended by the FDA for clinical use as a selective estrogen receptor modulator. However, its role in cardiovascular diseases has been poorly studied. In our study, we explored the mechanism of bazedoxifene’s protective effect against inflammatory injury of vascular endothelial cells (VECs) stimulated by TNF-α. Various methods were used to verify the effect of bazedoxifene on VECs, including a cell viability assay, a wound healing assay, immunofluorescence staining, and western blotting. Our results showed that TNF-α could induce inflammatory damage to VECs, which manifested as upregulated expression of CD40, increased production of ROS, enhanced adhesion of THP-1 cells to VECs, and impaired viability and migration of VECs, while bazedoxifene could significantly reduce the endothelial damage caused by TNF-α. In addition, we found that an siRNA targeting CD40 dramatically alleviated the VEC damage induced by TNF-α. Therefore, we explored the potential relationship between bazedoxifene and CD40. Our data suggest that bazedoxifene has a protective effect against VEC damage induced by TNF-α and that its underlying mechanism may be related to the regulation of CD40.

Published
2020
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37. Expression and localization of retinoid receptors in the testis of normal and infertile men

Author

Xiao-Long Wu, Guishuan Wang, Ajuan Liang, Yu‐Bing Dai, and Fei Sun

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, Receptors, Retinoic Acid, medicine.drug_class, Retinoic acid, Gene Expression, Retinoic acid receptor beta, Biology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Testis, Genetics, medicine, Humans, Tissue Distribution, Retinoid, Spermatogenesis, Infertility, Male, Sertoli Cells, 030219 obstetrics & reproductive medicine, Retinoid X receptor alpha, Sertoli Cell-Only Syndrome, Oligospermia, Cell Biology, Retinoic acid receptor gamma, Retinoid X receptor gamma, 030104 developmental biology, Endocrinology, chemistry, Retinoic acid receptor alpha, Case-Control Studies, Retinoid X receptor beta, Developmental Biology
Abstract

Retinoic acid (RA), the active metabolite of vitamin A, is one of the most important factors regulating spermatogenesis. RA activates downstream pathways through its receptors (retinoic acid receptor alpha [RARA], retinoic acid receptor beta, and retinoic acid receptor gamma [RARG]) and retinoid X receptors (retinoid X receptor alpha [RXRA], retinoid X receptor beta [RXRB], and retinoid X receptor gamma [RXRG]). These receptors may serve as therapeutic targets for infertile men. However, the localization and expression of retinoid receptors in normal and infertile men were unknown. In this study, we found RARA and RARG were mostly localized in spermatocytes and round spermatids, RXRB was mainly expressed in Sertoli cells, and RXRG was expressed in most cell types in the fertile human testis. The localization of RARA, RARG, RXRB, and RXRG in men with hypospermatogenesis (HYPO) was similar to that of men with normal fertility. In addition, the messenger RNA expression levels of RARA, RARG, RXRA, RXRB, and RXRG were significantly decreased in men with Sertoli cell-only syndrome (SCOS) and maturational arrest (MA), but not in men with HYPO. These results suggest that reduced levels of RARA, RARG, RXRB, RXRA, and RXRG are more closely associated with SCOS and MA spermatogenetic failure. These results could contribute to the development of new molecular indicators of spermatogenic dysfunction and might provide novel therapeutic targets for treating male infertility.

Published
2020
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38. Gut dysbiosis-influence on amygdala-based functional activity in patients with end stage renal disease: a preliminary study

Author

Ya Liu, Zhihong Zhang, Long Jiang Zhang, Jianhui Zhong, Guangming Lu, Li Lin, Yun Fei Wang, Li Juan Zheng, Han Zhang, Dehua Gong, Yu Bing Ye, and Xin Yuan Zhang

Subjects
Adult, Male, medicine.medical_specialty, Cognitive Neuroscience, Systemic inflammation, Amygdala, Gastroenterology, 050105 experimental psychology, End stage renal disease, 03 medical and health sciences, Behavioral Neuroscience, Cellular and Molecular Neuroscience, 0302 clinical medicine, Internal medicine, medicine, Humans, 0501 psychology and cognitive sciences, Radiology, Nuclear Medicine and imaging, Prospective Studies, Effects of sleep deprivation on cognitive performance, Anterior cingulate cortex, business.industry, 05 social sciences, Cognitive disorder, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Gastrointestinal Microbiome, Psychiatry and Mental health, medicine.anatomical_structure, Mood, Neurology, Dysbiosis, Kidney Failure, Chronic, Anxiety, Female, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

Patients with end-stage renal disease (ESRD) are notably accompanied by cognitive disorder and anxiety or depressive symptom. We aimed to explore the linkages of the amygdala-based MR parameters, cognitive and mood performance, systematic inflammation and gut microbiota in ESRD. This prospective study enrolled 28 ESRD patients (13 males and 15 females, mean age of 43.9 ± 13.8 years) and 19 age- and sex-matched healthy control (HC) (12 males and 7 females, mean age of 44.1 ± 10.0 years). All subjects underwent cognitive assessment, inflammatory factor and stool microbiota analysis, and brain MRI analysis [amygdala-based functional connectivity and voxel-based morphometry (VBM)]. ERSD was separated by different microbiota strains. All factors were compared between ESRD and HC, as well as between ESRD subgroups. Pearson correlation analysis and causal mediation analysis were conducted to further investigate the relationship among the factors derived from the gut microbiota, brain and systemic inflammation. ESRD displayed gut dysbiosis and increased systemic inflammation when compared to HC (all P

Published
2020
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39. Genetic diversity fuels gene discovery for tobacco and alcohol use

Author

Saunders, Gretchen R. B., Wang, Xingyan, Chen, Fang, Jang, Seon-Kyeong, Liu, Mengzhen, Wang, Chen, Gao, Shuang, Jiang, Yu, Khunsriraksakul, Chachrit, Otto, Jacqueline M., Addison, Clifton, Akiyama, Masato, Albert, Christine M., Aliev, Fazil, Alonso, Alvaro, Arnett, Donna K., Ashley-Koch, Allison E., Ashrani, Aneel A., Barnes, Kathleen C., Barr, R. Graham, Bartz, Traci M., Becker, Diane M., Bielak, Lawrence F., Benjamin, Emelia J., Bis, Joshua C., Bjornsdottir, Gyda, Blangero, John, Bleecker, Eugene R., Boardman, Jason D., Boerwinkle, Eric, Boomsma, Dorret, Boorgula, Meher Preethi, Bowden, Donald W., Brody, Jennifer A., Cade, Brian E., Chasman, Daniel, Chavan, Sameer, Chen, Yii-Der Ida, Chen, Zhengming, Cheng, Iona, Cho, Michael H., Choquet, Helene, Cole, John W., Cornelis, Marilyn C., Cucca, Francesco, Curran, Joanne E., de Andrade, Mariza, Dick, Danielle M., Docherty, Anna R., Duggirala, Ravindranath, Eaton, Charles B., Ehringer, Marissa A., Esko, Tonu, Faul, Jessica D., Silva, Lilian Fernandes, Fiorillo, Edoardo, Fornage, Myriam, Freedman, Barry, Gabrielsen, Maiken E., Garrett, Melanie E., Gharib, Sina A., Gieger, Christian, Gillespie, Nathan, Glahn, David C., Gordon, Scott D., Gu, Charles C., Gu, Dongfeng, Gudbjartsson, Daniel F., Guo, Xiuqing, Haessler, Jeffrey, Hall, Michael E., Haller, Toomas, Harris, Kathleen Mullan, He, Jiang, Herd, Pamela, Hewitt, John K., Hickie, Ian, Hidalgo, Bertha, Hokanson, John E., Hopfer, Christian, Hottenga, JoukeJan, Hou, Lifang, Huang, Hongyan, Hung, Yi-Jen, Hunter, David J., Hveem, Kristian, Hwang, Shih-Jen, Hwu, Chii-Min, Iacono, William, Irvin, Marguerite R., Jee, Yon Ho, Johnson, Eric O., Joo, Yoonjung Y., Jorgenson, Eric, Justice, Anne E., Kamatani, Yoichiro, Kaplan, Robert C., Kaprio, Jaakko, Kardia, Sharon L. R., Keller, Matthew C., Kelly, Tanika N., Kooperberg, Charles, Korhonen, Tellervo, Kraft, Peter, Krauter, Kenneth, Kuusisto, Johanna, Laakso, Markku, Lasky-Su, Jessica, Lee, Wen-Jane, Lee, James J., Levy, Daniel, Li, Liming, Li, Kevin, Li, Yuqing, Lin, Kuang, Lind, Penelope A., Liu, Chunyu, Lloyd-Jones, Donald M., Lutz, Sharon M., Ma, Jiantao, Magi, Reedik, Manichaikul, Ani, Martin, Nicholas G., Mathur, Ravi, Matoba, Nana, McArdle, Patrick F., McGue, Matt, McQueen, Matthew B., Medland, Sarah E., Metspalu, Andres, Meyers, Deborah A., Millwood, Iona Y., Mitchell, Braxton D., Mohlke, Karen L., Moll, Matthew, Montasser, May E., Morrison, Alanna C., Mulas, Antonella, Nielsen, Jonas B., North, Kari E., Oelsner, Elizabeth C., Okada, Yukinori, Orru, Valeria, Palmer, Nicholette D., Palviainen, Teemu, Pandit, Anita, Park, S. Lani, Peters, Ulrike, Peters, Annette, Peyser, Patricia A., Polderman, Tinca J. C., Rafaels, Nicholas, Redline, Susan, Reed, Robert M., Reiner, Alex P., Rice, John P., Rich, Stephen S., Richmond, Nicole E., Roan, Carol, Rotter, Jerome, Rueschman, Michael N., Runarsdottir, Valgerdur, Saccone, Nancy L., Schwartz, David A., Shadyab, Aladdin H., Shi, Jingchunzi, Shringarpure, Suyash S., Sicinski, Kamil, Skogholt, Anne Heidi, Smith, Jennifer A., Smith, Nicholas L., Sotoodehnia, Nona, Stallings, Michael C., Stefansson, Hreinn, Stefansson, Kari, Stitzel, Jerry A., Sun, Xiao, Syed, Moin, Tal-Singer, Ruth, Taylor, Amy E., Taylor, Kent D., Telen, Marilyn J., Thai, Khanh K., Tiwari, Hemant, Turman, Constance, Tyrfingsson, Thorarinn, Wall, Tamara L., Walters, Robin G., Weir, David R., Weiss, Scott T., White, Wendy B., Whitfield, John B., Wiggins, Kerri L., Willemsen, Gonneke, Willer, Cristen J., Winsvold, Bendik S., Xu, Huichun, Yanek, Lisa R., Yin, Jie, Young, Kristin L., Young, Kendra A., Yu, Bing, Zhao, Wei, Zhou, Wei, Zollner, Sebastian, Zuccolo, Luisa, Project, The Biobank Japan, Batini, Chiara, Bergen, Andrew W., Bierut, Laura J., David, Sean P., Taliun, Sarah A. Gagliano, Hancock, Dana B., Jiang, Bibo, Munafo, Marcus R., Thorgeirsson, Thorgeir E., Liu, Dajiang J., Vrieze, Scott, Pediatrics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Biological Psychology, Amsterdam Reproduction & Development, APH - Mental Health, APH - Methodology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Clinical Developmental Psychology, Institute for Molecular Medicine Finland, University Management, Tellervo Korhonen / Principal Investigator, Genetic Epidemiology, and University of Helsinki

Subjects
Multidisciplinary, Internationality, Protein, Genetic Predisposition to Disease/genetics, 1184 Genetics, developmental biology, physiology, Neurotrophic factors, Alcohol Drinking/genetics, Europe/ethnology, Genetic Variation/genetics, Tobacco Use/genetics, SDG 3 - Good Health and Well-being, Risk Factors, Sample Size, Genetic Loci/genetics, Genome-Wide Association Study/methods, Humans, Disease, 3111 Biomedicine, Prediction, Transcriptome, Multifactorial Inheritance/genetics, Model
Abstract

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury1–4. These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries5. Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.

Published
2022
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40. Panax notoginseng saponins prevent colitis-associated colorectal cancer via inhibition IDO1 mediated immune regulation

Author

Xue-Ming LI, Ding-Yi YUAN, Ya-Hui LIU, Lei ZHU, Hong-Kun QIN, Yu-Bing YANG, Yan LI, Fang YAN, and Ya-Jing WANG

Subjects
Mice, Complementary and alternative medicine, Macrophages, Drug Discovery, Tumor Microenvironment, Animals, Humans, Panax notoginseng, General Medicine, Colitis-Associated Neoplasms, Saponins, Colitis
Abstract

Colorectal cancer (CRC) is the third most lethal cancer and leading cause of cancer mortality worldwide. A key driver of CRC development is colon inflammatory responses especially in patients with inflammatory bowl disease (IBD). It has been proved that Panax notoginseng saponins (PNS) have anti-inflammatory, anti-oxidant and anti-tumor effects. The chemopreventive and immunomodulatory functions of PNS on colitis-associated colorectal cancer (CAC) have not been evaluated.This present study was designed to study the potential protective effects of PNS on AOM/DSS-induced CAC mice to explore the possible mechanism of PNS against CAC. Our study showed that PNS significantly alleviated colitis severity and prevented the occurrence of CAC. Functional assays revealed that PNS relieved immunosuppression of Treg cells in the CAC microenvironment by inhibiting the expression of IDO1 mediated directly by signal transducer and activator of transcription 1 (STAT1) rather than phosphorylated STAT1. Ultimately, Rh1, one of the PNS metabolites, exhibited the best inhibitory effect on IDO1 enzyme activity. Our study showed that PNS exerted significant chemopreventive function and immunomodulatory properties on CAC. It could reduce macrophages accumulation and Treg cells differentiation to reshape the immune microenvironment of CAC. These findings provided a promising approach for CAC intervention.

Published
2021

41. Intrathecally administered pizotifen alleviates neuropathic and inflammatory pain in mice by enhancing GABAergic inhibition

Author

Jun Li, Xue Zhang, Chu Xu, Yun-Xin Liu, Chun Ge, Zheng Zhao, Yu-Bing Zhu, and Hong-Guang Bao

Subjects
Analgesics, Pizotyline, Serotonin, Spinal Cord Dorsal Horn, General Neuroscience, Freund's Adjuvant, Disease Models, Animal, Mice, Spinal Cord, Hyperalgesia, Animals, Humans, Neuralgia, Chronic Pain
Abstract

Chronic pain, such as chronic neuropathic pain and chronic inflammatory pain, is often difficult to manage and bring great trouble to patients. 5-HT plays a key role in the process of pain transmission both in centrally and peripherally. Tricyclic antidepressants (TCA) such as amitriptyline are classical 5-HT reuptake inhibitors, are recommended as the first-line treatment for chronic pain. Pizotifen, a 5-HT2 receptor antagonist, is currently used in the prevention of vascular headaches. However, the antinociceptive effect of pizotifen on non-headache pain especially chronic pain in the spinal level is still unknown. Here we find that intrathecal pizotifen attenuates neuropathic and inflammatory pain mainly due to elevated GABAergic synaptic inhibition. Neuropathic pain is induced by segmental spinal nerve ligation (SNL), and inflammatory pain is induced by intraplantar injection of complete Freund's adjuvant (CFA). Both in SNL and CFA mice, spinally administered pizotifen reduced mechanical and thermal hyperalgesia dose-dependently. Since the levels of GAD65/67 were increased, and the frequency of mIPSCs in the spinal dorsal horn was increased, together with the antinociceptive effect being reversed by both GABA

Published
2021

42. Identification of vasospasm biomarkers for cerebral hemorrhage via bio-informatics analysis

Author

Li-Ya Wu, Yu-Bing Liang, Sheng-Yu Li, Guan-Feng Xie, Yu-Jia Mei, and Chao Qin

Subjects
Advanced and Specialized Nursing, Anesthesiology and Pain Medicine, Gene Expression Profiling, Computational Biology, Humans, Protein Interaction Maps, Biomarkers, Cerebral Hemorrhage
Abstract

The incidence of cerebral hemorrhage has rapidly increased over time, and vascular dysfunction has a significant influence on the pathogenesis and outcome of these patients. This is also the case for vasospasm in cerebral hemorrhage, but there is no method to assess this. We conducted this study to find molecular biomarkers of vasospasm in cerebral hemorrhage patients.Raw data of GSE37924 was downloaded from the Gene Expression Omnibus (GEO) database, including 66 samples with cerebral vasospasm and 62 samples without cerebral vasospasm. Differentially expressed genes (DEGs) between samples with cerebral vasospasm and those without cerebral vasospasm were analyzed using the limma package in R software. To determine the functions of DEGs, we conducted functional enrichment analysis of DEGs through the clusterProfiler package in R. The protein-protein interaction (PPI) network of DEGs was constructed through STRING (https://string-db.org/) and generated via Cytoscape software. To understand the correlation between DEGs and immune-related genes, immune-related cerebral vasospasm genes were obtained via intersecting immune-related genes and cerebral vasospasm DEGs. We also compared the infiltration of 28 immune cells between cases with cerebral vasospasm and those without cerebral vasospasm. Finally, we constructed a model to perform the validation experiments.Of the DEGs, there were 24 upregulated and 21 downregulated genes in the vasospasm samples compared to the no-vasospasm samples. Functional enrichment analysis showed that these genes play key roles in several biological processes and signaling pathways such as the bone morphogenetic protein (BMP) signaling pathway, cellular response to BMP stimulus, natural killer cell chemotaxis, negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway, MHC protein complex binding, and receptor ligand activity, among others. CCL4, HLA-DQA1, IGF2, NTS, and so on were the significant immune-related genes. Furthermore, the immune cell infiltration results showed that there were differences between patients with vasospasm and those without vasospasm. Finally, we found that CCL4 had significantly higher expression in patients with vasospasm than those without vasospasm.CCL4 is an important regulator of vascular dysfunction in cerebral hemorrhage.

Published
2021

43. hsa_circ_0006459 and hsa_circ_0015962 affect prognosis of Dengue fever

Author

Jin-Hua He, BoYing Dai, Jia-Bin Zhou, Meng Ling He, Yue Ming, Jianwei Jiang, Yuguang Li, Zeping Han, Mao Fang, Yu MinLi, and Yu-Bing Lv

Subjects
0301 basic medicine, Microarray, Molecular biology, lcsh:Medicine, Article, Dengue virus, Dengue, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, microRNA, Gene expression, Humans, lcsh:Science, Regulation of gene expression, Multidisciplinary, Chemistry, Microarray analysis techniques, Gene Expression Profiling, lcsh:R, RNA, Circular, Prognosis, Gene expression profiling, MicroRNAs, 030104 developmental biology, Real-time polymerase chain reaction, HEK293 Cells, Gene Expression Regulation, 030220 oncology & carcinogenesis, Leukocytes, Mononuclear, lcsh:Q
Abstract

Circular ribonucleic acids (circRNAs) are widely expressed in human cells and play an important role in the pathogenesis of many diseases. Some circRNAs have microRNA (miRNA) binding response elements and interact with miRNA to regulate the expression of target genes.Four patients with a preliminary diagnosis of dengue fever (DF), peripheral whole blood sample in anticoagulant was collected before treatment (pretreatment group) and after effective treatment (posttreatment group), and eight samples were separated and used to screen differentially expressed circRNAs with microarray analysis. The relative expression level of circRNAs was determined using reverse-transcription polymerase chain reaction (RT-PCR). TargetScan v7.1 and miRDB v5 bioinformatics software were used to predict circRNA-binding miRNAs; dual luciferase reporters were constructed to detect binding between circRNA and miRNA. Microarray screening revealed 263 differentially expressed circRNAs in peripheral leukocytes pretreatment versus posttreatment; 107 of these were upregulated and 156 were downregulated. RT-PCR confirmed that hsa_circ_0015962 was significantly upregulated and hsa_circ_0006459 significantly downregulated (P

Published
2019
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44. The gut microbiota-inflammation-brain axis in end-stage renal disease: perspectives from default mode network

Author

Guangming Lu, Yu Bing Ye, Dehua Gong, Ya Liu, Long Jiang Zhang, Yun Fei Wang, Li Juan Zheng, and Song Luo

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, inflammatory cytokine, resting state fMRI, Medicine (miscellaneous), Inflammation, Gut flora, Systemic inflammation, Gastroenterology, Proinflammatory cytokine, End stage renal disease, 03 medical and health sciences, default mode network, 0302 clinical medicine, Internal medicine, medicine, Humans, Cognitive Dysfunction, Prospective Studies, Prospective cohort study, Pharmacology, Toxicology and Pharmaceutics (miscellaneous), Default mode network, Brain Mapping, end-stage renal disease, Resting state fMRI, biology, gut microbiota, business.industry, Brain, Middle Aged, biology.organism_classification, Magnetic Resonance Imaging, Gastrointestinal Microbiome, 030104 developmental biology, Cytokines, Kidney Failure, Chronic, Female, medicine.symptom, business, 030217 neurology & neurosurgery, Research Paper
Abstract

The gut-brain axis in end-stage renal disease (ESRD) is attracting more and more attention. However, the mechanism of gut-brain axis based cognitive disorders in ESRD patients remains unclear. The purpose of this study was to investigate the linkages between the gut microbiota, inflammatory cytokines, brain default mode network (DMN) and cognitive function in ESRD patients. Methods: This prospective study enrolled 28 ESRD patients (13 males and 15 females, mean age of 44 ± 14 years) and 19 healthy controls (HCs) (12 males and 7 females, mean age of 44 ± 10 years). All subjects underwent stool microbiota analysis, blood inflammatory cytokines examination, brain MRI scans and cognitive assessments. Resting state functional MRI (rs-fMRI) data were used to construct DMN and graph theory was applied to characterize network topological properties. Two samples t-test was applied for the comparisons between ESRD and HCs. Correlation analysis and mediation analysis were conducted among factors with significant group differences. Results: ESRD patients displayed gut microbiota alterations, increased systemic inflammation and worse cognitive performance compared to HCs (all p < 0.05). Graph analysis revealed disrupted DMN topological organization, aberrant nodal centralities and functional connectivities (FCs) in ESRD patients relative to HCs (all p < 0.05, FDR corrected). Significant correlations were found between gut microbiota, inflammatory cytokines, DMN network measures and cognitive assessments. Mediation analysis found that gut microbiota alteration impaired DMN connectivity by increasing systemic inflammation. Conclusion: The present study first revealed gut microbiota alterations, systemic inflammation, DMN dissociation and cognitive dysfunction in ESRD patients simultaneously and further illuminated their inner relationship.

Published
2019

45. Global attitudes in the management of acute appendicitis during COVID-19 pandemic: ACIE Appy Study

Author

Benedetto, Ielpo, Mauro, Podda, Gianluca, Pellino, Pata, Francesco, Gianpiero, Gravante, Salomone Di Saverio, Gallo, Gaetano, Rashid, Lui, Adam, Orengia, Aditya, Chowdary, Aditya, Kulkarni, Adnan, Kuvvetli, Adolfo, Navarro, Adolfo, Pisanu, Adrian, Smith, Adriana Cavero Ibiricu, Aeris Jane, D Nacion, Ahmad, Alsaleh, Ahmad, Alhazmi, Ahmad, Elmabri, Ajaz, Wani, Ahmet, Rencuzogullari, Aingeru Sarriugarte Lasarte, Ainhoa Valle Rubio, Akshay, Bavikatte, Akshay, Kumar, Al-Radjid, Jamiri, Alain Michel Alvarado Padilla, Alban, Cacurri, Alberto de San Ildefonso, Alberto, Porcu, Alberto, Sartori, Aldo, Rocca, Alejandro Paz Yáñez, Alejandro, Becaria, Alejandro, Solís-Peña, Aleksandar, Sretenović, Alex, Urbistondo, Alfonso, Bandin, Alfonso, Najar, Alessandro De Luca, Alex, Boddy, Alexandros, Charalabopoulos, Alexios, Tzivanakis, Alfonso, Amendola, Alfredo Ramirez-Gutierrez de Velasco, Ali Cihat Yildirim, Alice, Frontali, Alpha Oumar Toure, Alvaro, García-Granero, Amaia Martínez Roldan, Amaia Sanz Larrainzar, Amila Sanjiva Ratnayake, Ana María Gonzalez-Ganso, Ana, M Minaya-Bravo, Andre, Das, Andrea, Bondurri, Andrea, Costanzi, Andrea, Lucchi, Andrea, Mazzari, Andrea, Musig, Andrea, Peloso, Andrea, Piano, Andrea, Police, Andrei, Mihailescu, Andrés, Pouy, Angela, Romano, Iossa, Angelo, Anna Carmen Leonetti, Anna, Guariniello, Anna, Isaac, Anna Pia Delli Bovi, Antonella, Chessa, Antonella, Tromba, Antonio Álvarez Martínez, Antonio, Brillantino, Antonio, Caira, Antonio, Castaldi, Antonio, Ferronetti, Antonio, Giuliani, Antonio, Prestera, Antonio Ramos-De la Medina, Antonio, Tarasconi, Antonino, Tornambè, Arcangelo, Picciariello, Argyrios, Ioannidis, Ari, Leppäniemi, Arshad, Khan, Arshad, Rashid, Arteaga Luis Eduardo Pérez-Sánchez, Ashok, Mittal, Ashrarur Rahman Mitul, Asif, Mehraj, Asim, Laharwal, Asnel, Dorismé, Athanasios, Marinis, Atif, Iqbal, Augusto, Moncada, Bartolomeo, Braccio, Basim, Alkhafaji, Beatriz de Andrés Asenjo, Beatriz, Martin-Perez, Belinda Sánchez Pérez, Ben, Creavin, Benedetto, Calì, Beniamino, Pascotto, Benjamin, Stubbs, Benjamin Zavala Retes, Branislav, Jovanovic, Brian Kp Goh, Bruno, Sensi, Carlo, Biddau, Carlo, Gazia, Carlo, Vallicelli, Carlos Alberto Fagundes, Carlos Cerdán Santacruz, Carlos, Chirico, Carlos Javier Gómez, Carlos, Petrola, Carlos Sánchez Rodriguez, Carlos Yánez Benítez, Carmelisa, Dammaro, Carmelo Lo Faro, Caroline, Reinke, Casandra Dominguez Paez, Catalina, Oliva, Charudutt, Paranjape, Charlotte, Thomas, Chi Fung Chia, Chi Kwan Kong, Chiara De Lucia, Christian Ovalle Chao, Claudio, Arcudi, Claudio, Guerci, Clement, Chia, Cristiano, Parise, Cristina, Folliero, Cristopher, Varela, Dalya, M Ferguson, Daniel, Camacho, Daniel, Popowich, Daniel Souza Lima, Daniela, Rega, Daniele, Delogu, Daniele, Zigiotto, Danilo, Vinci, Dario, D'Antonio, Dario, Parini, David Alessio Merlini, David DE Zimmerman, David, Moro-Valdezate, Davide, Pertile, Deborah Maria Giusti, Deborah, S Keller, Delko, Tarik, Denis, Kalivaçi, Dennis, Mazingi, Diana Gabriela Maldonado-Pintado, Diego, Sasia, Dimitrios, Linardoutsos, Dixon, Osilli, Domenico, Murrone, Domenico, Russello, Edgar, Rodas, Edisson Alberto Acuña Roa, Edoardo, Ricciardi, Edoardo, Rosso, Edoardo, Saladino, Eduardo, Flores-Villalba, Eduardo Ruiz Ajs, Eduardo, Smith-Singares, Efstratia, Baili, Efstratios, Kouroumpas, Eirini, Bourmpouteli, Eleftheria, Douka, Elena, Martin-Perez, Eleonora, Guaitoli, Elgun, Samadov, Elisa, Francone, Elisa, Vaterlini, Emilio, Morales, Emilio, Peña, Enhao, Zhao, Eneko Del Pozo Andres, Enrico, Benzoni, Enrico, Erdas, Enrico, Pinotti, Enrique, Colás-Ruiz, Erman, Aytac, Ernesto, Laterza, Ervis, Agastra, Esteban, Foianini, Esteban, Moscoso, Estefania, Laviano, Ester, Marra, Eugenia, Cardamone, Eugenio, Licardie, Eustratia, Mpaili, Eva, Pinna, Evaristo, Varo, Fabian Martín Navarro, Fabio, Marino, Fabio, Medas, Fabio, Romano, Fatlum, Maraska, Fatmir, Saliu, Fausto, Madrid, Fausto, Rosa, Federica, Mastella, Federico, Gheza, Federico, Luvisetto, Felipe, Alconchel, Felipe Monge Vieira, Felipe, Pareja, Ferdinando, Agresta, Fernanda, Luna, Fernando, Bonilla, Fernando, Cordera, Fernando, Burdió, Fernando, Mendoza-Moreno, Fernando Muñoz Flores, Fernando Pardo Aranda, Fiona, Taylor, Flavia, L Ramos, Flavio, Fernandes, Francesca Paola Tropeano, Francesco, Balestra, Francesco, Bianco, Francesco, Ceci, Francesco, Colombo, Francesco Di Marzo, Francesco, Ferrara, Francesco, Lancellotti, Francesco, Lazzarin, Francesco, Litta, Francesco, Martini, Francesco, Pizza, Francesco, Roscio, Francesco, Virdis, Francisco Blanco Antona, Francisco Cervantes Ramírez, Francisco Miguel Fernandez, Francisco Oliver Llinares, Francisco, Quezada, Francisco, Schlottmann, Gabriel, Herrera-Almario, Gabriel, Massaferro, Gabriele, Bislenghi, Gabrielle van Ramshorst, Gaetano, Gallo, Gaetano, Luglio, Georgios, Bointas, Georgios, Kampouroglou, Georgios, Papadopoulos, Gerardo Arredondo Manrique, Giacomo, Calini, Giacomo, Nastri, Giampaolo, Formisano, Giampaolo, Galiffa, Gian Marco Palini, Gianluca, Colucci, Gianluca, Pagano, Gianluca, Vanni, Gianmaria Casoni Pattacini, Gilda De Paola, Giorgio, Lisi, Giovanna, Partida, Giovanni, Bellanova, Giovanni De Nobili, Giovanni Sammy Necchi, Giovanni, Sinibaldi, Giovanni, Tebala, Giulia, Bagaglini, Giuliano, Izzo, Giulio, Argenio, Giuseppe, Brisinda, Giuseppe, Candilio, Giuseppe Di Grezia, Giuseppe, Esposito, Giuseppe, Faillace, Giuseppe, Frazzetta, Giuseppe La Gumina, Giuseppe, Nigri, Giuseppe, Romeo, Gloria Chocarro Amatriaín, Gloria, Ortega, Gonzalo, Martin-Martin, Gregor, A Stavrou, Gunadi, Gustavo Armand Ugon, Gustavo, Machain, Gustavo, Marcucci, Gustavo, Martínez-Mier, Gustavo Miguel Machain, Gustavo, Nari, Haydée, Calvo, Hamada, Fathy, Hamilto, Hazem, Ahmed, Hazem, Faraj, Hector, Nava, Hector Ordas Macias, Herald, Nikaj, Heriberto, Solano, Huma Ahmed Khan, Humberto Sánchez Alarcón, Husam, Ebied, Iacopo, Giani, Ibabe Villalabeitia Ateca, Ignacio, Neri, Igor Alberdi San Roman, Iliya, Fidoshev, Iñaki Martinez Rodriguez, Ionut, Negoi, Irene, Ortega, Irina, Bernescu, Iris Shari Russo, Irune Vincente Rodríguez, Irving, Palomares, Isaac, Baltazar, Isabel Jaén Torrejimeno, Isabel María Cornejo Jurado, Isabella, Reccia, Ishtiyaq, Hussain, Ismael Brito Toledo, Ismael, Mora-Guzmán, Iulia, Dogaru, Ivan, Romic, Izaskun, Balciscueta, J Cleo Kenington, Jackison, Sagolsem, Jae, Y Jang, James, Olivier, Jan, Lammel-Lindemann, Jana, Dziakova, Javier Ismael Roldán Villavicencio, Javier, Salinas, Jelena, Pejanovic, Jose Gustavo Parreira, Jovanovic, Jeny Rincón Pérez, Jeryl, Asreyes, Jesus Antonio Medina Luque, Joanna, Mak, Joanne Salas Rodriguez, Johnn Henry Herrera Kok, Jon, Krook, Jose Antonio Diaz-Elizondo, Jose, Castell, José Eduardo García-Flores, José María Jover Navalón, Jose Mauro Silva Rodrigues, José, Pereira, José Tomas Castell Gómez, Juan Bellido Luque, Juan Carlos Martín Del Olmo, Juan Carlos Salamea, Juan Francisco Coronel Olivier, Juan Luis Blas Laina, Juliana Maria Ordoñez, Julieta, Gutierrez, Julio, Abba, Junaid Ahmad Sofi, Kashaf, Sherafgan, Kapil, Sahnan, Katsuhiko, Yanaga, Kevin, Beatson, Laharwal, Asim, Laura, Alvarez, Leandro, Siragusa, Lee, Farber, Lester, Ong, Liarakos, Athanasios, Lorena, García-Bruña, Luca De Martino, Luca, Ferrario, Luca, Giordano, Luca, Gordini, Luca, Pio, Luca, Ponchietti, Lucia, Moletta, Luciano, Curella, Luciano, Poggi, Lucio, Taglietti, Luigi, Bonavina, Luigi, Conti, Luigi, Goffredi, Luis Angel Garcia Ruiz, Luis, Barrionuevo, Luis Enrique Fregoso, Luis, F Cabrera, Luis, G Rodriguez, Luis, Grande, Luis Gregorio Osoria, Luis Javier Kantun Gonzalez, Luis, Sánchez-Guillén, Luis, Tallon-Aguilar, Luis, Tresierra, Luisa, Giavarini, Mahmoud, Hasabelnabi, Maja, Odovic, Mamoru, Uemura, Mansoor, Khan, Manuel, Artiles-Armas, Mara, David, Marcello Di Martino, Marcello Giuseppe Spampinato, Marcelo A, F Ribeiro, Marcelo, Viola, Marco, Angrisani, Marco, Calussi, Marco, Cannistrà, Marco, Catarci, Marco, Cereda, Marco, Conte, Marco, Giordano, Marco, Pellicciaro, Marco Vito Marino, Maria, E Vaterlini, María, F Jiménez, María Giulia Lolli, Bellini, MARIA IRENE, Maria, Lemma, Maria Michela Chiarello, Maria, Nicola, Mario, Arrigo, Mario Caneda Mejia, Mario Montes Manrique, Mario, Rodriguez-Lopez, Mario, Serradilla-Martín, Mario Zambrano Lara, Marisa, Martínez, Mark, Bagnall, Mark, Peter, Marta Cañón Lara, Marta Jimenez Gomez, Marta, Paniagua-Garcia-Señorans, Marta Perez Gonzalez, Martin, Rutegård, Martin, Salö, Marzia, Franceschilli, Massimiliano, Silveri, Massimiliano, Veroux, Massimo, Pezzulo, Matteo, Nardi, Matteo, Rottoli, Matti, Tolonen, Mauricio Pedraza Ciro, Mauricio, Zuluagua, Maurizio, Cannavò, Maurizio, Cervellera, Maurizio, Iacobone, Mauro, Montuori, Melody García Domínguez, Meltem, Bingol-Kologlu, Mian, Tahir, Michael, Lim, Michael Sj Wilson, Michael, Wilson, Michela, Campanelli, Michele, Bisaccia, Michele De Rosa, Michele, Maruccia, Michele, Paterno, Michele, Pisano, Michele, Torre, Michele, Treviño, Michele, Zuolo, Miguel, A Hernandez Bartolome, Miguel, Farina, Miguel, Pera, Miguel Prieto Calvo, Milagros, Sotelo, Min Myat Thway, Mohamed, Hassan, Mohamed Salah Eldin Hassan, Mohammad, Azfar, Mohammad, Bouhuwaish, Mohammad, Taha, Mohammad, Zaieem, Mohammed, Korkoman, Montserrat, Guraieb, Mostafa, Shalaby, Muhammad Asif Raza, Muhammad Umar Younis, Muhammed, Elhadi, Mujahid Zulfiqar Ali, Nadeem, Quazi, Nagendra, N Dudi-Venkata, Nahar, Alselaim, Natasha, Loria, Nathalie Villan Ramírez, Nay Win Than, Neil, Smart, Nelson, Trelles, Nicanor, Pinto, Niccolò, Allievi, Niccolo, Petrucciani, Nicola, Antonacci, Nicola, Cillara, Nicolae, Gica, Nicolaescu Diana Cristiana, Nicolás, Nicolás, Nicolò, Falco, Nicolò, Pecorelli, Nicolò, Tamini, Nikolaos Andreas Dallas, Nikolaos, Machairas, Noelia, Brito, Nura Ahmed Fieturi, Nuria, Ortega, Octavio, Avilamercado, Oktay, Irkorucu, Omar, Alsherif, Orestes, Valles, Orestis, Ioannidis, Oscar Hernández Palmas, Oscar Isaac Hernandez Palmas, Oscar Sanz Guadarrama, Osman, Bozbiyik, Pablo, Omelanczuk, Pablo, Ottolino, Pablo, Rodrigues, Pablo, Ruiz, Paola, Campenni, Paola, Chiarade, Paola Prieto Olivares, Paolo, Baroffio, Pascal, Wintringer, Pasquale Di Fronzo, Pasquale, Talento, Pasqualino, Favoriti, Patricia, Sendino, Patrizia, Marsanic, Patricia, Mifsut, Paúl, Andrade, Pawel, Ajawin, Valentina, Ferri, Giuseppe Massimiliano de Luca, Sara, Ingallinella, Eva, Pueyo, Francesco, Palmieri, Jesus, Silva, Ken Min Chin, Nicholas, Syn, Brian K, P Goh, Ye Xin Koh, Valeria, Tonini, Ana, Gonzales-Ganso, Vicente, Simó, Maria Victoria Diago, Pedro, Abadía-Barnó, Pedro Alfonso Najar Castañeda, Pedro Omar Sillas Arevalos, Pedro Palazón Bellver, Peng Soon Koh, Petry, Souza, Piotr, Major, Rajandeep Singh Bali, Rakesh Mohan Khattar, Renato Bessa Melo, Reza, Ebrahiminia, Ricardo, Azar, Ricardo López Murga, Riccardo, Caruso, Riccardo, Pirolo, Richard, Brady, Richard Justin Davies, Rishi, Dholakia, Rishi, Rattan, Rishi, Singhal, Robert, Lim, Roberta, Angelico, Roberta Maria Isernia, Roberta, Tutino, Roberto, Faccincani, Roberto, Peltrini, Rocío, Carrera-Ceron, Rodrigo, Tejos, Rohit, Kashyap, Roosevelt, Fajardo, Rosa, Lozito, Royer Madariaga Pareja, Sabrina, Garbarino, Salvador, Morales-Conde, Sami, Benli, Sami, Mansour, Samir, Flores, Samuel Limon Suarez, Santiago Lopez Ben, Sara, Fuentes, Sara, Napetti, Sara Ortiz de Guzmán, Selmy, Awad, Sergio, A Weckmann Luján, Sergio, Gentilli, Sergio, Grimaldi, Sergio Olivares Pizarro, Serkan, Tayar, Shakeeb, Nabi, Shannon, M Chan, Sheikh, Junaid, Sidney, Rojas, Silvana, Monetti, Silvia, García, Silvia, Salvans, Silvia, Tenconi, Simon, Shaw, Simone, Santoni, Sofia Andrea Parra, Sofía, Cárdenas, Sonia, Pérez-Bertólez, Sonja, Chiappetta, Sophie, Dessureault, Spiros, Delis, Stefano Amore Bonapasta, Stefano, Rausei, Stefano, Scaringi, Sundeep, Keswani, Syed Muhammad Ali, Süleyman, Cetinkunar, Tak Lit Derek Fung, Tariq, Rawashdeh, Tatiana Nicolás López, Tercio De Campos, Teresa Calderon Duque, Teresa, Perra, Theodore, Liakakos, Theodoros, Daskalakis, Theodoros, Liakakos, Thomas, Barnes, Tijmen, Koëter, Tiku, Zalla, Tomás, E González, Tomás, Elosua, Tommaso, Campagnaro, Tommy, Brown, Topi, Luoto, Touré Alpha Oumar, Ugo, Giustizieri, Ugo, Grossi, Umberto, Bracale, Uriel, Rivas, Valentina, Sosa, Valentina, Testa, Valeria, Andriola, Valerio, Balassone, Valerio, Celentano, Valerio, Progno, Varun, Raju, Vanessa, Carroni, Venera, Cavallaro, Venkateswara Rao Katta, Veronica De Simone, Vicent Primo Romaguera, Victor Hugo García Orozco, Victor, Luraschi, Victor, Rachkov, Victor, Turrado-L, Victor, Visag-Castillo, Victoria, Dowling, Victoria, Graham, Vincenzo, Papagni, Vincenzo, Vigorita, Vinicius Cordeiro Fonseca, Virginia Jimenez Carneros, Vittoria, Bellato, Walyson, Gonçalves, William, F Powers, William, Grigg, Wolf, O Bechstein, Yu Bing Lim, Yuksel, Altinel, Zoran, Golubović, Zutoia, Balciscueta, Ielpo B., Podda M., Pellino G., Pata F., Caruso R., Gravante G., Di Saverio S., Gallo G., Lui R., Orengia A., Chowdary A., Kulkarni A., Kuvvetli A., Navarro A., Pisanu A., Smith A., Ibiricu A.C., Nacion A.J.D., Alsaleh A., Alhazmi A., Elmabri A., Wani A., Rencuzogullari A., Lasarte A.S., Rubio A.V., Bavikatte A., Kumar A., Jamiri A.-R., Padilla A.M.A., Cacurri A., de San Ildefonso A., Porcu A., Sartori A., Rocca A., Yanez A.P., Becaria A., Solis-Pena A., Sretenovic A., Urbistondo A., Bandin A., Najar A., De Luca A., Boddy A., Charalabopoulos A., Tzivanakis A., Amendola A., de Velasco A.R.-G., Yildirim A.C., Frontali A., Toure A.O., Garcia-Granero A., Roldan A.M., Larrainzar A.S., Ratnayake A.S., Gonzalez-Ganso A.M., Minaya-Bravo A.M., Das A., Bondurri A., Costanzi A., Lucchi A., Mazzari A., Musig A., Peloso A., Piano A., Police A., Mihailescu A., Pouy A., Romano A., Iossa A., Leonetti A.C., Guariniello A., Isaac A., Bovi A.P.D., Chessa A., Tromba A., Martinez A.A., Brillantino A., Caira A., Castaldi A., Ferronetti A., Giuliani A., Prestera A., la Medina A.R.-D., Tarasconi A., Tornambe A., Picciariello A., Ioannidis A., Leppaniemi A., Khan A., Rashid A., Perez-Sanchez A.L.E., Mittal A., Mitul A.R., Mehraj A., Laharwal A., Dorisme A., Marinis A., Iqbal A., Moncada A., Braccio B., Alkhafaji B., de Andres Asenjo B., Martin-Perez B., Perez B.S., Creavin B., Cali B., Pascotto B., Stubbs B., Retes B.Z., Jovanovic B., Goh B.K.P., Sensi B., Biddau C., Gazia C., Vallicelli C., Fagundes C.A., Santacruz C.C., Chirico C., Diaz C.J.G., Petrola C., Rodriguez C.S., Benitez C.Y., Dammaro C., Faro C.L., Reinke C., Paez C.D., Oliva C., Paranjape C., Thomas C., Chia C.F., Kong C.K., De Lucia C., Chao C.O., Arcudi C., Guerci C., Chia C., Parise C., Folliero C., Varela C., Ferguson D.M., Camacho D., Popowich D., Lima D.S., Rega D., Delogu D., Zigiotto D., Vinci D., D'Antonio D., Parini D., Merlini D.A., Zimmerman D.D.E., Moro-Valdezate D., Pertile D., Giusti D.M., Keller D.S., Tarik D., Kalivaci D., Mazingi D., Maldonado-Pintado D.G., Sasia D., Linardoutsos D., Osilli D., Murrone D., Russello D., Rodas E., Roa E.A.A., Ricciardi E., Rosso E., Saladino E., Flores-Villalba E., Ajs E.R., Smith-Singares E., Baili E., Kouroumpas E., Bourmpouteli E., Douka E., Martin-Perez E., Guaitoli E., Samadov E., Francone E., Vaterlini E., Morales E., Pena E., Zhao E., Andres E.D.P., Benzoni E., Erdas E., Pinotti E., Colas-Ruiz E., Aytac E., Laterza E., Agastra E., Foianini E., Moscoso E., Laviano E., Marra E., Cardamone E., Licardie E., Mpaili E., Pinna E., Varo E., Navarro F.M., Marino F., Medas F., Romano F., Maraska F., Saliu F., Madrid F., Rosa F., Mastella F., Gheza F., Luvisetto F., Alconchel F., Vieira F.M., Pareja F., Agresta F., Luna F., Bonilla F., Cordera F., Burdio F., Mendoza-Moreno F., Flores F.M., Aranda F.P., Taylor F., Ramos F.L., Fernandes F., Tropeano F.P., Balestra F., Bianco F., Ceci F., Colombo F., Di Marzo F., Ferrara F., Lancellotti F., Lazzarin F., Litta F., Martini F., Pizza F., Roscio F., Virdis F., Antona F.B., Ramirez F.C., Fernandez F.M., Llinares F.O., Quezada F., Schlottmann F., Herrera-Almario G., Massaferro G., Bislenghi G., van Ramshorst G., Luglio G., Bointas G., Kampouroglou G., Papadopoulos G., Manrique G.A., Calini G., Nastri G., Formisano G., Galiffa G., Palini G.M., Colucci G., Pagano G., Vanni G., Pattacini G.C., De Paola G., Lisi G., Partida G., Bellanova G., De Nobili G., Necchi G.S., Sinibaldi G., Tebala G., Bagaglini G., Izzo G., Argenio G., Brisinda G., Candilio G., Di Grezia G., Esposito G., Faillace G., Frazzetta G., La Gumina G., Nigri G., Romeo G., Amatriain G.C., Ortega G., Martin-Martin G., Stavrou G.A., Gunadi, Ugon G.A., Machain G., Marcucci G., Martinez-Mier G., Machain G.M., Nari G., Calvo H., Fathy H., Hamilto, Ahmed H., Faraj H., Nava H., Macias H.O., Nikaj H., Solano H., Khan H.A., Alarcon H.S., Ebied H., Giani I., Ateca I.V., Neri I., Roman I.A.S., Fidoshev I., Rodriguez I.M., Negoi I., Ortega I., Bernescu I., Russo I.S., Rodriguez I.V., Palomares I., Baltazar I., Torrejimeno I.J., Jurado I.M.C., Reccia I., Hussain I., Toledo I.B., Mora-Guzman I., Dogaru I., Romic I., Balciscueta I., Kenington J.C., Sagolsem J., Jang J.Y., Olivier J., Lammel-Lindemann J., Dziakova J., Villavicencio J.I.R., Salinas J., Parreira J.P.J.G., Jovanovic, Perez J.R., Reyes J.A.S., Luque J.A.M., Mak J., Rodriguez J.S., Kok J.H.H., Krook J., Diaz-Elizondo J.A., Castell J., Garcia-Flores J.E., Navalon J.M.J., Rodrigues J.M.S., Pereira J., Gomez J.T.C., Luque J.B., del Olmo J.C.M., Salamea J.C., Olivier J.F.C., Laina J.L.B., Ordonez J.M., Gutierrez J., Abba J., Sofi J.A., Sherafgan K., Sahnan K., Yanaga K., Beatson K., Asim L., Alvarez L., Siragusa L., Farber L., Ong L., Athanasios L., Garcia-Bruna L., De Martino L., Ferrario L., Giordano L., Gordini L., Pio L., Ponchietti L., Moletta L., Curella L., Poggi L., Taglietti L., Bonavina L., Conti L., Goffredi L., Ruiz L.A.G., Barrionuevo L., Fregoso L.E., Cabrera L.F., Rodriguez L.G., Grande L., Osoria L.G., Gonzalez L.J.K., Sanchez-Guillen L., Tallon-Aguilar L., Tresierra L., Giavarini L., Hasabelnabi M., Odovic M., Uemura M., Khan M., Artiles-Armas M., David M., Di Martino M., Spampinato M.G., Ribeiro M.A.F., Viola M., Angrisani M., Calussi M., Cannistra M., Catarci M., Cereda M., Conte M., Giordano M., Pellicciaro M., Marino M.V., Vaterlini M.E., Jimenez M.F., Lolli M.G., Bellini M.I., Lemma M., Chiarello M.M., Nicola M., Arrigo M., Mejia M.C., Manrique M.M., Rodriguez-Lopez M., Serradilla-Martin M., Lara M.Z., Martinez M., Bagnall M., Peter M., Lara M.C., Gomez M.J., Paniagua-Garcia-Senorans M., Gonzalez M.P., Rutegard M., Salo M., Franceschilli M., Silveri M., Veroux M., Pezzulo M., Nardi M., Rottoli M., Tolonen M., Ciro M.P., Zuluagua M., Cannavo M., Cervellera M., Iacobone M., Montuori M., Dominguez M.G., Bingol-Kologlu M., Tahir M., Lim M., Wilson M.S., Wilson M., Campanelli M., Bisaccia M., De Rosa M., Maruccia M., Paterno M., Pisano M., Torre M., Trevino M., Zuolo M., Hernandez Bartolome M.A., Farina M., Pera M., Calvo M.P., Sotelo M., Thway M.M., Hassan M., Hassan M.S.E., Azfar M., Bouhuwaish M., Taha M., Zaieem M., Korkoman M., Guraieb M., Shalaby M., Raza M.A., Younis M.U., Elhadi M., Ali M.Z., Quazi N., Dudi-Venkata N.N., Alselaim N., Loria N., Ramirez N.V., Than N.W., Smart N., Trelles N., Pinto N., Allievi N., Petrucciani N., Antonacci N., Cillara N., Gica N., Cristiana N.D., Krystek N., Falco N., Pecorelli N., Tamini N., Dallas N.A., Machairas N., Brito N., Fieturi N.A., Ortega N., Mercado O.A., Irkorucu O., Alsherif O., Valles O., Ioannidis O., Palmas O.H., Palmas O.I.H., Guadarrama O.S., Bozbiyik O., Omelanczuk P., Ottolino P., Rodrigues P., Ruiz P., Campenni P., Chiarade P., Olivares P.P., Baroffio P., Panaccio P., Wintringer P., Di Fronzo P., Talento P., Favoriti P., Sendino P., Marsanic P., Mifsut P., Andrade P., Ajawin P., Abadia-Barno P., Castaneda P.A.N., Arevalos P.O.S., Bellver P.P., Koh P.S., Souza P., Major P., Bali R.S., Khattar R.M., Melo R.B., Ebrahiminia R., Azar R., Murga R.L., Pirolo R., Brady R., Davies R.J., Dholakia R., Rattan R., Singhal R., Lim R., Angelico R., Isernia R.M., Tutino R., Faccincani R., Peltrini R., Carrera-Ceron R., Tejos R., Kashyap R., Fajardo R., Lozito R., Pareja R.M., Garbarino S., Morales-Conde S., Benli S., Mansour S., Flores S., Suarez S.L., Ben S.L., Fuentes S., Napetti S., de Guzman S.O., Awad S., Weckmann Lujan S.A., Gentilli S., Grimaldi S., Pizarro S.O., Tayar S., Nabi S., Chan S.M., Junaid S., Rojas S., Monetti S., Garcia S., Salvans S., Tenconi S., Shaw S., Santoni S., Parra S.A., Cardenas S., Perez-Bertolez S., Chiappetta S., Dessureault S., Delis S., Bonapasta S.A., Rausei S., Scaringi S., Keswani S., Ali S.M., Cetinkunar S., Fung T.L.D., Rawashdeh T., Lopez T.N., De Campos T., Duque T.C., Perra T., Liakakos T., Daskalakis T., Barnes T., Koeter T., Zalla T., Gonzalez T.E., Elosua T., Campagnaro T., Brown T., Luoto T., Oumar T.A., Giustizieri U., Grossi U., Bracale U., Rivas U., Sosa V., Testa V., Andriola V., Tonini V., Balassone V., Celentano V., Progno V., Raju V., Carroni V., Cavallaro V., Katta V.R., De Simone V., Romaguera V.P., Orozco V.H.G., Luraschi V., Rachkov V., Turrado-L V., Visag-Castillo V., Dowling V., Graham V., Papagni V., Vigorita V., Fonseca V.C., Carneros V.J., Bellato V., Goncalves W., Powers W.F., Grigg W., Bechstein W.O., Lim Y.B., Altinel Y., Golubovic Z., Balciscueta Z., Ielpo, B., Podda, M., Pellino, G., Pata, F., Caruso, R., Gravante, G., Di Saverio, S., Gallo, G., Lui, R., Orengia, A., Chowdary, A., Kulkarni, A., Kuvvetli, A., Navarro, A., Pisanu, A., Smith, A., Ibiricu, A. C., Nacion, A. J. D., Alsaleh, A., Alhazmi, A., Elmabri, A., Wani, A., Rencuzogullari, A., Lasarte, A. S., Rubio, A. V., Bavikatte, A., Kumar, A., Jamiri, A. -R., Padilla, A. M. A., Cacurri, A., de San Ildefonso, A., Porcu, A., Sartori, A., Rocca, A., Yanez, A. P., Becaria, A., Solis-Pena, A., Sretenovic, A., Urbistondo, A., Bandin, A., Najar, A., De Luca, A., Boddy, A., Charalabopoulos, A., Tzivanakis, A., Amendola, A., de Velasco, A. R. -G., Yildirim, A. C., Frontali, A., Toure, A. O., Garcia-Granero, A., Roldan, A. M., Larrainzar, A. S., Ratnayake, A. S., Gonzalez-Ganso, A. M., Minaya-Bravo, A. M., Das, A., Bondurri, A., Costanzi, A., Lucchi, A., Mazzari, A., Musig, A., Peloso, A., Piano, A., Police, A., Mihailescu, A., Pouy, A., Romano, A., Iossa, A., Leonetti, A. C., Guariniello, A., Isaac, A., Bovi, A. P. D., Chessa, A., Tromba, A., Martinez, A. A., Brillantino, A., Caira, A., Castaldi, A., Ferronetti, A., Giuliani, A., Prestera, A., la Medina, A. R. -D., Tarasconi, A., Tornambe, A., Picciariello, A., Ioannidis, A., Leppaniemi, A., Khan, A., Rashid, A., Perez-Sanchez, A. L. E., Mittal, A., Mitul, A. R., Mehraj, A., Laharwal, A., Dorisme, A., Marinis, A., Iqbal, A., Moncada, A., Braccio, B., Alkhafaji, B., de Andres Asenjo, B., Martin-Perez, B., Perez, B. S., Creavin, B., Cali, B., Pascotto, B., Stubbs, B., Retes, B. Z., Jovanovic, B., Goh, B. K. P., Sensi, B., Biddau, C., Gazia, C., Vallicelli, C., Fagundes, C. A., Santacruz, C. C., Chirico, C., Diaz, C. J. G., Petrola, C., Rodriguez, C. S., Benitez, C. Y., Dammaro, C., Faro, C. L., Reinke, C., Paez, C. D., Oliva, C., Paranjape, C., Thomas, C., Chia, C. F., Kong, C. K., De Lucia, C., Chao, C. O., Arcudi, C., Guerci, C., Chia, C., Parise, C., Folliero, C., Varela, C., Ferguson, D. M., Camacho, D., Popowich, D., Lima, D. S., Rega, D., Delogu, D., Zigiotto, D., Vinci, D., D'Antonio, D., Parini, D., Merlini, D. A., Zimmerman, D. D. E., Moro-Valdezate, D., Pertile, D., Giusti, D. 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Z., Martinez, M., Bagnall, M., Peter, M., Lara, M. C., Gomez, M. J., Paniagua-Garcia-Senorans, M., Gonzalez, M. P., Rutegard, M., Salo, M., Franceschilli, M., Silveri, M., Veroux, M., Pezzulo, M., Nardi, M., Rottoli, M., Tolonen, M., Ciro, M. P., Zuluagua, M., Cannavo, M., Cervellera, M., Iacobone, M., Montuori, M., Dominguez, M. G., Bingol-Kologlu, M., Tahir, M., Lim, M., Wilson, M. S., Wilson, M., Campanelli, M., Bisaccia, M., De Rosa, M., Maruccia, M., Paterno, M., Pisano, M., Torre, M., Trevino, M., Zuolo, M., Hernandez Bartolome, M. A., Farina, M., Pera, M., Calvo, M. P., Sotelo, M., Thway, M. M., Hassan, M., Hassan, M. S. E., Azfar, M., Bouhuwaish, M., Taha, M., Zaieem, M., Korkoman, M., Guraieb, M., Shalaby, M., Raza, M. A., Younis, M. U., Elhadi, M., Ali, M. Z., Quazi, N., Dudi-Venkata, N. N., Alselaim, N., Loria, N., Ramirez, N. V., Than, N. W., Smart, N., Trelles, N., Pinto, N., Allievi, N., Petrucciani, N., Antonacci, N., Cillara, N., Gica, N., Cristiana, N. D., Krystek, N., Falco, N., Pecorelli, N., Tamini, N., Dallas, N. A., Machairas, N., Brito, N., Fieturi, N. A., Ortega, N., Mercado, O. A., Irkorucu, O., Alsherif, O., Valles, O., Ioannidis, O., Palmas, O. H., Palmas, O. I. H., Guadarrama, O. S., Bozbiyik, O., Omelanczuk, P., Ottolino, P., Rodrigues, P., Ruiz, P., Campenni, P., Chiarade, P., Olivares, P. P., Baroffio, P., Panaccio, P., Wintringer, P., Di Fronzo, P., Talento, P., Favoriti, P., Sendino, P., Marsanic, P., Mifsut, P., Andrade, P., Ajawin, P., Abadia-Barno, P., Castaneda, P. A. N., Arevalos, P. O. S., Bellver, P. P., Koh, P. S., Souza, P., Major, P., Bali, R. S., Khattar, R. M., Melo, R. B., Ebrahiminia, R., Azar, R., Murga, R. L., Pirolo, R., Brady, R., Davies, R. J., Dholakia, R., Rattan, R., Singhal, R., Lim, R., Angelico, R., Isernia, R. M., Tutino, R., Faccincani, R., Peltrini, R., Carrera-Ceron, R., Tejos, R., Kashyap, R., Fajardo, R., Lozito, R., Pareja, R. 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Subjects
medicine.medical_specialty, Anti-Bacterial Agents, Appendectomy, Appendicitis, COVID-19 Testing, Hospital Administration, Humans, Pandemics, Personal Protective Equipment, Practice Patterns, Physicians', Surveys and Questionnaires, Attitude of Health Personnel, COVID-19, Surgeons, Coronavirus disease 2019 (COVID-19), Settore MED/18 - CHIRURGIA GENERALE, COVID-19 pandemic. Acute appendicitis, MEDLINE, Practice Patterns, 030230 surgery, Health administration, 03 medical and health sciences, 0302 clinical medicine, Anti-Bacterial Agent, Pandemic, medicine, Surveys and Questionnaire, Appendiciti, General, Laparoscopy, Personal protective equipment, Physicians', medicine.diagnostic_test, business.industry, General surgery, Original Articles, medicine.disease, Anti-bacterial agents, appendectomy, appendicitis, COVID-19 testing, hospital administration, humans, pandemics, personal protective equipment, practice patterns physicians', surveys and questionnaires, attitude of health personnel, surgeons, appendicitis - COVI-19 - ACIE study - management, Acute appendicitis, Original Article, Surgery, Covid-19, business, Human
Abstract

Background Surgical strategies are being adapted to face the COVID‐19 pandemic. Recommendations on the management of acute appendicitis have been based on expert opinion, but very little evidence is available. This study addressed that dearth with a snapshot of worldwide approaches to appendicitis. Methods The Association of Italian Surgeons in Europe designed an online survey to assess the current attitude of surgeons globally regarding the management of patients with acute appendicitis during the pandemic. Questions were divided into baseline information, hospital organization and screening, personal protective equipment, management and surgical approach, and patient presentation before versus during the pandemic. Results Of 744 answers, 709 (from 66 countries) were complete and were included in the analysis. Most hospitals were treating both patients with and those without COVID. There was variation in screening indications and modality used, with chest X‐ray plus molecular testing (PCR) being the commonest (19·8 per cent). Conservative management of complicated and uncomplicated appendicitis was used by 6·6 and 2·4 per cent respectively before, but 23·7 and 5·3 per cent, during the pandemic (both P, The COVID‐19 pandemic required reorganization of surgical services, affecting patients with common surgical diseases including acute appendicitis. No evidence is available on the topic. This study found global variation in screening policies, use of personal protective equipment and intraoperative directives. There has been increased adoption of non‐operative management and open appendicectomy. Hands off

Published
2021

46. Correlation between corin, N-terminal pro-atrial natriuretic peptide and neonatal adverse prognostic in hypertensive disorders of pregnancy

Author

Yi Lin, Wei Song, Hai-ying Li, Ying Zhang, Yu-bing Dong, and Yi-rou Liu

Subjects
Adult, medicine.medical_specialty, medicine.drug_class, 030204 cardiovascular system & hematology, Gastroenterology, Correlation, 03 medical and health sciences, 0302 clinical medicine, Atrial natriuretic peptide, Pregnancy, Internal medicine, Internal Medicine, medicine, Natriuretic peptide, Birth Weight, Humans, Risk factor, Adverse effect, 030219 obstetrics & reproductive medicine, business.industry, Serine Endopeptidases, Infant, Newborn, Obstetrics and Gynecology, Gestational age, Hypertension, Pregnancy-Induced, medicine.disease, Blood pressure, Cross-Sectional Studies, Case-Control Studies, Apgar Score, Premature Birth, Female, business, Atrial Natriuretic Factor, Biomarkers
Abstract

INTRODUCTION Atrial natriuretic peptide (ANP) regulates water-salt balance and blood pressure by promoting renal sodium and water excretion. OBJECTIVE Our study was to investigate plasma N-terminal pro-atrial natriuretic peptide (NT-proANP) and corin in hypertensive disorders of pregnancy (HDP) patients. Furthermore, the relationship between corin/NT-proANP and neonatal adverse prognosis were evaluated. METHODS Seventy-seven HDP patients and forty-eight normotensive women as control group were recruited. Clinical characteristic and plasma were collected. Plasma NT-proANP and corin were determined by ELISA. Gestational age, neonatal weight and APGAR scores were recorded. Statistical analysis was conducted. RESULTS NT-proANP and corin were significantly increased in HDP group compared with that of control (P

Published
2020

47. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Author

Shah, Sonia, Henry, Albert, Roselli, Carolina, Lin, Honghuang, Sveinbjornsson, Gardar, Fatemifar, Ghazaleh, Hedman, Asa K, Wilk, Jemma B, Morley, Michael P, Chaffin, Mark D, Helgadottir, Anna, Verweij, Niek, Dehghan, Abbas, Almgren, Peter, Andersson, Charlotte, Aragam, Krishna G, Arnlov, Johan, Backman, Joshua D, Biggs, Mary L, Bloom, Heather L, Brandimarto, Jeffrey, Brown, Michael R, Buckbinder, Leonard, Carey, David J, Chasman, Daniel I, Chen, Xing, Chen, Xu, Chung, Jonathan, Chutkow, William, Cook, James P, Delgado, Graciela E, Denaxas, Spiros, Doney, Alexander S, Doerr, Marcus, Dudley, Samuel C, Dunn, Michael E, Engstrom, Gunnar, Esko, Tonu, Felix, Stephan B, Finan, Chris, Ford, Ian, Ghanbari, Mohsen, Ghasemi, Sahar, Giedraitis, Vilmantas, Giulianini, Franco, Gottdiener, John S, Gross, Stefan, Gudbjartsson, Daniel F, Gutmann, Rebecca, Haggerty, Christopher M, van der Harst, Pim, Hyde, Craig L, Ingelsson, Erik, Jukema, J Wouter, Kavousi, Maryam, Khaw, Kay-Tee, Kleber, Marcus E, Kober, Lars, Koekemoer, Andrea, Langenberg, Claudia, Lind, Lars, Lindgren, Cecilia M, London, Barry, Lotta, Luca A, Lovering, Ruth C, Luan, Jian'an, Magnusson, Patrik, Mahajan, Anubha, Margulies, Kenneth B, Maerz, Winfried, Melander, Olle, Mordi, Ify R, Morgan, Thomas, Morris, Andrew D, Morris, Andrew P, Morrison, Alanna C, Nagle, Michael W, Nelson, Christopher P, Niessner, Alexander, Niiranen, Teemu, O'Donoghue, Michelle L, Owens, Anjali T, Palmer, Colin NA, Parry, Helen M, Perola, Markus, Portilla-Fernandez, Eliana, Psaty, Bruce M, Rice, Kenneth M, Ridker, Paul M, Romaine, Simon PR, Rotter, Jerome I, Salo, Perttu, Salomaa, Veikko, van Setten, Jessica, Shalaby, Alaa A, Smelser, Diane T, Smith, Nicholas L, Stender, Steen, Stott, David J, Svensson, Per, Tammesoo, Mari-Liis, Taylor, Kent D, Teder-Laving, Maris, Teumer, Alexander, Thorgeirsson, Gudmundur, Thorsteinsdottir, Unnur, Torp-Pedersen, Christian, Trompet, Stella, Tyl, Benoit, Uitterlinden, Andre G, Veluchamy, Abirami, Voelker, Uwe, Voors, Adriaan A, Wang, Xiaosong, Wareham, Nicholas J, Waterworth, Dawn, Weeke, Peter E, Weiss, Raul, Wiggins, Kerri L, Xing, Heming, Yerges-Armstrong, Laura M, Yu, Bing, Zannad, Faiez, Zhao, Jing Hua, Hemingway, Harry, Samani, Nilesh J, McMurray, John JV, Yang, Jian, Visscher, Peter M, Newton-Cheh, Christopher, Malarstig, Anders, Holm, Hilma, Lubitz, Steven A, Sattar, Naveed, Holmes, Michael V, Cappola, Thomas P, Asselbergs, Folkert W, Hingorani, Aroon D, Kuchenbaecker, Karoline, Ellinor, Patrick T, Lang, Chim C, Stefansson, Kari, Smith, J Gustav, Vasan, Ramachandran S, Swerdlow, Daniel I, Lumbers, R Thomas, Abecasis, Goncalo, Backman, Joshua, Bai, Xiaodong, Balasubramanian, Suganthi, Banerjee, Nilanjana, Baras, Aris, Barnard, Leland, Beechert, Christina, Blumenfeld, Andrew, Cantor, Michael, Chai, Yating, Coppola, Giovanni, Damask, Amy, Dewey, Frederick, Economides, Aris, Eom, Gisu, Forsythe, Caitlin, Fuller, Erin D, Gu, Zhenhua, Gurski, Lauren, Guzzardo, Paloma M, Habegger, Lukas, Hahn, Young, Hawes, Alicia, van Hout, Cristopher, Jones, Marcus B, Khalid, Shareef, Lattari, Michael, Li, Alexander, Lin, Nan, Liu, Daren, Lopez, Alexander, Manoochehri, Kia, Marchini, Jonathan, Marcketta, Anthony, Maxwell, Evan K, McCarthy, Shane, Mitnaul, Lyndon J, O'Dushlaine, Colm, Overton, John D, Padilla, Maria Sotiropoulos, Paulding, Charles, Penn, John, Pradhan, Manasi, Reid, Jeffrey G, Schleicher, Thomas D, Schurmann, Claudia, Shuldiner, Alan, Staples, Jeffrey C, Sun, Dylan, Toledo, Karina, Ulloa, Ricardo H, Widom, Louis, Wolf, Sarah E, Yadav, Ashish, Ye, Bin, Ctr, Regeneron Genetics, Shah, Sonia [0000-0001-5860-4526], Henry, Albert [0000-0001-7422-2288], Roselli, Carolina [0000-0001-5267-6756], Lin, Honghuang [0000-0003-3043-3942], Chaffin, Mark D. [0000-0002-1234-5562], Helgadottir, Anna [0000-0002-1806-2467], Verweij, Niek [0000-0002-4303-7685], Almgren, Peter [0000-0002-0473-0241], Chen, Xu [0000-0002-7299-3238], Ghanbari, Mohsen [0000-0002-9476-7143], Giedraitis, Vilmantas [0000-0003-3423-2021], Gross, Stefan [0000-0003-4121-7161], Guðbjartsson, Daníel F. [0000-0002-5222-9857], Hyde, Craig L. [0000-0002-6939-287X], Ingelsson, Erik [0000-0003-2256-6972], Jukema, J. Wouter [0000-0002-3246-8359], Kleber, Marcus E. [0000-0003-0663-7275], Koekemoer, Andrea [0000-0001-8222-3547], Langenberg, Claudia [0000-0002-5017-7344], Lindgren, Cecilia M. [0000-0002-4903-9374], Lovering, Ruth C. [0000-0002-9791-0064], Luan, Jian’an [0000-0003-3137-6337], Magnusson, Patrik [0000-0002-7315-7899], Mahajan, Anubha [0000-0001-5585-3420], Mordi, Ify R. [0000-0002-2686-729X], Morris, Andrew D. [0000-0002-1766-0473], Nagle, Michael W. [0000-0002-4677-7582], Nelson, Christopher P. [0000-0001-8025-2897], Palmer, Colin N. A. [0000-0002-6415-6560], Rice, Kenneth M. [0000-0002-3071-7278], Rotter, Jerome I. [0000-0001-7191-1723], Salomaa, Veikko [0000-0001-7563-5324], van Setten, Jessica [0000-0002-4934-7510], Svensson, Per [0000-0003-0372-6272], Taylor, Kent D. [0000-0002-2756-4370], Teder-Laving, Maris [0000-0002-5872-1850], Teumer, Alexander [0000-0002-8309-094X], Tyl, Benoit [0000-0001-5297-8412], Uitterlinden, Andre G. [0000-0002-7276-3387], Völker, Uwe [0000-0002-5689-3448], Wiggins, Kerri L. [0000-0003-2749-1279], Hemingway, Harry [0000-0003-2279-0624], Yang, Jian [0000-0003-2001-2474], Visscher, Peter M. [0000-0002-2143-8760], Lubitz, Steven A. [0000-0002-9599-4866], Sattar, Naveed [0000-0002-1604-2593], Cappola, Thomas P. [0000-0002-9630-7204], Asselbergs, Folkert W. [0000-0002-1692-8669], Kuchenbaecker, Karoline [0000-0001-9726-603X], Ellinor, Patrick T. [0000-0002-2067-0533], Vasan, Ramachandran S. [0000-0001-7357-5970], Lumbers, R. Thomas [0000-0002-9077-4741], Apollo - University of Cambridge Repository, Chaffin, Mark D [0000-0002-1234-5562], Guðbjartsson, Daníel F [0000-0002-5222-9857], Hyde, Craig L [0000-0002-6939-287X], Jukema, J Wouter [0000-0002-3246-8359], Kleber, Marcus E [0000-0003-0663-7275], Lindgren, Cecilia M [0000-0002-4903-9374], Lovering, Ruth C [0000-0002-9791-0064], Luan, Jian'an [0000-0003-3137-6337], Mordi, Ify R [0000-0002-2686-729X], Morris, Andrew D [0000-0002-1766-0473], Nagle, Michael W [0000-0002-4677-7582], Nelson, Christopher P [0000-0001-8025-2897], Palmer, Colin NA [0000-0002-6415-6560], Rice, Kenneth M [0000-0002-3071-7278], Rotter, Jerome I [0000-0001-7191-1723], Taylor, Kent D [0000-0002-2756-4370], Uitterlinden, Andre G [0000-0002-7276-3387], Wiggins, Kerri L [0000-0003-2749-1279], Visscher, Peter M [0000-0002-2143-8760], Lubitz, Steven A [0000-0002-9599-4866], Cappola, Thomas P [0000-0002-9630-7204], Asselbergs, Folkert W [0000-0002-1692-8669], Ellinor, Patrick T [0000-0002-2067-0533], Vasan, Ramachandran S [0000-0001-7357-5970], Lumbers, R Thomas [0000-0002-9077-4741], Palmer, Colin N A [0000-0002-6415-6560], Cardiovascular Centre (CVC), University of Queensland [Brisbane], University College of London [London] (UCL), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], University Medical Center Groningen [Groningen] (UMCG), Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Framingham Heart Study, National Heart, Lung, and Blood Institute [Bethesda] (NHLBI)-Boston University [Boston] (BU), deCODE genetics [Reykjavik], Karolinska Institutet [Stockholm], Pfizer, University of Pennsylvania [Philadelphia], University of Groningen [Groningen], Imperial College London, Lund University [Lund], Herlev and Gentofte Hospital, Massachusetts General Hospital [Boston], Department of Neurobiology, Care Sciences and Society [Stockholm, Sweden] (Division of Family Medicine), Dalarna University, Regeneron Genetics Center, 777 Old Saw Mill River Road, Tarrytown, Department of Biostatistics, University of Washington [Seattle], Emory University School of Medicine, Emory University [Atlanta, GA], The University of Texas Medical School at Houston, Department of Molecular and Functional Genomics, Geisinger, Danville, PA, Brigham and Women's Hospital [Boston], Harvard Medical School [Boston] (HMS), Regeneron Genetics Center, 777 Old Saw Mill River Road, Tarrytown, NY, Novartis Institutes for BioMedical Research (NIBR), University of Liverpool, Universität Heidelberg [Heidelberg], Medizinische Fakultät Mannheim, The Alan Turing Institute, Ninewells Hospital and Medical School [Dundee], Universität Greifswald - University of Greifswald, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), University of Minnesota System, Regeneron Pharmaceuticals [Tarrytown], Department of Clinical Sciences, Cardiovascular Epidemiology, Skane University Hospital [Lund], Institute of Genomics [Tartu, Estonia], University of Tartu, Robertson Centre for Biostatistics, University of Glasgow, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Uppsala University, Brigham & Women’s Hospital [Boston] (BWH), University of Maryland School of Medicine, University of Maryland System, School of Science and Engineering (Reykjavik University), Carver College of Medicine, University of Iowa, Geisinger Health System [Danville, PA, USA], Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Stanford Cardiovascular Institute, Uppsala Universitet [Uppsala], Leiden University Medical Center (LUMC), Einthoven Laboratory for Experimental Vascular Medicine (ELEVM - LEIDEN), Department of Public Health and Primary Care, University of Cambridge [UK] (CAM), Rigshospitalet [Copenhagen], Copenhagen University Hospital, Glenfield Hospital, University Hospitals Leicester, MRC Epidemiology Unit, University of Cambridge [UK] (CAM)-Institute of Metabolic Science, Big Data Institute, University of Oxford [Oxford], University of Iowa [Iowa City], The Wellcome Trust Centre for Human Genetics [Oxford], Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, Medical University Graz, Skane University Hospital [Malmo], Vanderbilt University School of Medicine [Nashville], University of Edinburgh, Université médicale de Vienne, Autriche, National Institute for Health and Welfare [Helsinki], University of Turku, Birmingham Women's and Children's NHS Foundation Trust, Kaiser Permanente, Harbor UCLA Medical Center [Torrance, Ca.], Los Angeles Biomedical Research Institute (LA BioMed), University Medical Center [Utrecht], University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Seattle Epidemiologic Research and Information Center [Seattle], Institute of Cardiovascular and Medical Sciences [Glasgow], University of Glasgow, Department of Cardiology, Södersjukhuset, Stockholm, Estonian Genome and Medicine, Landspitali National University Hospital of Iceland, University of Iceland [Reykjavik], Aalborg University [Denmark] (AAU), Institut de Recherches SERVIER (IRS), Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt-Universität Greifswald, GlaxoSmithKline, Glaxo Smith Kline, Northeastern Ohio Medical University (NEOMED), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, British Heart Foundation Glasgow Cardiovascular Research Centre (BHF GCRC), University of Glasgow-NHS Greater Glasgow and Clyde, Department of Cardiovascular Sciences [Leicester], University of Leicester, Queensland Brain Institute, Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, University of Dundee, National Heart and Lung Institute [London] (NHLI), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, Atherosclerosis Risk in Communities Study (ARIC)The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC- 55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC55021, N01-HC-55022, R01HL087641, R01HL59367, R01HL086694 and RC2 HL102419, National Human Genome Research Institute contract U01HG004402, and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. A systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT- CHF)This project was funded by a grant from the European Commission (FP7‐242209‐ BIOSTAT‐CHF, EudraCT 2010–020808–29). Cardiovascular Health Study (CHS) This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, HHSN268200960009C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and U01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. deCODE Heart Failure Study (deCODE) We at deCODE thank the women and men of Iceland that have participated in our studies and our colleagues that contributed to data collection and processing. DiscovEHR We acknowledge and thank all participants in Geisinger’s MyCode Community Health Initiative for their support and permission to use their health and genomic information in the DiscovEHR collaboration. This work was supported by the Regeneron Genetics Center and Geisinger. Estonian Genome Center at the University of Tartu (EGCUT) This study was supported by Estonian Research Council Grant IUT20-60, EU, H2020 grant 692145, European Union through the European Regional Development Fund (Project No. 2014-2020.4.01.15-0012) GENTRANSMED. Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) The EPHESUS was supported by Pfizer, Inc. The European Prospective Investigation of Cancer, Norfolk study (EPIC-Norfolk) The EPIC-Norfolk Study is supported by programme grants from the Medical Research Council UK (G1000143) and Cancer Research UK (C864/A14136) and with additional support from the European Union, Stroke Association, British Heart Foundation, Research into Ageing, Department of Health, The Wellcome Trust and the Food Standards Agency. NJW and CL also acknowledge support from the Medical Research Council, UK (MC_UU_12015/1, MC_PC_13048). We thank all EPIC participants and staff for their contribution to the study, and thank staff from the Technical, Field Epidemiology and Data Functional Group Teams of the Medical Research Council Epidemiology Unit in Cambridge, UK, for carrying out sample preparation, DNA provision and quality control, genotyping and data handling work. Framingham Heart Study (FHS) This work was conducted using data and resources from the Framingham Heart Study (FHS) of the National Heart Lung and Blood Institute and Boston University School of Medicine. The study was supported by the National Heart, Lung and Blood Institute’s Framingham Heart Study (Contract No. N01-HC-25195 and HHSN268201500001I) and its contract with Affymetrix, Inc for genotyping services (Contract No.N02-HL-6-4278). The work was also supported by R01 HL093328, R01 HL105993, and R01 HL71039 (PI: Ramachandran). FINRISK V.S. has been supported by the Finnish Foundation for Cardiovascular Research. Genetics of Diabetes Audit and Research Tayside Scotland GoDARTS) The Wellcome Trust United Kingdom Type 2 Diabetes Case Control Collection (supporting GoDARTS) was funded by the Wellcome Trust (072960/Z/03/Z, 084726/Z/08/Z, 084727/Z/08/Z, 085475/Z/08/Z, 085475/B/08/Z) and as part of the EU IMI-SUMMIT programme. We acknowledge the support of the Health Informatics Centre, University of Dundee, for managing and supplying the anonymized data and NHS Tayside, the original data owner. The Genetic Risk Assessment of Defibrillator Events (GRADE) NIH-NHLBI R01 HL77398 (Genetic Modulators of Sudden Death). S.L. is supported by NIH grant 1R01HL139731 and American Heart Association 18SFRN34250007. The LUdwigshafen RIsk and Cardiovascular Health (LURIC) study We extend our appreciation to the participants of the LURIC study, without their collaboration, this article would not have been written. We thank the LURIC study team who were either temporarily or permanently involved in patient recruitment as well as sample and data handling, in addition to the laboratory staff at the Ludwigshafen General Hospital and the Universities of Freiburg and Ulm, Germany. LURIC has received funding from the 7th Framework Program (RiskyCAD, grant agreement number 305739 and Atheroremo, grant agreement number 201668) of the European Union. Malmö Diet and Cancer Study (MDCS) J. Gustav Smith was supported by grants from the Swedish Heart-Lung Foundation (2016- 0134 and 2016-0315), the Swedish Research Council (2017-02554), the European Research Council (ERC-STG-2015-679242), the Crafoord Foundation, Skåne University Hospital, the Scania county, governmental funding of clinical research within the Swedish National Health Service, a generous donation from the Knut and Alice Wallenberg foundation to the Wallenberg Center for Molecular Medicine in Lund, and funding from the Swedish Research Council (Linnaeus grant Dnr 349-2006-237, Strategic Research Area Exodiab Dnr 2009-1039) and Swedish Foundation for Strategic Research (Dnr IRC15- 0067) to the Lund University Diabetes Center. The Malmo Diet and Cancer Study was made possible by grants from the Swedish Cancer Society, the Swedish Medical Research Council, the Swedish Dairy Association, and the Malmo city council. Penn Heart Failure Study (PHFS) The study was supported by NIH grants (NIH R01L088577 and NIH R01H105993). Prevention of REnal and Vascular ENd-stage Disease (PREVEND) The Prevention of Renal and Vascular Endstage Disease Study (PREVEND) genetics is supported by the Dutch Kidney Foundation (Grant E033), the EU project grant GENECURE (FP-6 LSHM CT 2006 037697), the National Institutes of Health (grant LM010098), the Netherlands organisation for health research and development (NWO VENI grant 916.761.70), and the Dutch Inter University Cardiology Institute Netherlands (ICIN). Niek Verweij was supported by NWO VENI grant 016.186.125. PROspective Study of Pravastatin in the Elderly at Risk for vascular disease (PROSPER)The PROSPER study was supported by an investigator-initiated grant obtained from Bristol- Myers Squibb. Support for genotyping was provided by the seventh framework program of the European commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810). J.W.J. is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Study of Health in Pomerania (SHIP) SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network ‘Greifswald Approach to Individualized Medicine (GANI_MED)’ funded by the Federal Ministry of Education and Research (grant 03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthineers, Erlangen, Germany and the Federal State of Mecklenburg- West Pomerania. The University of Greifswald is a member of the Caché Campus program of the InterSystems GmbH. Stabilization of Plaque using Darapladib-Thrombolysis in Myocardial Infarction 52 (SOLID)SOLID-TIMI 52 was funded by GlaxoSmithKline. TwinGene (TwinGene) TwinGene received funding from the Swedish Research Council (M-2005-1112), GenomEUtwin (EU/QLRT-2001-01254, QLG2-CT-2002-01254), NIH DK U01-066134, The Swedish Foundation for Strategic Research (SSF) and the Heart and Lung foundation no. 20070481. TwinGene is part of the Swedish Twin Registry which is managed by Karolinska Institutet and receives funding through the Swedish Research Council (2017–00641). UK Biobank (UKBiobank) This research has been conducted using the UK Biobank Resource under Application Number 15422. This work was supported in part by grants to R.T.L. from the EU/EFPIA Innovative Medicines Initiative 2 Joint Undertaking BigData@Heart grant no. 116074, MRC Proximity to Discovery Award Scheme, the American Heart Association Institute for Precision Mecidine, Pfizer Ltd, the University College London British Heart Foundation Research Accelerator (AA/18/6/34223), and was supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. A. H. is supported by the British Heart Foundation Cardiovascular Biomedicine PhD studentship. R.T.L is supported by a UK Research and Innovation Rutherford Fellowship and was previously supported by a National Institutes of Health Research Clinical Lectureship. Uppsala Longitudinal Study of Adult Men (ULSAM) J.Ä. is supported by the Swedish Research Council and the Swedish Heart Lung foundation. C.M.L is supported by the Li Ka Shing Foundation, WT-SSI/John Fell funds and by the NIHR Biomedical Research Centre, Oxford, by Widenlife and NIH (5P50HD028138- 27). Women’s Genome Health Study (WGHS) The WGHS is supported by the National Heart, Lung, and Blood Institute (HL043851 and HL080467, HL099355) and the National Cancer Institute (CA047988 and UM1CA182913), with collaborative scientific support and funding for genotyping provided by Amgen., Epidemiology, Internal Medicine, Læknadeild (HÍ), Faculty of Medicine (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Engineering and Natural Sciences (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, and University of Iceland

Subjects
0301 basic medicine, Dánartíðni, Epidemiology, LOCI, 45/43, General Physics and Astronomy, Muscle Proteins, Genome-wide association study, Disease, Coronary Artery Disease, 030204 cardiovascular system & hematology, Bioinformatics, Genome-wide association studies, DISEASE, Ventricular Function, Left, Coronary artery disease, 0302 clinical medicine, Risk Factors, Atrial Fibrillation, IMPUTATION, Medicine, Blóðrásarsjúkdómar, 692/308/174, lcsh:Science, 2. Zero hunger, RISK, Multidisciplinary, Microfilament Proteins, article, Atrial fibrillation, Mendelian Randomization Analysis, CATALOG, 3. Good health, OBESITY, Erfðarannsóknir, Cardiomyopathies, Medical Genetics, Cyclin-Dependent Kinase Inhibitor p21, Science, 631/208/205/2138, Heart failure, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 631/443/592/2727, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, RESOURCE, Humans, Mortality, METAANALYSIS, Genetic association, Medicinsk genetik, Adaptor Proteins, Signal Transducing, Heart Failure, HYPERTENSION, business.industry, Case-control study, Klinisk medicin, 692/699/75/230, General Chemistry, Cardiovascular genetics, medicine.disease, R1, 030104 developmental biology, Case-Control Studies, lcsh:Q, Morbidity, Clinical Medicine, business, Apoptosis Regulatory Proteins, Carrier Proteins, Genome-Wide Association Study
Abstract

Publisher's version (útgefin grein), Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies., We acknowledge the contribution from the EchoGen Consortium.

Published
2020
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48. Prognostic factors for breast cancer patients with T1-2 tumors and 1-3 positive lymph nodes and the role of postmastectomy radiotherapy in these patients

Author

Jia-Ming, Zhao, Qi, An, Chao-Nan, Sun, Yu-Bing, Li, Zi-Lan, Qin, Hong, Guo, Xue, Zeng, Yao-Tian, Zhang, Lin-Lin, Wei, Ning, Han, Shi-Chen, Sun, and Na, Zhang

Subjects
Adult, Breast Neoplasms, Middle Aged, Prognosis, Tumor Burden, Treatment Outcome, Risk Factors, Lymphatic Metastasis, Axilla, Humans, Lymph Node Excision, Female, Radiotherapy, Adjuvant, Lymph Nodes, Neoplasm Recurrence, Local, Mastectomy, Aged, Follow-Up Studies, Neoplasm Staging, Retrospective Studies
Abstract

The purpose of this study was to identify independent prognostic factors for breast cancer patients with T1-2 tumors and 1-3 positive lymph nodes, and discuss the role of postmastectomy radiotherapy(PMRT) in these patients.Between January 2005 and December 2015, the data on 840 eligible patients with breast cancer were retrospectively reviewed. Of these patients, 368 women received PMRT and 472 did not. The endpoints were locoregional recurrence (LRR) and distant metastasis (DM).With a median follow-up of 62.0 months, multivariate analysis identified the following independent risk factors for increased LRR: tumor size ≥ 4 cm (HR: 2.994, 95% CI: 1.190-7.535, P = 0.020), ER- and PR-negative tumor (HR: 2.540, 95% CI: 1.165-5.537, P = 0.019), preoperative high neutrophil-to-lymphocyte ratio (NLR) (HR: 4.716, 95% CI: 1.776-12.528, P = 0.002)and low neutrophil-to-monocyte ratio (NMR) (HR: 0.231, 95% CI: 0.084-0.633, P = 0.004). And independent risk factors for increased DM: ER- and PR-negative tumor (HR: 2.540, 95% CI: 1.880-5.625, P = 0.000), high NLR (HR: 2.693, 95% CI: 1.426-5.084, P = 0.002) and low NMR (HR: 0.460, 95% CI: 0.257-0.824, P = 0.009). The high-risk patients (≥ 2 risk factors) had worse LRRFS and DFS than low-risk patients (0-1 risk factor) (all, P 0.05). In the subgroup analysis, both low- and high-risk patients received PMRT had better LRRFS and DFS than those who without PMRT (all, P 0.05), and the high-risk patients received PMRT had similar 5-year rates of LRRFS and DFS than low-risk patients who without PMRT (94.5 vs. 94.3%, P = 0.402; 83.4 vs.87.4%, P = 0.877, respectively).Tumor size, ER/PR status, preoperative NLR and NMR were independent predictors of risk of recurrence. PMRT could improve locoregional control even in low-risk subgroup of breast cancer patients with T1-2 tumors and 1-3 positive lymph nodes significantly.

Published
2020

49. DCC-Mediated Dab1 Phosphorylation Participates in the Multipolar-to-Bipolar Transition of Migrating Neurons

Author

Lei Cui, Mingming Lai, Hua Li Yu, Yi Fei Zhao, Jia Hui Xu, Lei Zhang, Xiao Xiao He, Yu-Qiang Ding, Lin Liu, Dong Dong Zhao, Ling Hu, Wen Cheng Xiong, Yu Bing Wang, Wei Xiang Guo, Jian-Hua Zhang, Ying Huang, Xiao Juan Zhu, Yang Zhao, and Zi Xuan He

Subjects
0301 basic medicine, Deleted in Colorectal Cancer, Neocortex, Nerve Tissue Proteins, Proto-Oncogene Mas, General Biochemistry, Genetics and Molecular Biology, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, FYN, Protein Domains, Cell Movement, Netrin, Animals, Humans, Reelin, Phosphorylation, lcsh:QH301-705.5, Neurons, biology, fungi, Tyrosine phosphorylation, Netrin-1, DCC Receptor, DAB1, Cell biology, Mice, Inbred C57BL, Reelin Protein, HEK293 Cells, 030104 developmental biology, lcsh:Biology (General), Animals, Newborn, nervous system, chemistry, biology.protein, Female, Tyrosine kinase, 030217 neurology & neurosurgery
Abstract

Summary: Newborn neurons undergo inside-out migration to their final destinations during neocortical development. Reelin-induced tyrosine phosphorylation of disabled 1 (Dab1) is a critical mechanism controlling cortical neuron migration. However, the roles of Reelin-independent phosphorylation of Dab1 remain unclear. Here, we report that deleted in colorectal carcinoma (DCC) interacts with Dab1 via its P3 domain. Netrin 1, a DCC ligand, induces Dab1 phosphorylation at Y220 and Y232. Interestingly, knockdown of DCC or truncation of its P3 domain dramatically delays neuronal migration and impairs the multipolar-to-bipolar transition of migrating neurons. Notably, the migration delay and morphological transition defects are rescued by the expression of a phospho-mimetic Dab1 or a constitutively active form of Fyn proto-oncogene (Fyn), a member of the Src-family tyrosine kinases that effectively induces Dab1 phosphorylation. Collectively, these findings illustrate a DCC-Dab1 interaction that ensures proper neuronal migration during neocortical development. : Non-Reelin-induced Dab1 phosphorylation was previously identified, but not characterized. Zhang et al. find that DCC interacts with Dab1, and DCC-mediated signaling effectively induces Dab1 phosphorylation. The DCC/Dab1 signaling complex is essential for neuronal migration, especially during the multipolar-to-bipolar transition. Keywords: Dab1, DCC, Fyn, morphological transition, netrin 1, neocortex development, neuronal migration, Reelin, tyrosine phosphorylation

Published
2018
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50. Analyzing the LncRNA, miRNA, and mRNA Regulatory Network in Prostate Cancer with Bioinformatics Software

Author

Yuguang Li, Jia Bin Zhou, Ming-Rong Cao, Li Wang, Zeping Han, Yu Bing Lv, Mao-Xian Zou, and Jin-Hua He

Subjects
Male, 0301 basic medicine, ved/biology.organism_classification_rank.species, Computational biology, Biology, Bioinformatics, Genome, 03 medical and health sciences, microRNA, Genetics, Humans, Gene Regulatory Networks, RNA, Messenger, Model organism, Molecular Biology, Gene, Biological data, ved/biology, Microarray analysis techniques, Computational Biology, Prostatic Neoplasms, Long non-coding RNA, Gene Expression Regulation, Neoplastic, MicroRNAs, Computational Mathematics, 030104 developmental biology, Computational Theory and Mathematics, Modeling and Simulation, RNA, Long Noncoding, Vascular smooth muscle contraction, Software
Abstract

Information processing tools and bioinformatics software have significantly advanced researchers' ability to process and analyze biological data. Molecular data from human and model organism genomes help researchers identify topics for study, which, in turn, improves predictive accuracy, facilitates the identification of relevant genes, and simplifies the validation of laboratory data. The objective of this study was to explore the regulatory network constituted by long noncoding RNA (lncRNA), miRNA, and mRNA in prostate cancer (PCa). Microarray data of PCa were downloaded from The Cancer Genome Atlas database and DESeq package in R language were used to identify the differentially expressed genes (DEGs) between PCa and normal samples. Gene ontology enrichment analysis of DEGs was conducted using the Database for Annotation, Visualization, and Integrated Discovery. TargetScan, microcosm, miRanda, miRDB, and PicTar were used to predict target genes. LncRNA associated with PCa was exploited in the lncRNASNP database, and the LncRNA-miRNA-mRNA regulatory network was visualized using Cytoscape. Our study identified 57 differentially expressed miRNAs and 1252 differentially expressed mRNAs; of these, 691 were downregulated genes primarily involved in focal adhesion, vascular smooth muscle contraction, calcium signaling pathway, and so on. The remaining 561 were upregulated genes principally involved in systemic lupus erythematosus, progesterone-mediated oocyte maturation, oocyte meiosis, and so on. Through the integrated analysis of correlation and target gene prediction, our studies identified 1214 miRNA:mRNA pairs, including 52 miRNAs and 395 mRNAs, and screened out 455 lncRNA-miRNA pairs containing 52 miRNAs. Therefore, owing to the interrelationship of lncRNAs and miRNAs with mRNAs, our study screened out 19,075 regulatory relationships. Our data provide a comprehensive bioinformatics analysis of genes, functions, and pathways that may be involved in the pathogenesis of PCa.

Published
2018
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