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36 results on '"Lee-Ming Chuang"'

1. Positive correlation of ANGPTL8 expression in human visceral adipose tissue with body mass index

Author

Shiau-Mei Chen, Tse-Ying Huang, Wei-Jei Lee, Lee-Ming Chuang, and Tien-Jyun Chang

Subjects
ANGPTL8, Bariatric surgery, Obesity, Visceral fat, Body mass index, Medicine (General), R5-920
Abstract

Background: Angiopoietin-like protein 8 (ANGPTL8) is an important regulator of lipid metabolism. We aimed to investigate the difference of ANGPTL8 expression in different depots of adipose tissues between individuals with and without obesity, and its correlation with various metabolic parameters. Methods: Subcutaneous (SAT) and visceral adipose tissue (VAT) samples were collected from patients who underwent bariatric or intra-abdominal surgery. Expression levels of ANGPTL8, monoglyceride lipase (MGL), monocyte chemoattractant protein-1 (MCP-1), leptin and adiponectin (APM1) were determined using real-time quantitative polymerase chain reaction. The correlation of ANGPTL8 expression with various metabolic parameters and other gene expression levels was analyzed using Person's correlation analysis. Logistic regression was used to establish a prediction model of obesity. Results: Totally 330 subjects (obese: 281, non-obese: 49) were recruited. ANGPTL8 expression in VAT was significantly higher in the obesity group than in the non-obesity group (P = 0.0096). ANGPTL8 expression in VAT was positively correlated with body mass index (BMI) (r = 0.1169, P

Published
2024
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2. Recent advances in the treatment of type 2 diabetes mellitus using new drug therapies

Author

Keong Chong, Jack Keng‐Jui Chang, and Lee‐Ming Chuang

Subjects
glucagon‐like peptide‐1 (GLP‐1) receptor agonists, insulin icodec, retatrutide, sodium glucose co‐transporters 2 (SGLT2) inhibitors, tirzepatide, Medicine (General), R5-920
Abstract

Abstract Several recent advances provide multiple health benefits to individuals with type 2 diabetes mellitus (T2DM). Pharmacological therapy is governed by person‐centered factors, including comorbidities and treatment goals. Adults with T2DM who have an established/high risk of atherosclerotic cardiovascular disease, heart failure, and/or chronic kidney disease, require a treatment regimen that includes agents that are proven to reduce cardiorenal risk. Weight management plays a key role in reducing glucose for patients with T2DM. A glucose‐reduction treatment regimen must consider weight management. Sodium glucose co‐transporter 2 (SGLT2) inhibitors reduce the risk of heart failure, cardiovascular and renal events. Glucagon‐like peptide‐1 (GLP‐1) receptor agonists allow better control of glycemia, promote weight loss and reduce the risk of cardiovascular events. Newer Glucose‐dependent insulinotropic polypeptide (GIP) and GLP‐1 dual agonist, which activate GIP and GLP‐1 receptors improve glycemic control and promote greater weight loss than GLP‐1 receptor agonists. Several novel drugs are in the clinical development phase. This review pertains to recent advances in pharmacological management of type 2 diabetes.

Published
2024
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3. Diabetes self-management education on the sustainability of metabolic control in type 2 diabetes patients: Diabetes share care program in Taiwan

Author

Ying-Chuen Lai, Yi-Shuan Chen, Yi-Der Jiang, Chiou-Shiang Wang, I-Ching Wang, Hsiu-Fen Huang, Hui-Yu Peng, Hui-Chuen Chen, Tien-Jyun Chang, and Lee-Ming Chuang

Subjects
Pay-for-performance, Diabetes self-management education, Self-monitoring of blood glucose, Diabetes education, Glycemic control, Diabetes share care program, Medicine (General), R5-920
Abstract

Background: Diabetes self-management education (DSME) improves glycemic and metabolic control. However, the frequency, duration and sustainability of DSME for improving metabolic control have not been well studied. Methods: The Diabetes Share Care Program (DSCP) stage 1 provided DSME every 3 months. If participants entering DSCP stage 1 ≥ 2 years and HbA1c < 7%, they can be transferred to stage 2 (DSME frequency: once a year). Three-to-one matching between DSCP stage 1 and stage 2 groups based on the propensity score method to match the two groups in terms of HbA1c and diabetes duration. We identified 311 people living with type 2 diabetes in DSCP stage 1 and 86 in stage 2 and evaluated their metabolic control and healthy behaviors annually for 5 years. Results: In the first year, HbA1c in the DSCP stage 2 group was significantly lower than that in the stage 1 group. In the first and the fifth years, the percentage of patients achieving HbA1c < 7% was significantly higher in the DSCP stage 2 group than the stage 1 group. There was no significant difference in other metabolic parameters between the two groups during the 5-year follow-up. Self-monitoring of blood glucose (SMBG) frequency was associated with a reduced HbA1c after 5 years (95% CI: −0.0665 to −0.0004). Conclusion: We demonstrated sustainable effects of at least 2-year DSME on achieving better glycemic control for at least 1 year. SMBG contributed to improved glycemic control. The results may be applied to the reimbursement strategy in diabetes education.

Published
2024
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4. Residual risk of cardiovascular complications in statin-using patients with type 2 diabetes: the Taiwan Diabetes Registry Study

Author

Chin-Sung Kuo, Nai-Rong Kuo, Yun-Kai Yeh, Yau-Jiunn Lee, Lee-Ming Chuang, Hua-Fen Chen, Ching-Chu Chen, Chun-Chuan Lee, Chih-Cheng Hsu, Hung-Yuan Li, Horng-Yih Ou, and Chii-Min Hwu

Subjects
Diabetes, Residual risk, Statin, Nutritional diseases. Deficiency diseases, RC620-627
Abstract

Abstract Background The residual risks of atherosclerotic cardiovascular disease in statin-treated patients with diabetes remain unclear. This study was conducted to identify factors associated with these residual risks in patients with no prior vascular event. Methods Data on 683 statin-using patients with type 2 diabetes mellitus (T2DM) from the Taiwan Diabetes Registry were used in this study. Patients aged 65 years at the time of diabetes diagnosis and those with diabetes durations ≥ 20 years were excluded. The United Kingdom Prospective Diabetes Study risk engine (version 2.01; https://www.dtu.ox.ac.uk/riskengine/ ) was used to calculate 10-year residual nonfatal and fatal coronary heart disease (CHD) and stroke risks. Associations of these risks with physical and biochemical variables, including medication use and comorbidity, were examined. Results The 10-year risks of nonfatal CHD in oral anti-diabetic drug (OAD), insulin and OAD plus insulin groups were 11.8%, 16.0%, and 16.8%, respectively. The 10-year risks of nonfatal stroke in OAD, insulin and OAD plus insulin groups were 3.0%, 3.4%, and 4.3%, respectively. In the multivariate model, chronic kidney disease (CKD), neuropathy, insulin use, calcium-channel blocker (CCB) use, higher body mass indices (BMI), low-density lipoprotein (LDL), fasting glucose, log-triglyceride (TG), and log–alanine transaminase (ALT) levels were associated with an increased CHD risk. The residual risk of stroke was associated with CKD, neuropathy, CCB use, and lower LDL cholesterol levels, higher BMI and diastolic blood pressure. Conclusion This study indicated that insulin was probably a residual risk factor of CHD but not stroke, and that there was a possible presence of obesity paradox in patients with T2DM on statin therapy. In addition to lowering TG and normalizing fasting glucose levels, lower LDL cholesterol level is better for reduction of risk of CHD on statin therapy. On the other hand, lower LDL cholesterol level could potentially be related to higher risk of stroke among populations receiving statin therapy. These findings suggest potential therapeutic targets for residual cardiovascular risk reduction in patients with T2DM on statin therapy.

Published
2024
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5. A common East-Asian ALDH2 mutation causes metabolic disorders and the therapeutic effect of ALDH2 activators

Author

Yi-Cheng Chang, Hsiao-Lin Lee, Wenjin Yang, Meng-Lun Hsieh, Cai-Cin Liu, Tung-Yuan Lee, Jing-Yong Huang, Jiun-Yi Nong, Fu-An Li, Hsiao-Li Chuang, Zhi-Zhong Ding, Wei-Lun Su, Li-Yun Chueh, Yi-Ting Tsai, Che-Hong Chen, Daria Mochly-Rosen, and Lee-Ming Chuang

Subjects
Science
Abstract

Abstract Obesity and type 2 diabetes have reached pandemic proportion. ALDH2 (acetaldehyde dehydrogenase 2, mitochondrial) is the key metabolizing enzyme of acetaldehyde and other toxic aldehydes, such as 4-hydroxynonenal. A missense Glu504Lys mutation of the ALDH2 gene is prevalent in 560 million East Asians, resulting in reduced ALDH2 enzymatic activity. We find that male Aldh2 knock-in mice mimicking human Glu504Lys mutation were prone to develop diet-induced obesity, glucose intolerance, insulin resistance, and fatty liver due to reduced adaptive thermogenesis and energy expenditure. We find reduced activity of ALDH2 of the brown adipose tissue from the male Aldh2 homozygous knock-in mice. Proteomic analyses of the brown adipose tissue from the male Aldh2 knock-in mice identifies increased 4-hydroxynonenal-adducted proteins involved in mitochondrial fatty acid oxidation and electron transport chain, leading to markedly decreased fatty acid oxidation rate and mitochondrial respiration of brown adipose tissue, which is essential for adaptive thermogenesis and energy expenditure. AD-9308 is a water-soluble, potent, and highly selective ALDH2 activator. AD-9308 treatment ameliorates diet-induced obesity and fatty liver, and improves glucose homeostasis in both male Aldh2 wild-type and knock-in mice. Our data highlight the therapeutic potential of reducing toxic aldehyde levels by activating ALDH2 for metabolic diseases.

Published
2023
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6. ER ribosomal-binding protein 1 regulates blood pressure and potassium homeostasis by modulating intracellular renin trafficking

Author

Chu-Hsuan Chiu, Chin-Feng Hsuan, Shih-Hua Lin, Yi-Jen Hung, Chii-Min Hwu, Siow-Wey Hee, Shu-Wha Lin, Sitt-Wai Fong, Patrick Ching-Ho Hsieh, Wei-Shun Yang, Wei-Chou Lin, Hsiao-Lin Lee, Meng-Lun Hsieh, Wen-Yi Li, Jou-Wei Lin, Chih-Neng Hsu, Vin-Cent Wu, Gwo-Tsann Chuang, Yi-Cheng Chang, and Lee-Ming Chuang

Subjects
Arrhythmia, Blood pressure, Cardiovascular disease, Hyperkalemia, Hyporeninemic hypoaldosteronism, Renin–angiotensin–aldosterone system, Medicine
Abstract

Abstract Background Genome-wide association studies (GWASs) have linked RRBP1 (ribosomal-binding protein 1) genetic variants to atherosclerotic cardiovascular diseases and serum lipoprotein levels. However, how RRBP1 regulates blood pressure is unknown. Methods To identify genetic variants associated with blood pressure, we performed a genome-wide linkage analysis with regional fine mapping in the Stanford Asia–Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) cohort. We further investigated the role of the RRBP1 gene using a transgenic mouse model and a human cell model. Results In the SAPPHIRe cohort, we discovered that genetic variants of the RRBP1 gene were associated with blood pressure variation, which was confirmed by other GWASs for blood pressure. Rrbp1- knockout (KO) mice had lower blood pressure and were more likely to die suddenly from severe hyperkalemia caused by phenotypically hyporeninemic hypoaldosteronism than wild-type controls. The survival of Rrbp1-KO mice significantly decreased under high potassium intake due to lethal hyperkalemia-induced arrhythmia and persistent hypoaldosteronism, which could be rescued by fludrocortisone. An immunohistochemical study revealed renin accumulation in the juxtaglomerular cells of Rrbp1-KO mice. In the RRBP1-knockdown Calu-6 cells, a human renin-producing cell line, transmission electron and confocal microscopy revealed that renin was primarily retained in the endoplasmic reticulum and was unable to efficiently target the Golgi apparatus for secretion. Conclusions RRBP1 deficiency in mice caused hyporeninemic hypoaldosteronism, resulting in lower blood pressure, severe hyperkalemia, and sudden cardiac death. In juxtaglomerular cells, deficiency of RRBP1 reduced renin intracellular trafficking from ER to Golgi apparatus. RRBP1 is a brand-new regulator of blood pressure and potassium homeostasis discovered in this study. Graphical Abstract

Published
2023
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7. A randomized trial on the effect of transcutaneous electrical nerve stimulator on glycemic control in patients with type 2 diabetes

Author

Jin-Ying Lu, Horng-Yih Ou, Chung-Ze Wu, Chwen-Yi Yang, Ju-Ying Jiang, Chieh-Hsiang Lu, Yi-Der Jiang, Tien-Jyun Chang, Yi-Cheng Chang, Meng-Lun Hsieh, Wan-Chen Wu, Hung-Yuan Li, Ye-Fong Du, Ching-Han Lin, Hao-Chang Hung, Kai-Jen Tien, Nai-Cheng Yeh, Shang-Yu Lee, Hui-I. Yu, and Lee-Ming Chuang

Subjects
Medicine, Science
Abstract

Abstract Transcutaneous electrical nerve stimulator (TENS) has been demonstrated to be beneficial in glycemic control in animal models, but its application in humans has not been well studied. We randomly assigned 160 patients with type 2 diabetes on oral antidiabetic drugs 1:1 to the TENS study device (n = 81) and placebo (n = 79). 147 (92%) randomized participants (mean [SD] age 59 [10] years, 92 men [58%], mean [SD] baseline HbA1c level 8.1% [0.6%]) completed the trial. At week 20, HbA1c decreased from 8.1% to 7.9% in the TENS group (− 0.2% [95% CI − 0.4% to − 0.1%]) and from 8.1% to 7.8% in the placebo group (− 0.3% [95% CI − 0.5% to − 0.2%]) (P = 0.821). Glycemic variability, measured as mean amplitude of glycemic excursion (MAGE) at week 20 were significantly different in the TENS group vs. the placebo group (66 mg/dL [95% CI 58, 73] vs. 79 mg/dL [95% CI 72, 87]) (P = 0.009). Our study provides the clinical evidence for the first time in humans that TENS does not demonstrate a statistically significant HbA1c reduction. However, it is a safe complementary therapy to improve MAGE in patients with type 2 diabetes.

Published
2023
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8. 15-keto-PGE2 alleviates nonalcoholic steatohepatitis through its covalent modification of NF-κB factors

Author

Siow-Wey Hee, Yi-Cheng Chang, Lynn Su, Ing-Jung Chen, Yung-Ming Jeng, Meng-Lun Hsieh, Yu-Chia Chang, Fu-An Li, Daniel Liao, Shiau-Mei Chen, and Lee-Ming Chuang

Subjects
Cognitive neuroscience, Machine learning, Science
Abstract

Summary: 15-keto-PGE2 is one of the eicosanoids with anti-inflammatory properties. In this study, we demonstrated that 15-keto-PGE2 post-translationally modified the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) subunits p105/p50 and p65 at Cys59 and Cys120 sites, respectively, hence inhibiting the activation of NF-κB signaling in macrophages. In mice fed a high-fat and high-sucrose diet (HFHSD), 15-keto-PGE2 treatment reduced pro-inflammatory cytokines and fasting glucose levels. In mice with non-alcoholic steatohepatitis (NASH) induced by a prolonged HFHSD, 15-keto-PGE2 treatment significantly decreased liver inflammation, lowered serum levels of alanine transaminase (ALT) and aspartate transferase (AST), and inhibited macrophage infiltration. It also reduced lipid droplet size and downregulated key regulators of lipogenesis. These findings highlight the potential of 15-keto-PGE2, through NF-κB modification, in preventing the development and progression of steatohepatitis, emphasizing the significance of endogenous lipid mediators in the inflammatory response.

Published
2023
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9. Epigenome-wide DNA methylation association study of circulating IgE levels identifies novel targets for asthmaResearch in context

Author

Kathryn Recto, Priyadarshini Kachroo, Tianxiao Huan, David Van Den Berg, Gha Young Lee, Helena Bui, Dong Heon Lee, Jessica Gereige, Chen Yao, Shih-Jen Hwang, Roby Joehanes, Scott T. Weiss, George T. O’Connor, Daniel Levy, Dawn L. DeMeo, Namiko Abe, Gonçalo Abecasis, Francois Aguet, Christine Albert, Laura Almasy, Alvaro Alonso, Seth Ament, Peter Anderson, Pramod Anugu, Deborah Applebaum-Bowden, Kristin Ardlie, Dan Arking, Donna K. Arnett, Allison Ashley-Koch, Stella Aslibekyan, Tim Assimes, Paul Auer, Dimitrios Avramopoulos, Najib Ayas, Adithya Balasubramanian, John Barnard, Kathleen Barnes, R. Graham Barr, Emily Barron-Casella, Lucas Barwick, Terri Beaty, Gerald Beck, Diane Becker, Lewis Becker, Rebecca Beer, Amber Beitelshees, Emelia Benjamin, Takis Benos, Marcos Bezerra, Larry Bielak, Joshua Bis, Thomas Blackwell, John Blangero, Nathan Blue, Eric Boerwinkle, Donald W. Bowden, Russell Bowler, Jennifer Brody, Ulrich Broeckel, Jai Broome, Deborah Brown, Karen Bunting, Esteban Burchard, Carlos Bustamante, Erin Buth, Brian Cade, Jonathan Cardwell, Vincent Carey, Julie Carrier, April P. Carson, Cara Carty, Richard Casaburi, Juan P. Casas Romero, James Casella, Peter Castaldi, Mark Chaffin, Christy Chang, Yi-Cheng Chang, Daniel Chasman, Sameer Chavan, Bo-Juen Chen, Wei-Min Chen, Yii-Der Ida Chen, Michael Cho, Seung Hoan Choi, Lee-Ming Chuang, Mina Chung, Ren-Hua Chung, Clary Clish, Suzy Comhair, Matthew Conomos, Elaine Cornell, Adolfo Correa, Carolyn Crandall, James Crapo, L. Adrienne Cupples, Joanne Curran, Jeffrey Curtis, Brian Custer, Coleen Damcott, Dawood Darbar, Sean David, Colleen Davis, Michelle Daya, Mariza de Andrade, Lisa de las Fuentes, Paul de Vries, Michael DeBaun, Ranjan Deka, Dawn DeMeo, Scott Devine, Huyen Dinh, Harsha Doddapaneni, Qing Duan, Shannon Dugan-Perez, Ravi Duggirala, Jon Peter Durda, Susan K. Dutcher, Charles Eaton, Lynette Ekunwe, Adel El Boueiz, Patrick Ellinor, Leslie Emery, Serpil Erzurum, Charles Farber, Jesse Farek, Tasha Fingerlin, Matthew Flickinger, Myriam Fornage, Nora Franceschini, Chris Frazar, Mao Fu, Stephanie M. Fullerton, Lucinda Fulton, Stacey Gabriel, Weiniu Gan, Shanshan Gao, Yan Gao, Margery Gass, Heather Geiger, Bruce Gelb, Mark Geraci, Soren Germer, Robert Gerszten, Auyon Ghosh, Richard Gibbs, Chris Gignoux, Mark Gladwin, David Glahn, Stephanie Gogarten, Da-Wei Gong, Harald Goring, Sharon Graw, Kathryn J. Gray, Daniel Grine, Colin Gross, C. Charles Gu, Yue Guan, Xiuqing Guo, Namrata Gupta, Jeff Haessler, Michael Hall, Yi Han, Patrick Hanly, Daniel Harris, Nicola L. Hawley, Jiang He, Ben Heavner, Susan Heckbert, Ryan Hernandez, David Herrington, Craig Hersh, Bertha Hidalgo, James Hixson, Brian Hobbs, John Hokanson, Elliott Hong, Karin Hoth, Chao (Agnes) Hsiung, Jianhong Hu, Yi-Jen Hung, Haley Huston, Chii Min Hwu, Marguerite Ryan Irvin, Rebecca Jackson, Deepti Jain, Cashell Jaquish, Jill Johnsen, Andrew Johnson, Craig Johnson, Rich Johnston, Kimberly Jones, Hyun Min Kang, Robert Kaplan, Sharon Kardia, Shannon Kelly, Eimear Kenny, Michael Kessler, Alyna Khan, Ziad Khan, Wonji Kim, John Kimoff, Greg Kinney, Barbara Konkle, Charles Kooperberg, Holly Kramer, Christoph Lange, Ethan Lange, Leslie Lange, Cathy Laurie, Cecelia Laurie, Meryl LeBoff, Jiwon Lee, Sandra Lee, Wen-Jane Lee, Jonathon LeFaive, David Levine, Joshua Lewis, Xiaohui Li, Yun Li, Henry Lin, Honghuang Lin, Xihong Lin, Simin Liu, Yongmei Liu, Yu Liu, Ruth J.F. Loos, Steven Lubitz, Kathryn Lunetta, James Luo, Ulysses Magalang, Michael Mahaney, Barry Make, Ani Manichaikul, Alisa Manning, JoAnn Manson, Lisa Martin, Melissa Marton, Susan Mathai, Rasika Mathias, Susanne May, Patrick McArdle, Merry-Lynn McDonald, Sean McFarland, Stephen McGarvey, Daniel McGoldrick, Caitlin McHugh, Becky McNeil, Hao Mei, James Meigs, Vipin Menon, Luisa Mestroni, Ginger Metcalf, Deborah A. Meyers, Emmanuel Mignot, Julie Mikulla, Nancy Min, Mollie Minear, Ryan L. Minster, Braxton D. Mitchell, Matt Moll, Zeineen Momin, May E. Montasser, Courtney Montgomery, Donna Muzny, Josyf C. Mychaleckyj, Girish Nadkarni, Rakhi Naik, Take Naseri, Pradeep Natarajan, Sergei Nekhai, Sarah C. Nelson, Bonnie Neltner, Caitlin Nessner, Deborah Nickerson, Osuji Nkechinyere, Kari North, Jeff O'Connell, Tim O'Connor, Heather Ochs-Balcom, Geoffrey Okwuonu, Allan Pack, David T. Paik, Nicholette Palmer, James Pankow, George Papanicolaou, Cora Parker, Gina Peloso, Juan Manuel Peralta, Marco Perez, James Perry, Ulrike Peters, Patricia Peyser, Lawrence S. Phillips, Jacob Pleiness, Toni Pollin, Wendy Post, Julia Powers Becker, Meher Preethi Boorgula, Michael Preuss, Bruce Psaty, Pankaj Qasba, Dandi Qiao, Zhaohui Qin, Nicholas Rafaels, Laura Raffield, Mahitha Rajendran, Vasan S. Ramachandran, D.C. Rao, Laura Rasmussen-Torvik, Aakrosh Ratan, Susan Redline, Robert Reed, Catherine Reeves, Elizabeth Regan, Alex Reiner, Muagututi‘a Sefuiva Reupena, Ken Rice, Stephen Rich, Rebecca Robillard, Nicolas Robine, Dan Roden, Carolina Roselli, Jerome Rotter, Ingo Ruczinski, Alexi Runnels, Pamela Russell, Sarah Ruuska, Kathleen Ryan, Ester Cerdeira Sabino, Danish Saleheen, Shabnam Salimi, Sejal Salvi, Steven Salzberg, Kevin Sandow, Vijay G. Sankaran, Jireh Santibanez, Karen Schwander, David Schwartz, Frank Sciurba, Christine Seidman, Jonathan Seidman, Frédéric Sériès, Vivien Sheehan, Stephanie L. Sherman, Amol Shetty, Aniket Shetty, Wayne Hui-Heng Sheu, M. Benjamin Shoemaker, Brian Silver, Edwin Silverman, Robert Skomro, Albert Vernon Smith, Jennifer Smith, Josh Smith, Nicholas Smith, Tanja Smith, Sylvia Smoller, Beverly Snively, Michael Snyder, Tamar Sofer, Nona Sotoodehnia, Adrienne M. Stilp, Garrett Storm, Elizabeth Streeten, Jessica Lasky Su, Yun Ju Sung, Jody Sylvia, Adam Szpiro, Daniel Taliun, Hua Tang, Margaret Taub, Kent Taylor, Matthew Taylor, Simeon Taylor, Marilyn Telen, Timothy A. Thornton, Machiko Threlkeld, Lesley Tinker, David Tirschwell, Sarah Tishkoff, Hemant Tiwari, Catherine Tong, Russell Tracy, Michael Tsai, Dhananjay Vaidya, Peter VandeHaar, Scott Vrieze, Tarik Walker, Robert Wallace, Avram Walts, Fei Fei Wang, Heming Wang, Jiongming Wang, Karol Watson, Jennifer Watt, Daniel E. Weeks, Joshua Weinstock, Bruce Weir, Lu-Chen Weng, Jennifer Wessel, Cristen Willer, Kayleen Williams, L. Keoki Williams, Scott Williams, Carla Wilson, James Wilson, Lara Winterkorn, Quenna Wong, Baojun Wu, Joseph Wu, Huichun Xu, Lisa Yanek, Ivana Yang, Ketian Yu, Seyedeh Maryam Zekavat, Yingze Zhang, Snow Xueyan Zhao, Wei Zhao, Xiaofeng Zhu, Elad Ziv, Michael Zody, and Sebastian Zoellner

Subjects
EWAS, DNA methylation, IgE, Asthma, RNA-Sequencing, Mendelian randomization, Medicine, Medicine (General), R5-920
Abstract

Summary: Background: Identifying novel epigenetic signatures associated with serum immunoglobulin E (IgE) may improve our understanding of molecular mechanisms underlying asthma and IgE-mediated diseases. Methods: We performed an epigenome-wide association study using whole blood from Framingham Heart Study (FHS; n = 3,471, 46% females) participants and validated results using the Childhood Asthma Management Program (CAMP; n = 674, 39% females) and the Genetic Epidemiology of Asthma in Costa Rica Study (CRA; n = 787, 41% females). Using the closest gene to each IgE-associated CpG, we highlighted biologically plausible pathways underlying IgE regulation and analyzed the transcription patterns linked to IgE-associated CpGs (expression quantitative trait methylation loci; eQTMs). Using prior UK Biobank summary data from genome-wide association studies of asthma and allergy, we performed Mendelian randomization (MR) for causal inference testing using the IgE-associated CpGs from FHS with methylation quantitative trait loci (mQTLs) as instrumental variables. Findings: We identified 490 statistically significant differentially methylated CpGs associated with IgE in FHS, of which 193 (39.3%) replicated in CAMP and CRA (FDR < 0.05). Gene ontology analysis revealed enrichment in pathways related to transcription factor binding, asthma, and other immunological processes. eQTM analysis identified 124 cis-eQTMs for 106 expressed genes (FDR < 0.05). MR in combination with drug-target analysis revealed CTSB and USP20 as putatively causal regulators of IgE levels (Bonferroni adjusted P

Published
2023
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10. Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Author

Stavroula Kanoni, Sarah E. Graham, Yuxuan Wang, Ida Surakka, Shweta Ramdas, Xiang Zhu, Shoa L. Clarke, Konain Fatima Bhatti, Sailaja Vedantam, Thomas W. Winkler, Adam E. Locke, Eirini Marouli, Greg J. M. Zajac, Kuan-Han H. Wu, Ioanna Ntalla, Qin Hui, Derek Klarin, Austin T. Hilliard, Zeyuan Wang, Chao Xue, Gudmar Thorleifsson, Anna Helgadottir, Daniel F. Gudbjartsson, Hilma Holm, Isleifur Olafsson, Mi Yeong Hwang, Sohee Han, Masato Akiyama, Saori Sakaue, Chikashi Terao, Masahiro Kanai, Wei Zhou, Ben M. Brumpton, Humaira Rasheed, Aki S. Havulinna, Yogasudha Veturi, Jennifer Allen Pacheco, Elisabeth A. Rosenthal, Todd Lingren, QiPing Feng, Iftikhar J. Kullo, Akira Narita, Jun Takayama, Hilary C. Martin, Karen A. Hunt, Bhavi Trivedi, Jeffrey Haessler, Franco Giulianini, Yuki Bradford, Jason E. Miller, Archie Campbell, Kuang Lin, Iona Y. Millwood, Asif Rasheed, George Hindy, Jessica D. Faul, Wei Zhao, David R. Weir, Constance Turman, Hongyan Huang, Mariaelisa Graff, Ananyo Choudhury, Dhriti Sengupta, Anubha Mahajan, Michael R. Brown, Weihua Zhang, Ketian Yu, Ellen M. Schmidt, Anita Pandit, Stefan Gustafsson, Xianyong Yin, Jian’an Luan, Jing-Hua Zhao, Fumihiko Matsuda, Hye-Mi Jang, Kyungheon Yoon, Carolina Medina-Gomez, Achilleas Pitsillides, Jouke Jan Hottenga, Andrew R. Wood, Yingji Ji, Zishan Gao, Simon Haworth, Noha A. Yousri, Ruth E. Mitchell, Jin Fang Chai, Mette Aadahl, Anne A. Bjerregaard, Jie Yao, Ani Manichaikul, Chii-Min Hwu, Yi-Jen Hung, Helen R. Warren, Julia Ramirez, Jette Bork-Jensen, Line L. Kårhus, Anuj Goel, Maria Sabater-Lleal, Raymond Noordam, Pala Mauro, Floris Matteo, Aaron F. McDaid, Pedro Marques-Vidal, Matthias Wielscher, Stella Trompet, Naveed Sattar, Line T. Møllehave, Matthias Munz, Lingyao Zeng, Jianfeng Huang, Bin Yang, Alaitz Poveda, Azra Kurbasic, Claudia Lamina, Lukas Forer, Markus Scholz, Tessel E. Galesloot, Jonathan P. Bradfield, Sanni E. Ruotsalainen, EWarwick Daw, Joseph M. Zmuda, Jonathan S. Mitchell, Christian Fuchsberger, Henry Christensen, Jennifer A. Brody, Miguel Vazquez-Moreno, Mary F. Feitosa, Mary K. Wojczynski, Zhe Wang, Michael H. Preuss, Massimo Mangino, Paraskevi Christofidou, Niek Verweij, Jan W. Benjamins, Jorgen Engmann, Noah L. Tsao, Anurag Verma, Roderick C. Slieker, Ken Sin Lo, Nuno R. Zilhao, Phuong Le, Marcus E. Kleber, Graciela E. Delgado, Shaofeng Huo, Daisuke D. Ikeda, Hiroyuki Iha, Jian Yang, Jun Liu, Ayşe Demirkan, Hampton L. Leonard, Jonathan Marten, Mirjam Frank, Börge Schmidt, Laura J. Smyth, Marisa Cañadas-Garre, Chaolong Wang, Masahiro Nakatochi, Andrew Wong, Nina Hutri-Kähönen, Xueling Sim, Rui Xia, Alicia Huerta-Chagoya, Juan Carlos Fernandez-Lopez, Valeriya Lyssenko, Suraj S. Nongmaithem, Swati Bayyana, Heather M. Stringham, Marguerite R. Irvin, Christopher Oldmeadow, Han-Na Kim, Seungho Ryu, Paul R. H. J. Timmers, Liubov Arbeeva, Rajkumar Dorajoo, Leslie A. Lange, Gauri Prasad, Laura Lorés-Motta, Marc Pauper, Jirong Long, Xiaohui Li, Elizabeth Theusch, Fumihiko Takeuchi, Cassandra N. Spracklen, Anu Loukola, Sailalitha Bollepalli, Sophie C. Warner, Ya Xing Wang, Wen B. Wei, Teresa Nutile, Daniela Ruggiero, Yun Ju Sung, Shufeng Chen, Fangchao Liu, Jingyun Yang, Katherine A. Kentistou, Bernhard Banas, Giuseppe Giovanni Nardone, Karina Meidtner, Lawrence F. Bielak, Jennifer A. Smith, Prashantha Hebbar, Aliki-Eleni Farmaki, Edith Hofer, Maoxuan Lin, Maria Pina Concas, Simona Vaccargiu, Peter J. van der Most, Niina Pitkänen, Brian E. Cade, Sander W. van der Laan, Kumaraswamy Naidu Chitrala, Stefan Weiss, Amy R. Bentley, Ayo P. Doumatey, Adebowale A. Adeyemo, Jong Young Lee, Eva R. B. Petersen, Aneta A. Nielsen, Hyeok Sun Choi, Maria Nethander, Sandra Freitag-Wolf, Lorraine Southam, Nigel W. Rayner, Carol A. Wang, Shih-Yi Lin, Jun-Sing Wang, Christian Couture, Leo-Pekka Lyytikäinen, Kjell Nikus, Gabriel Cuellar-Partida, Henrik Vestergaard, Bertha Hidalgo, Olga Giannakopoulou, Qiuyin Cai, Morgan O. Obura, Jessica van Setten, Xiaoyin Li, Jingjing Liang, Hua Tang, Natalie Terzikhan, Jae Hun Shin, Rebecca D. Jackson, Alexander P. Reiner, Lisa Warsinger Martin, Zhengming Chen, Liming Li, Takahisa Kawaguchi, Joachim Thiery, Joshua C. Bis, Lenore J. Launer, Huaixing Li, Mike A. Nalls, Olli T. Raitakari, Sahoko Ichihara, Sarah H. Wild, Christopher P. Nelson, Harry Campbell, Susanne Jäger, Toru Nabika, Fahd Al-Mulla, Harri Niinikoski, Peter S. Braund, Ivana Kolcic, Peter Kovacs, Tota Giardoglou, Tomohiro Katsuya, Dominique de Kleijn, Gert J. de Borst, Eung Kweon Kim, Hieab H. H. Adams, M. Arfan Ikram, Xiaofeng Zhu, Folkert W. Asselbergs, Adriaan O. Kraaijeveld, Joline W. J. Beulens, Xiao-Ou Shu, Loukianos S. Rallidis, Oluf Pedersen, Torben Hansen, Paul Mitchell, Alex W. Hewitt, Mika Kähönen, Louis Pérusse, Claude Bouchard, Anke Tönjes, Yii-Der Ida Chen, Craig E. Pennell, Trevor A. Mori, Wolfgang Lieb, Andre Franke, Claes Ohlsson, Dan Mellström, Yoon Shin Cho, Hyejin Lee, Jian-Min Yuan, Woon-Puay Koh, Sang Youl Rhee, Jeong-Taek Woo, Iris M. Heid, Klaus J. Stark, Martina E. Zimmermann, Henry Völzke, Georg Homuth, Michele K. Evans, Alan B. Zonderman, Ozren Polasek, Gerard Pasterkamp, Imo E. Hoefer, Susan Redline, Katja Pahkala, Albertine J. Oldehinkel, Harold Snieder, Ginevra Biino, Reinhold Schmidt, Helena Schmidt, Stefania Bandinelli, George Dedoussis, Thangavel Alphonse Thanaraj, Sharon L. R. Kardia, Patricia A. Peyser, Norihiro Kato, Matthias B. Schulze, Giorgia Girotto, Carsten A. Böger, Bettina Jung, Peter K. Joshi, David A. Bennett, Philip L. De Jager, Xiangfeng Lu, Vasiliki Mamakou, Morris Brown, Mark J. Caulfield, Patricia B. Munroe, Xiuqing Guo, Marina Ciullo, Jost B. Jonas, Nilesh J. Samani, Jaakko Kaprio, Päivi Pajukanta, Teresa Tusié-Luna, Carlos A. Aguilar-Salinas, Linda S. Adair, Sonny Augustin Bechayda, H. Janaka de Silva, Ananda R. Wickremasinghe, Ronald M. Krauss, Jer-Yuarn Wu, Wei Zheng, Anneke Iden Hollander, Dwaipayan Bharadwaj, Adolfo Correa, James G. Wilson, Lars Lind, Chew-Kiat Heng, Amanda E. Nelson, Yvonne M. Golightly, James F. Wilson, Brenda Penninx, Hyung-Lae Kim, John Attia, Rodney J. Scott, D. C. Rao, Donna K. Arnett, Steven C. Hunt, Mark Walker, Heikki A. Koistinen, Giriraj R. Chandak, Josep M. Mercader, Maria C. Costanzo, Dongkeun Jang, Noël P. Burtt, Clicerio Gonzalez Villalpando, Lorena Orozco, Myriam Fornage, EShyong Tai, Rob M. van Dam, Terho Lehtimäki, Nish Chaturvedi, Mitsuhiro Yokota, Jianjun Liu, Dermot F. Reilly, Amy Jayne McKnight, Frank Kee, Karl-Heinz Jöckel, Mark I. McCarthy, Colin N. A. Palmer, Veronique Vitart, Caroline Hayward, Eleanor Simonsick, Cornelia M. van Duijn, Zi-Bing Jin, Jia Qu, Haretsugu Hishigaki, Xu Lin, Winfried März, Vilmundur Gudnason, Jean-Claude Tardif, Guillaume Lettre, Leen M.‘t Hart, Petra J. M. Elders, Scott M. Damrauer, Meena Kumari, Mika Kivimaki, Pim van der Harst, Tim D. Spector, Ruth J. F. Loos, Michael A. Province, Esteban J. Parra, Miguel Cruz, Bruce M. Psaty, Ivan Brandslund, Peter P. Pramstaller, Charles N. Rotimi, Kaare Christensen, Samuli Ripatti, Elisabeth Widén, Hakon Hakonarson, Struan F. A. Grant, Lambertus A. L. M. Kiemeney, Jacqueline de Graaf, Markus Loeffler, Florian Kronenberg, Dongfeng Gu, Jeanette Erdmann, Heribert Schunkert, Paul W. Franks, Allan Linneberg, J. Wouter Jukema, Amit V. Khera, Minna Männikkö, Marjo-Riitta Jarvelin, Zoltan Kutalik, Cucca Francesco, Dennis O. Mook-Kanamori, Ko Willems van Dijk, Hugh Watkins, David P. Strachan, Niels Grarup, Peter Sever, Neil Poulter, Lee-Ming Chuang, Jerome I. Rotter, Thomas M. Dantoft, Fredrik Karpe, Matt J. Neville, Nicholas J. Timpson, Ching-Yu Cheng, Tien-Yin Wong, Chiea Chuen Khor, Hengtong Li, Charumathi Sabanayagam, Annette Peters, Christian Gieger, Andrew T. Hattersley, Nancy L. Pedersen, Patrik K. E. Magnusson, Dorret I. Boomsma, Allegonda H. M. Willemsen, LAdrienne Cupples, Joyce B. J. van Meurs, Mohsen Ghanbari, Penny Gordon-Larsen, Wei Huang, Young Jin Kim, Yasuharu Tabara, Nicholas J. Wareham, Claudia Langenberg, Eleftheria Zeggini, Johanna Kuusisto, Markku Laakso, Erik Ingelsson, Goncalo Abecasis, John C. Chambers, Jaspal S. Kooner, Paul S. de Vries, Alanna C. Morrison, Scott Hazelhurst, Michèle Ramsay, Kari E. North, Martha Daviglus, Peter Kraft, Nicholas G. Martin, John B. Whitfield, Shahid Abbas, Danish Saleheen, Robin G. Walters, Michael V. Holmes, Corri Black, Blair H. Smith, Aris Baras, Anne E. Justice, Julie E. Buring, Paul M. Ridker, Daniel I. Chasman, Charles Kooperberg, Gen Tamiya, Masayuki Yamamoto, David A. van Heel, Richard C. Trembath, Wei-Qi Wei, Gail P. Jarvik, Bahram Namjou, M. Geoffrey Hayes, Marylyn D. Ritchie, Pekka Jousilahti, Veikko Salomaa, Kristian Hveem, Bjørn Olav Åsvold, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada, Yoshinori Murakami, Bong-Jo Kim, Unnur Thorsteinsdottir, Kari Stefansson, Jifeng Zhang, YEugene Chen, Yuk-Lam Ho, Julie A. Lynch, Daniel J. Rader, Philip S. Tsao, Kyong-Mi Chang, Kelly Cho, Christopher J. O’Donnell, John M. Gaziano, Peter W. F. Wilson, Timothy M. Frayling, Joel N. Hirschhorn, Sekar Kathiresan, Karen L. Mohlke, Yan V. Sun, Andrew P. Morris, Michael Boehnke, Christopher D. Brown, Pradeep Natarajan, Panos Deloukas, Cristen J. Willer, Themistocles L. Assimes, and Gina M. Peloso

Subjects
Cholesterol, Lipids, Genetics, Genome-wide association study, GWAS, Biology (General), QH301-705.5, QH426-470
Abstract

Abstract Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.

Published
2022
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11. Whole genome sequence analysis of blood lipid levels in >66,000 individuals

Author

Margaret Sunitha Selvaraj, Xihao Li, Zilin Li, Akhil Pampana, David Y. Zhang, Joseph Park, Stella Aslibekyan, Joshua C. Bis, Jennifer A. Brody, Brian E. Cade, Lee-Ming Chuang, Ren-Hua Chung, Joanne E. Curran, Lisa de las Fuentes, Paul S. de Vries, Ravindranath Duggirala, Barry I. Freedman, Mariaelisa Graff, Xiuqing Guo, Nancy Heard-Costa, Bertha Hidalgo, Chii-Min Hwu, Marguerite R. Irvin, Tanika N. Kelly, Brian G. Kral, Leslie Lange, Xiaohui Li, Martin Lisa, Steven A. Lubitz, Ani W. Manichaikul, Preuss Michael, May E. Montasser, Alanna C. Morrison, Take Naseri, Jeffrey R. O’Connell, Nicholette D. Palmer, Patricia A. Peyser, Muagututia S. Reupena, Jennifer A. Smith, Xiao Sun, Kent D. Taylor, Russell P. Tracy, Michael Y. Tsai, Zhe Wang, Yuxuan Wang, Wei Bao, John T. Wilkins, Lisa R. Yanek, Wei Zhao, Donna K. Arnett, John Blangero, Eric Boerwinkle, Donald W. Bowden, Yii-Der Ida Chen, Adolfo Correa, L. Adrienne Cupples, Susan K. Dutcher, Patrick T. Ellinor, Myriam Fornage, Stacey Gabriel, Soren Germer, Richard Gibbs, Jiang He, Robert C. Kaplan, Sharon L. R. Kardia, Ryan Kim, Charles Kooperberg, Ruth J. F. Loos, Karine A Viaud-Martinez, Rasika A. Mathias, Stephen T. McGarvey, Braxton D. Mitchell, Deborah Nickerson, Kari E. North, Bruce M. Psaty, Susan Redline, Alexander P. Reiner, Ramachandran S. Vasan, Stephen S. Rich, Cristen Willer, Jerome I. Rotter, Daniel J. Rader, Xihong Lin, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Gina M. Peloso, and Pradeep Natarajan

Subjects
Science
Abstract

Although the common genetic variants contributing to blood lipid levels have been studied, the contribution of rare variants is less understood. Here, the authors perform a rare coding and noncoding variant association study of blood lipid levels using whole genome sequencing data.

Published
2022
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12. Visit‐to‐visit variability in albuminuria predicts renal function deterioration in patients with type 2 diabetes

Author

Chih‐Hung Lin, Ying‐Chuen Lai, Tien‐Jyun Chang, Yi‐Der Jiang, Yi‐Cheng Chang, and Lee‐Ming Chuang

Subjects
Albuminuria, Type 2 diabetes, Visit‐to‐visit variability, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

Abstract Aims/Introduction We aimed to study the predictive ability of visit‐to‐visit variability in albuminuria for changes in renal function in patients with type 2 diabetes mellitus. Materials and Methods The cohort study was carried out in a single medical center. In the model development cohort of 1008 subjects, we developed the albuminuria variability score (AVS) to evaluate the visit‐to‐visit variability in albuminuria, which was the percentage of the number of changes in the urine albumin : creatinine ratio ≥3.39 mg/mmol among all visit‐to‐visit urine albumin : creatinine ratio differences within an individual. Multivariate logistic regression was applied to predict the influence of AVS levels on the occurrence of study end‐points. In another independent validation cohort of 310 participants, survival analysis was carried out to evaluate the ability of AVS in predicting the study end‐point. Results In the model development cohort, a higher AVS was associated with higher adjusted odds of having a declined or rapidly declined estimated glomerular filtration rate (eGFR) trajectory (1.84, 95% confidence interval 1.23–2.76 and 5.70, 95% confidence interval 2.28–14.25, respectively), a resultant eGFR 40% decline in eGFR from baseline (6.44, 95% confidence interval 2.15–19.26). In the validation cohort, a higher AVS independently predicted a 5‐year decrease of >40% in eGFR to

Published
2022
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13. The impact of glucose tolerance state on seropositivity rate after hepatitis B vaccination

Author

Maria Mercedes Chang Villacreses, Rudruidee Karnchanasorn, Horng-Yih Ou, Raynald Samoa, Lee-Ming Chuang, and Ken C. Chiu

Subjects
Medicine, Science
Abstract

Abstract Immunization is recommended for people with diabetes mellitus (DM), but little information is available on their seropositivity rates. To determine the impact of glucose tolerance state on seropositivity rate after hepatitis B vaccination, we included 7645 adult participants from the National Health and Nutrition Examination Survey 2005–2016 who reported three doses of hepatitis B vaccine and were seropositive for anti-hepatitis B surface antibody (≥ 12.0 mIU/mL), after exclusion of those positive for anti-hepatitis B core antibody and/or hepatitis B surface antigen. We classified the states of glucose tolerance as normal glucose tolerance (NGT, 61.68%), abnormal glucose tolerance (AGT, 26.02%), or DM (13.30%). We observed a stepwise decline in hepatitis B seropositivity rate from NGT (53.64%) to AGT (45.52%) to DM (28.84%) (P

Published
2022
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14. Different cutoffs of hypertension, risk of incident diabetes and progression of insulin resistance: A prospective cohort study

Author

Chia-Hung Lin, Jung-Nan Wei, Kang-Chih Fan, Chi-Tai Fang, Wan-Chen Wu, Chung-Yi Yang, Mao-Shin Lin, Shyang-Rong Shih, Cyue-Huei Hua, Yenh-Chen Hsein, Jou-Wei Lin, Lee-Ming Chuang, and Hung-Yuan Li

Subjects
Cutoffs, Diabetes mellitus, Hypertension, Insulin resistance, Medicine (General), R5-920
Abstract

Background/Purpose: Hypertension is a risk factor of incident diabetes. In 2017, the ACC/AHA updated the definition of hypertension to above 130/80 mmHg, while the 2018 ESC/ESH guideline and the JNC7 criteria remained the cutoff of 140/90 mmHg. This study was aimed to investigate how different cutoffs of hypertension affect the association of hypertension to incident diabetes and the progression of insulin resistance. Methods: A total of 1177 subjects without diabetes at baseline were followed for 4.5 years. Diabetes was diagnosed by the results of oral glucose tolerance tests and hemoglobin A1c, or if anti-diabetic agents were used. Results: Hypertension by both criteria was associated with incident diabetes. Change of HOMA2-IR every 5 years (ΔHOMA2-IR/5 yr) was higher in subjects with hypertension than those without (adjusted p = 0.044). Subjects with treated hypertension had the highest risk of diabetes (HR 2.98, p

Published
2022
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15. Emerging Therapy for Diabetic Cardiomyopathy: From Molecular Mechanism to Clinical Practice

Author

Chin-Feng Hsuan, Sean I. F. Teng, Chih-Neng Hsu, Daniel Liao, Allen Jiun-Wei Chang, Hsiao-Lin Lee, Siow-Wey Hee, Yi-Cheng Chang, and Lee-Ming Chuang

Subjects
diabetic cardiomyopathy, emerging therapy, mechanism, Biology (General), QH301-705.5
Abstract

Diabetic cardiomyopathy is characterized by abnormal myocardial structure or performance in the absence of coronary artery disease or significant valvular heart disease in patients with diabetes mellitus. The spectrum of diabetic cardiomyopathy ranges from subtle myocardial changes to myocardial fibrosis and diastolic function and finally to symptomatic heart failure. Except for sodium–glucose transport protein 2 inhibitors and possibly bariatric and metabolic surgery, there is currently no specific treatment for this distinct disease entity in patients with diabetes. The molecular mechanism of diabetic cardiomyopathy includes impaired nutrient-sensing signaling, dysregulated autophagy, impaired mitochondrial energetics, altered fuel utilization, oxidative stress and lipid peroxidation, advanced glycation end-products, inflammation, impaired calcium homeostasis, abnormal endothelial function and nitric oxide production, aberrant epidermal growth factor receptor signaling, the activation of the renin–angiotensin–aldosterone system and sympathetic hyperactivity, and extracellular matrix accumulation and fibrosis. Here, we summarize several important emerging treatments for diabetic cardiomyopathy targeting specific molecular mechanisms, with evidence from preclinical studies and clinical trials.

Published
2023
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16. Activation of Aldehyde Dehydrogenase 2 Ameliorates Glucolipotoxicity of Pancreatic Beta Cells

Author

Shiau-Mei Chen, Siow-Wey Hee, Shih-Yun Chou, Meng-Wei Liu, Che-Hong Chen, Daria Mochly-Rosen, Tien-Jyun Chang, and Lee-Ming Chuang

Subjects
aldehyde dehydrogenase 2 (ALDH2), glucolipotoxicity, beta cell function, Alda-1, Microbiology, QR1-502
Abstract

Chronic hyperglycemia and hyperlipidemia hamper beta cell function, leading to glucolipotoxicity. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) detoxifies reactive aldehydes, such as methylglyoxal (MG) and 4-hydroxynonenal (4-HNE), derived from glucose and lipids, respectively. We aimed to investigate whether ALDH2 activators ameliorated beta cell dysfunction and apoptosis induced by glucolipotoxicity, and its potential mechanisms of action. Glucose-stimulated insulin secretion (GSIS) in MIN6 cells and insulin secretion from isolated islets in perifusion experiments were measured. The intracellular ATP concentrations and oxygen consumption rates of MIN6 cells were assessed. Furthermore, the cell viability, apoptosis, and mitochondrial and intracellular reactive oxygen species (ROS) levels were determined. Additionally, the pro-apoptotic, apoptotic, and anti-apoptotic signaling pathways were investigated. We found that Alda-1 enhanced GSIS by improving the mitochondrial function of pancreatic beta cells. Alda-1 rescued MIN6 cells from MG- and 4-HNE-induced beta cell death, apoptosis, mitochondrial dysfunction, and ROS production. However, the above effects of Alda-1 were abolished in Aldh2 knockdown MIN6 cells. In conclusion, we reported that the activator of ALDH2 not only enhanced GSIS, but also ameliorated the glucolipotoxicity of beta cells by reducing both the mitochondrial and intracellular ROS levels, thereby improving mitochondrial function, restoring beta cell function, and protecting beta cells from apoptosis and death.

Published
2021
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17. Kidney and Cardiovascular Effects of Canagliflozin According to Age and Sex

Author

Tae Won Yi, Brendan Smyth, Gian Luca Di Tanna, Clare Arnott, Kathryn Cardoza, Amy Kang, Carol Pollock, Rajiv Agarwal, George Bakris, David M. Charytan, Dick de Zeeuw, Hiddo J.L. Heerspink, Bruce Neal, David C. Wheeler, Christopher P. Cannon, Hong Zhang, Bernard Zinman, Vlado Perkovic, Adeera Levin, Kenneth W. Mahaffey, Meg Jardine, Barry M. Brenner, Tom Greene, Meg J. Jardine, Gary Meininger, Nicole Li, Inna Kolesnyk, Diego Aizenberg, Roberto Pecoits-Filho, David Cherney, Gregorio Obrador, Glenn Chertow, Tara Chang, Carmel Hawley, Linong Ji, Takashi Wada, Vivekanand Jha, Soo Kun Lim, Mary Anne Lim-Abrahan, Florence Santos, Dong-Wan Chae, Shang-Jyh Hwang, Evgueniy Vazelov, Ivan Rychlík, Samy Hadjadj, Vera Krane, László Rosivall, Luca De Nicola, Alexander Dreval, Michał Nowicki, Adalbert Schiller, Larry Distiller, Jose L. Górriz, Mykola Kolesnyk, null David, C. Wheeler, Rodolfo Andres Ahuad Guerrero, Juan Pablo Albisu, Andres Alvarisqueta, Ines Bartolacci, Mario Alberto Berli, Anselmo Bordonava, Pedro Calella, Maria Cecilia Cantero, Luis Rodolfo Cartasegna, Esteban Cercos, Gabriela Cecilia Coloma, Hugo Colombo, Victor Commendatore, Jesus Cuadrado, Carlos Alberto Cuneo, Ana Maria Cusumano, Walter Guillermo Douthat, Ricardo Dario Dran, Eduardo Farias, Maria Florencia Fernandez, Hernan Finkelstein, Guillermo Fragale, Jose Osvaldo Fretes, Nestor Horacio Garcia, Anibal Gastaldi, Elizabeth Gelersztein, Jorge Archibaldo Glenny, Joaquin Pablo Gonzalez, Patricia del Carmen Gonzalez Colaso, Claudia Goycoa, Gustavo Cristian Greloni, Adrian Guinsburg, Sonia Hermida, Luis Isaias Juncos, Maria Isabel Klyver, Florencia Kraft, Fernando Krynski, Paulina Virginia Lanchiotti, Ricardo Alfonso Leon de la Fuente, Nora Marchetta, Pablo Mele, Silvia Nicolai, Pablo Antonio Novoa, Silvia Ines Orio, Fabian Otreras, Alejandra Oviedo, Pablo Raffaele, Jorge Hector Resk, Lucas Rista, Nelson Rodriguez Papini, Jorgelina Sala, Juan Carlos Santos, Lilia Beatriz Schiavi, Horacio Sessa, Tomas Smith Casabella, Maria Rosa Ulla, Maria Valdez, Augusto Vallejos, Adriana Villarino, Virginia Esther Visco, Alfredo Wassermann, Cesar Javier Zaidman, Ngai Wah Cheung, Carolyn Droste, Ian Fraser, David Johnson, Peak Mann Mah, Kathy Nicholls, David Packham, Joseph Proietto, Anthony Roberts, Simon Roger, Venessa Tsang, Roberto Abrão Raduan, Fernando Augusto Alves da Costa, Celso Amodeo, Luiz Alberto Andreotti Turatti, Rachel Bregman, Fernanda Cristina Camelo Sanches, Luis Henrique Canani, Antônio Roberto Chacra, João Lindolfo Cunha Borges, Sérgio Alberto Cunha Vêncio, Roberto Jorge da Silva Franco, Domingos d’Avila, Evandro de Souza Portes, Pedro de Souza, Luciane Mônica Deboni, Fadlo Fraige Filho, Bruno Geloneze Neto, Marcus Gomes, Suely Keiko Kohara, Elizete Keitel, Jose Francisco Kerr Saraiva, Hugo Roberto Kurtz Lisboa, Fabiana Loss de Carvalho Contieri, Rosângela Milagres, Renan Montenegro Junior, Claudia Moreira de Brito, Miguel Nasser Hissa, Ângela Regina Nazario Sabbag, Irene Noronha, Daniel Panarotto, Roberto Pecoits Filho, Márcio Antônio Pereira, Wladmir Saporito, Antonio Scafuto Scotton, Tiago Schuch, Roberto Simões de Almeida, Cássio Slompo Ramos, João Soares Felício, Fernando Thomé, Jean Carlo Tibes Hachmann, Sérgio Yamada, Cesar Yoiti Hayashida, Tarissa Beatrice Zanata Petry, Maria Teresa Zanella, Viktoria Andreeva, Angelina Angelova, Stefan Dimitrov, Veselka Genadieva, Gabriela Genova-Hristova, Kiril Hristozov, Zdravko Kamenov, Atanas Koundurdjiev, Lachezar Lozanov, Viktor Margaritov, Boyan Nonchev, Rangel Rangelov, Alexander Shinkov, Margarita Temelkova, Ekaterina Velichkova, Andrian Yakov, Naresh Aggarwal, Ronnie Aronson, Harpreet Bajaj, Guy Chouinard, James Conway, Serge Cournoyer, Gerald DaRoza, Sacha De Serres, François Dubé, Ronald Goldenberg, Anil Gupta, Milan Gupta, Sam Henein, Hasnain Khandwala, Lawrence Leiter, François Madore, Alan McMahon, Norman Muirhead, Vincent Pichette, Remi Rabasa-Lhoret, Andrew Steele, Navdeep Tangri, Ali Torshizi, Vincent Woo, Nadia Zalunardo, María Alicia Fernández Montenegro, Juan Gonzalo Godoy Jorquera, Marcelo Medina Fariña, Victor Saavedra Gajardo, Margarita Vejar, Nan Chen, Qinkai Chen, Shenglian Gan, Yaozhong Kong, Detian Li, Wenge Li, Xuemei Li, Hongli Lin, Jian Liu, Weiping Lu, Hong Mao, Yan Ren, Weihong Song, Jiao Sun, Lin Sun, Ping Tu, Guixia Wang, Jinkui Yang, Aiping Yin, Xueqing Yu, Minghui Zhao, Hongguang Zheng, Jose Luis Accini Mendoza, Edgar Arcos, Jorge Avendano, Jorge Ernesto Andres Diaz Ruiz, Luis Hernando Garcia Ortiz, Alexander Gonzalez, Eric Hernandez Triana, Juan Diego Higuera, Natalia Malaver, Dora Inés Molina de Salazar, Ricardo Rosero, Monica Alexandra Terront Lozano, Luis Valderrama Cometa, Alex Valenzuela, Ruben Dario Vargas Alonso, Ivan Villegas, Hernan Yupanqui, Dagmar Bartaskova, Petr Barton, Jana Belobradkova, Lenka Dohnalova, Tomas Drasnar, Richard Ferkl, Katarina Halciakova, Vera Klokocnikova, Richard Kovar, Jiri Lastuvka, Martin Lukac, Satu Pesickova, Karel Peterka, Jiri Pumprla, Ivan Rychlik, Frantisek Saudek, Vladimir Tesar, Martin Valis, Pavel Weiner, Stanislav Zemek, Eric Alamartine, Sophie Borot, Bertrand Cariou, Bertrand Dussol, Jean-Pierre Fauvel, Pierre Gourdy, Alexandre Klein, Yannick Le Meur, Alfred Penfornis, Ronan Roussel, Pierre-Jean Saulnier, Eric Thervet, Philippe Zaoui, Volker Burst, Markus Faghih, Grit Faulmann, Hermann Haller, Reinhold Jerwan-Keim, Stephan Maxeiner, Björn Paschen, Georg Plassmann, Ludger Rose, Ronaldo Arturo Gonzalez Orellana, Franklin Paul Haase, Juan Pablo Moreira Diaz, Luis Alberto Ramirez Roca, Jose Antonio Sánchez Arenales, José Vicente Sanchez Polo, Erick Turcios Juarez, Gyongyi Csecsei, Botond Csiky, Peter Danos, Laszlo Deak, Mihaly Dudas, Eleonora Harcsa, Katalin Keltai, Sandor Keresztesi, Krisztian Kiss, Laszlo Konyves, Lajos Major, Margit Mileder, Marta Molnar, Janos Mucsi, Tamas Oroszlan, Ivan Ory, Gyorgy Paragh, Eva Peterfai, Gizella Petro, Katalin Revesz, Robert Takacs, Sandor Vangel, Szilard Vasas, Marianna Zsom, Oomman Abraham, Raju Sree Bhushan, Dewan Deepak, Fernando M. Edwin, Natarajan Gopalakrishnan, Noble Gracious, Alva Hansraj, Dinesh Jain, C.B. Keshavamurthy, Dinesh Khullar, Sahay Manisha, Jayameena Peringat, Narayan Prasad, Rao K. Satyanarayana, Reddy Sreedhar, Melemadathil Sreelatha, Bhimavarapu Sudhakar, Ramesh Chandra Vyasam, Riccardo Bonadonna, Pietro Castellino, Antonio Ceriello, Luca Chiovato, Salvatore De Cosmo, Giuseppe Derosa, Alberto Di Carlo, Graziano Di Cianni, Giovanni Frascà, Giorgio Fuiano, Giovanni Gambaro, Giacomo Garibotto, Carlo Giorda, Fabio Malberti, Marcora Mandreoli, Edoardo Mannucci, Emanuela Orsi, Piermarco Piatti, Domenico Santoro, Ferdinando Carlo Sasso, Gaetano Serviddio, Andrea Stella, Roberto Trevisan, Anna Maria Veronelli, Luca Zanoli, Hitoshi Akiyama, Hiromi Aoki, Akimichi Asano, Tadashi Iitsuka, Shizuo Kajiyama, Susumu Kashine, Toshio Kawada, Takamoto Kodera, Hiroshi Kono, Kazunori Koyama, Yasuro Kumeda, Shozo Miyauchi, Kazuyuki Mizuyama, Tetsuji Niiya, Hiroko Oishi, Satoshi Ota, Terue Sakakibara, Masahiko Takai, Osamu Tomonaga, Mitsuru Tsujimoto, Masakiyo Wakasugi, Yasushi Wakida, Takayuki Watanabe, Masayo Yamada, Kazuhiro Yanagida, Toshihiko Yanase, Wataru Yumita, Egle Gaupsiene, Dalia Kozloviene, Antanas Navickas, Egle Urbanaviciene, Rohana Abdul Ghani, Khalid Abdul Kadir, Norsiah Ali, Mohd Daud Che Yusof, Chye Lee Gan, Mastura Ismail, Wei Yen Kong, Swee Win Lam, Li Yuan Lee, Chek Loong Loh, Anita Bhajan Manocha, Kee Sing Ng, Nik Nur Fatnoon Nik Ahmad, Vanassa Ratnasingam, Saiful Shahrizal Bin Shudim, Paranthaman Vengadasalam, Luis David Abraira Munoz, Melchor Alpizar Salazar, Juan Baas Cruz, Mario Burgos Soto, Jose Chevaile Ramos, Alfredo Chew Wong, Jose Ricardo Correa Rotter, Tonatiu Diaz Escalante, Favio Edmundo Enriquez Sosa, Fernando Flores Lozano, Luis Fernando Flota Cervera, Paul Frenk Baron, Cecilia Garcia Ballesteros, Jose David Gomez Rangel, Luis Enrique Herrera Jimenez, Sergio Saul Irizar Santana, Fernando Jimenez Flores, Hugo Laviada Molina, Rosa Isela Luna Ceballos, Belia Martin del Campo Blanco, Guadalupe Morales Franco, Oscar Tarsicio Moreno Loza, Cynthia Mustieles Rocha, Gregorio Obrador Vera, Ricardo Orozco Castellanos, Juan Peralta Calcaneo, Miguel Angel Reyes Rosano, Hiromi Rodriguez Pattzi, Juan Rosas Guzman, Isabel Erika Rucker Joerg, Sandra Berenice Saavedra Sanchez, Jose Hector Sanchez Mijangos, Pablo Serrano Sanson, Juan Alfredo Tamayo y Orozco, Eloisa Tellez Chavez, Alejandro Valdes Cepeda, Luis Venegas Carrillo, Juan Villagordoa Mesa, Rolando Zamarripa Escobedo, John Baker, Paul Noonan, Russell Scott, Robert Walker, Edward Watson, Michael Williams, Simon Young, Zaynab Abejuela, Jeimeen Agra, Grace Aquitania, Clodoaido Caringal, Rhea Severina Comia, Lalaine Delos Santos, Olivert Gomez, Cecilia Jimeno, Gerry Tan, Marsha Tolentino, Christy Yao, Yvette Ethel Yap, Ma. Dovie Lallaine Ygpuara, Renata Bijata-Bronisz, Lucyna Hotlos, Andrzej Januszewicz, Barbara Kaczmarek, Anna Kaminska, Lech Lazuka, Andrzej Madej, Stanislaw Mazur, Dorota Mlodawska-Choluj, Michal Nowicki, Grazyna Orlowska-Kowalik, Grazyna Popenda, Barbara Rewerska, Dariusz Sowinski, Liliana Monica Angelescu, Veronica Anghel, Rodica-Ioana Avram, Mihaela-Magdalena Busegeanu, Adriana Cif, Dana Cosma, Carmen Crisan, Luiza Despina Demian, Ioana Emilia Ferariu, Ildiko Halmagyi, Nicolae Hancu, Mircea Munteanu, Doru Negru, Adriana Gabriela Onaca, Ligia Petrica, Amorin Remus Popa, Aurelian-Emil Ranetti, Cristian Serafinceanu, Cristina Toarba, Alina Agafyina, Olga Barbarash, Olga Barysheva, Daniil Chizhov, Vladimir Dobronravov, Irina Glinkina, Elena Grineva, Vladimir Khirmanov, Elena Kolmakova, Tatiana Koroleva, Liudmila Kvitkova, Viacheslav Marasaev, Ashot Mkrtumyan, Tatiana Morugova, Galina Nagibovich, Oleg Nagibovich, Sergei Nedogoda, Irina Osipova, Tatiana Raskina, Yulia Samoylova, Olga Sazonova, Minara Shamkhalova, Elena Shutemova, Yuriy Shwartz, Oleg Uriasyev, Sergey Vorobyev, Anna Zateyshchikova, Dmitry Zateyshshikov, Tatyana Zykova, Slobodan Antic, Miodrag Djordjevic, Aleksandra Kendereski, Katarina Lalic, Nebojsa Lalic, Vesna Popovic-Radinovic, Jana Babikova, Olga Benusova, Ingrid Buganova, Jan Culak, Andrej Dzupina, Jana Dzuponova, Peter Fulop, Adriana Ilavska, Emil Martinka, Zuzana Ochodnicka, Daniel Pella, Iveta Smatanova, Fayzal Ahmed, Aysha Badat, Johannes Breedt, Lawrence Distiller, Vimladhevi Govender, Ravendran Govender, Mukesh Joshi, Jaco Jurgens, Gulam Latiff, Landman Lombard, Mohamed Mookadam, Nomangesi Ngcakani, Hendrik Nortje, Helena Oosthuizen, Larisha Pillay-Ramaya, Hans Prozesky, Jeevren Reddy, Paul Rheeder, Mary Seeber, Young Min Cho, In-Kyung Jeong, Sin Gon Kim, Yeong Hoon Kim, Hyuk-Sang Kwon, Min Jeong Kwon, Byung-Wan Lee, JungEun Lee, Moon-Kyu Lee, Moon-Suk Nam, Kook-Hwan Oh, Cheol- Young Park, Sun-Hee Park, Kun Ho Yoon, Pere Alvarez Garcia, Luis Asmarats Mercadal, Clara Barrios, Fernando Cereto Castro, Secundino Cigarran Guldris, Marta Dominguez Lopez, Jesus Egido de los Rios, Gema Fernandez Fresnedo, Antonio Galan Serrano, Isabel Garcia, Francisco Javier Gonzalez Martinez, Jose Esteban Jodar Gimeno, Manuel Lopez Mendoza, Tamara Malek Marin, Cristobal Morales Portillo, Maria Antonia Munar Vila, Manuel Muñoz Torres, Javier Nieto Iglesias, Jonay Pantoja Perez, Merce Perez Vera, Jose M. Portoles Perez, María Angustias Quesada Simón, Rafael Simo Canonge, Alfonso Soto Gonzalez, Manel Terns Riera, Francisco Jose Tinahones Madueno, Mercedes Velo Plaza, Chwen-Tzuei Chang, Lee-Ming Chuang, Te-Lin Hsia, Chang-Hsun Hsieh, Chih-Ching Lin, Yung- Chuan Lu, Wayne H-H Sheu, Olga Barna, Svitlana D. Bilyk, Volodymyr Botsyurko, Iryna Dudar, Ivan Fushtey, Olga Godlevska, Oleksandr Golovchenko, Olga Gyrina, Anatoliy Kazmirchuk, Iuliia Komisarenko, Oleksii Korzh, Nonna Kravchun, Oleg Legun, Borys Mankovskyy, Liliya Martynyuk, Yuriy Mostovoy, Nataliia Pashkovska, Larysa Pererva, Tetyana Pertseva, Oleksandr Samoylov, Ivan Smirnov, Yevgeniya Svyshchenko, Halyna Tomashkevych, Ivan Topchii, Nadiya Tryshchuk, Vira Tseluyko, Vadym Vizir, Maryna Vlasenko, Tetiana Zlova, Liliia Zub, Salah Abusnana, Mohamed Railey, Kamal Abouglila, Paul Ainsworth, Zishan Ali, Vijayaraman Arutchelvam, Maria Barnard, Srikanth Bellary, Emyr Davies, Mark Davies, Simon Davies, Alison Dawson, Mohsen El Kossi, Patrick English, Donald Fraser, Luigi Gnudi, Anthony Gunstone, Timothy Hall, Wasim Hanif, Alan Jackson, Andrew Johnson, Franklin Joseph, Singhan Krishnan, Mick Kumwenda, Iain MacDougall, Paul Nixon, Joseph O'Hare, Sam Philip, Shenaz Ramtoola, Manish Saxena, Davesh Sennik, Godwin Simon, Baldev Singh, Jeffrey Stephens, Anna Strzelecka, Rehan Symonds, Wayne Turner, Mona Wahba, John Wakeling, David Wheeler, Peter Winocour, Joseph Abdallah, Raied Abdullah, Matthew Abramowitz, Idalia Acosta, Joseph Aiello, Laura Akright, Ayim Akyea-Djamson, Rajendran Alappan, Radica Alicic, Amer Al-Karadsheh, Dale Crawford Allison, Carlos Arauz-Pacheco, Shahabul Arfeen, Ahmed Arif, Moogali Arvind, Naveen Atray, Ahmed Awad, Peggy Barnhill, Elizabeth Barranco, Carlos Barrera, Matthew Beacom, Venkata Behara, Diogo Belo, Rhonda Bentley-Lewis, Ramon Berenguer, Lidia Bermudez, Marializa Bernardo, Mihaela Biscoveanu, Cynthia Bowman-Stroud, Donald Brandon, Osvaldo Brusco, Robert Busch, Yamil Canaan, Alicia Chilito, Tom Christensen, Cynthia Christiano, Elena Christofides, Caroucel Chuateco, Kenneth Cohen, Robert Cohen, Debbie Cohen-Stein, Charles Cook, Daniel Coyne, Nizar Daboul, Riad Darwish, Adarsh Daswani, Kenneth Deck, Cyrus Desouza, Devasmita Dev, Monika Dhillon, Sohan Dua, Frank Eder, Ana Maria Elosegui, Mohamed El-Shahawy, John Ervin, Alberto Esquenazi, John Evans, Steven Fishbane, Juan Frias, Eugenia Galindo-Ramos, Claude Galphin, Adline Ghazi, Enrique Gonzalez, David Gorson, Anupama Gowda, Barbara Greco, Stephen Grubb, Rakesh Gulati, Jamal Hammoud, Stuart Handelsman, Israel Hartman, Kenneth Hershon, Daniel Hiser, George Hon, Radu Jacob, Maria Jaime, Aamir Jamal, Charles Kaupke, Gerald Keightley, Elizabeth Kern, Rakhi Khanna, Zeid Khitan, Sun Kim, Nelson Kopyt, Csaba Kovesdy, Gopal Krishna, Jeffrey (Jay) Kropp, Amrendra Kumar, Jayant Kumar, Neil Kumar, Jorge Kusnir, Wendy Lane, Mary Lawrence, Lawrence Lehrner, John Lentz, Dennis Levinson, Derek Lewis, Kenneth Liss, Andreas Maddux, Hiralal Maheshwari, Sreedhar Mandayam, Isam Marar, Bhasker Mehta, John Middleton, Jorge Mordujovich, Ramon Moreda, Moustafa Moustafa, Samuel Mujica Trenche, Mohanram Narayanan, Javier Narvarte, Tareq Nassar, George Newman, Brian Nichol, Philip Nicol, Josier Nisnisan, A. Kaldun Nossuli, Chamberlain Obialo, Sarah Olelewe, Michael Oliver, Andrew O'Shaughnessy, John Padron, Rohit Pankhaniya, Reginald Parker, Devesh Patel, Gnyandev Patel, Nina Patel, Humberto Pavon, Armando Perez, Carlos Perez, Alan Perlman, Karlton Pettis, Walter Pharr, Andrea Phillips, Raman Purighalla, Luis Quesada-Suarez, Rajiv Ranjan, Sanjeev Rastogi, Jakkidi Reddy, Marc Rendell, Lisa Rich, Michael Robinson, Hector Rodriguez, Sylvia Rosas, Fadi Saba, Rallabhandi Sankaram, Ravi Sarin, Robert Schreiman, David Scott, Mohamed Sekkarie, John Sensenbrenner, Muhammad Shakeel, Michael Shanik, Sylvia Shaw, Stephen Smith, Richard Solomon, Amy Sprague, Leslie Spry, Pusadee Suchinda, Senan Sultan, Prasanth Surampudi, Sherry Sussman, Anjanette Tan, Antonio Terrelonge, Michael Thompson, Fernando Trespalacios, Bruce Trippe, Pilar Trueba, Marcel Twahirwa, John Updegrove, Peter Van Buren, Mark Vannorsdall, Freemu Varghese, Pedro Velasquez-Mieyer, Sailaja Ventrapragada, Goga Vukotic, Khurram Wadud, Mark Warren, Henry Watson, Ronald Watts, Daniel Weiner, James Welker, Jean Welsh, Shelley Williams, and Michelle Zaniewski-Singh

Subjects
age, diabetes, Nephrology, kidney outcomes, sex, Diabetic kidney disease, canagliflozin, cardiovascular outcomes, chronic kidney disease, sodium/glucose cotransporter 2 inhibitors
Abstract

Rationale & Objective: It is unclear whether the effect of canagliflozin on adverse kidney and cardiovascular events in those with diabetic kidney disease varies by age and sex. We assessed the effects of canagliflozin among age group categories and between sexes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study.Study Design: Secondary analysis of a randomized controlled trial.Setting & Participants: Participants in the CREDENCE trial.Intervention: Participants were randomly assigned to receive canagliflozin 100 mg/d or placebo.Outcomes: Primary composite outcome of kidney failure, doubling of serum creatinine concentration, or death due to kidney or cardiovascular disease. Prespecified secondary and safety outcomes were also analyzed. Outcomes were evaluated by age at baseline (Results: The mean age of the cohort was 63.0 ± 9.2 years, and 34% were female. Older age and female sex were independently associated with a lower risk of the composite of adverse kidney outcomes. There was no evidence that the effect of canagliflozin on the primary outcome (a composite of kidney failure, a doubling of serum creatinine concentration, or death from kidney or cardiovascular causes) differed between age groups (HRs, 0.67 [95% CI, 0.52-0.87], 0.63 [0.48-0.82], and 0.89 [0.61-1.29] for ages Limitations: This was a post hoc analysis with multiple comparisons.Conclusions: Canagliflozin consistently reduced the relative risk of kidney events in people with diabetic kidney disease in both sexes and across age subgroups. As a result of greater background risk, the absolute reduction in adverse kidney outcomes was greater in younger participants.Funding: This post hoc analysis of the CREDENCE trial was not funded. The CREDENCE study was sponsored by Janssen Research and Development and was conducted collaboratively by the sponsor, an academic-led steering committee, and an academic research organization, George Clinical.Trial Registration: The original CREDENCE trial was registered at ClinicalTrials.gov with study number NCT02065791.

Published
2023

18. Insights From a Large-Scale Whole-Genome Sequencing Study of Systolic Blood Pressure, Diastolic Blood Pressure, and Hypertension

Author

Tanika N, Kelly, Xiao, Sun, Karen Y, He, Michael R, Brown, Sarah A Gagliano, Taliun, Jacklyn N, Hellwege, Marguerite R, Irvin, Xuenan, Mi, Jennifer A, Brody, Nora, Franceschini, Xiuqing, Guo, Shih-Jen, Hwang, Paul S, de Vries, Yan, Gao, Arden, Moscati, Girish N, Nadkarni, Lisa R, Yanek, Tali, Elfassy, Jennifer A, Smith, Ren-Hua, Chung, Amber L, Beitelshees, Amit, Patki, Stella, Aslibekyan, Brandon M, Blobner, Juan M, Peralta, Themistocles L, Assimes, Walter R, Palmas, Chunyu, Liu, Adam P, Bress, Zhijie, Huang, Lewis C, Becker, Chii-Min, Hwa, Jeffrey R, O'Connell, Jenna C, Carlson, Helen R, Warren, Sayantan, Das, Ayush, Giri, Lisa W, Martin, W, Craig Johnson, Ervin R, Fox, Erwin P, Bottinger, Alexander C, Razavi, Dhananjay, Vaidya, Lee-Ming, Chuang, Yen-Pei C, Chang, Take, Naseri, Deepti, Jain, Hyun Min, Kang, Adriana M, Hung, Vinodh, Srinivasasainagendra, Beverly M, Snively, Dongfeng, Gu, May E, Montasser, Muagututi'a Sefuiva, Reupena, Benjamin D, Heavner, Jonathon, LeFaive, James E, Hixson, Kenneth M, Rice, Fei Fei, Wang, Jonas B, Nielsen, Jianfeng, Huang, Alyna T, Khan, Wei, Zhou, Jovia L, Nierenberg, Cathy C, Laurie, Nicole D, Armstrong, Mengyao, Shi, Yang, Pan, Adrienne M, Stilp, Leslie, Emery, Quenna, Wong, Nicola L, Hawley, Ryan L, Minster, Joanne E, Curran, Patricia B, Munroe, Daniel E, Weeks, Kari E, North, Russell P, Tracy, Eimear E, Kenny, Daichi, Shimbo, Aravinda, Chakravarti, Stephen S, Rich, Alex P, Reiner, John, Blangero, Susan, Redline, Braxton D, Mitchell, Dabeeru C, Rao, Yii-Der, Ida Chen, Sharon L R, Kardia, Robert C, Kaplan, Rasika A, Mathias, Jiang, He, Bruce M, Psaty, Myriam, Fornage, Ruth J F, Loos, Adolfo, Correa, Eric, Boerwinkle, Jerome I, Rotter, Charles, Kooperberg, Todd L, Edwards, Gonçalo R, Abecasis, Xiaofeng, Zhu, Daniel, Levy, Donna K, Arnett, and Alanna C, Morrison

Subjects
Hypertension, Internal Medicine, Humans, Blood Pressure, Genomics, Precision Medicine, Polymorphism, Single Nucleotide, Genome-Wide Association Study
Abstract

Background: The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure. Methods: We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants. Results: Two blood pressure signals achieved genome-wide significance in meta-analyses of stage-1 and stage-2 single variant findings ( P -8 ). Among them, a rare intergenic variant at novel locus, LOC100506274 , was associated with lower systolic blood pressure in stage-1 (beta [SE]=−32.6 [6.0]; P =4.99×10 -8 ) but not stage-2 analysis ( P =0.11). Furthermore, a novel common variant at the known INSR locus was suggestively associated with diastolic blood pressure in stage-1 (beta [SE]=−0.36 [0.07]; P =4.18×10 -7 ) and attained genome-wide significance in stage-2 (beta [SE]=−0.29 [0.03]; P =7.28×10 -23 ). Nineteen additional signals suggestively associated with blood pressure in meta-analysis of single and aggregate rare variant findings ( P -6 and P -4 , respectively). Discussion: We report one promising but unconfirmed rare variant for blood pressure and, more importantly, contribute insights for future blood pressure sequencing studies. Our findings suggest promise of aggregate analyses to complement single variant analysis strategies and the need for larger, diverse samples, and family studies to enable robust rare variant identification.

Published
2023

19. Multi-ancestry transcriptome-wide association analyses yield insights into tobacco use biology and drug repurposing

Author

Fang Chen, Xingyan Wang, Seon-Kyeong Jang, Bryan C. Quach, J. Dylan Weissenkampen, Chachrit Khunsriraksakul, Lina Yang, Renan Sauteraud, Christine M. Albert, Nicholette D. D. Allred, Donna K. Arnett, Allison E. Ashley-Koch, Kathleen C. Barnes, R. Graham Barr, Diane M. Becker, Lawrence F. Bielak, Joshua C. Bis, John Blangero, Meher Preethi Boorgula, Daniel I. Chasman, Sameer Chavan, Yii-Der I. Chen, Lee-Ming Chuang, Adolfo Correa, Joanne E. Curran, Sean P. David, Lisa de las Fuentes, Ranjan Deka, Ravindranath Duggirala, Jessica D. Faul, Melanie E. Garrett, Sina A. Gharib, Xiuqing Guo, Michael E. Hall, Nicola L. Hawley, Jiang He, Brian D. Hobbs, John E. Hokanson, Chao A. Hsiung, Shih-Jen Hwang, Thomas M. Hyde, Marguerite R. Irvin, Andrew E. Jaffe, Eric O. Johnson, Robert Kaplan, Sharon L. R. Kardia, Joel D. Kaufman, Tanika N. Kelly, Joel E. Kleinman, Charles Kooperberg, I-Te Lee, Daniel Levy, Sharon M. Lutz, Ani W. Manichaikul, Lisa W. Martin, Olivia Marx, Stephen T. McGarvey, Ryan L. Minster, Matthew Moll, Karine A. Moussa, Take Naseri, Kari E. North, Elizabeth C. Oelsner, Juan M. Peralta, Patricia A. Peyser, Bruce M. Psaty, Nicholas Rafaels, Laura M. Raffield, Muagututi’a Sefuiva Reupena, Stephen S. Rich, Jerome I. Rotter, David A. Schwartz, Aladdin H. Shadyab, Wayne H-H. Sheu, Mario Sims, Jennifer A. Smith, Xiao Sun, Kent D. Taylor, Marilyn J. Telen, Harold Watson, Daniel E. Weeks, David R. Weir, Lisa R. Yanek, Kendra A. Young, Kristin L. Young, Wei Zhao, Dana B. Hancock, Bibo Jiang, Scott Vrieze, and Dajiang J. Liu

Subjects
Tobacco Smoke and Health, Human Genome, Drug Repositioning, Single Nucleotide, Biological Sciences, Medical and Health Sciences, Brain Disorders, Tobacco Use, Substance Misuse, Good Health and Well Being, Tobacco, Genetics, Humans, Genetic Predisposition to Disease, Polymorphism, Transcriptome, Drug Abuse (NIDA only), Biology, Genome-Wide Association Study, Developmental Biology
Abstract

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction.

Published
2023

22. Data from Serum Vascular Adhesion Protein-1 Level Predicts Risk of Incident Cancers in Subjects with Type II Diabetes

Author

Lee-Ming Chuang, Ching-Chi Chu, Chi-Ming Lin, Jung-Nan Wei, Tien-Jyun Chang, Yi-Der Jiang, Hung-Yuan Li, and Tse-Ya Yu

Abstract

Background: Serum vascular adhesion protein-1 (VAP-1) predicts cancer-related mortality in diabetic subjects. However, whether serum VAP-1 predicts cancer incidence or cancer progression remains unclear. We conducted a cohort study to investigate whether serum VAP-1 and related clinical variables predict incident cancers in type II diabetic subjects.Methods: From 1996 to 2003, we enrolled 568 type II diabetic subjects who were free of cancer at baseline. Serum VAP-1 at enrollment was measured by time-resolved immunofluorometric assay. Chronic kidney disease (CKD) was defined as estimated glomerular filtration rate 2. The subjects were followed until first occurrence of cancer or until December 31, 2011.Results: During a mean follow-up of 11.3 years, 71 subjects developed incident cancers. The HRs for incident cancers in subjects with highest tertile of serum VAP-1 and in subjects with CKD were 2.95 [95% confidence interval (CI), 1.31–6.63; P = 0.009] and 2.29 (95% CI, 1.18–4.44; P = 0.015), respectively, after multivariate adjustment. There was an interaction between serum VAP-1 and CKD on the risk of incident cancers (P = 0.01 for log-transformed VAP-1 × CKD). The relationship among serum VAP-1, CKD, and incident cancers was similar if death was considered in the competing risk models or if subjects with shorter follow-up period were excluded.Conclusions: Higher serum VAP-1 and CKD can independently predict future development of cancers in type II diabetic subjects.Impact: Physicians should be aware of the early signs of cancer in diabetic individuals with elevated VAP-1 or renal dysfunction. More aggressive treatment strategies might be considered. Cancer Epidemiol Biomarkers Prev; 23(7); 1366–73. ©2014 AACR.

Published
2023

24. Whole Genome Sequence Analysis of the Plasma Proteome in Black Adults Provides Novel Insights Into Cardiovascular Disease

Author

Daniel H. Katz, Usman A. Tahir, Alexander G. Bick, Akhil Pampana, Debby Ngo, Mark D. Benson, Zhi Yu, Jeremy M. Robbins, Zsu-Zsu Chen, Daniel E. Cruz, Shuliang Deng, Laurie Farrell, Sumita Sinha, Alec A. Schmaier, Dongxiao Shen, Yan Gao, Michael E. Hall, Adolfo Correa, Russell P. Tracy, Peter Durda, Kent D. Taylor, Yongmei Liu, W. Craig Johnson, Xiuqing Guo, Jie Yao, Yii-Der Ida Chen, Ani W. Manichaikul, Deepti Jain, Claude Bouchard, Mark A. Sarzynski, Stephen S. Rich, Jerome I. Rotter, Thomas J. Wang, James G. Wilson, Pradeep Natarajan, Robert E. Gerszten, Namiko Abe, Gonçalo Abecasis, Francois Aguet, Christine Albert, Laura Almasy, Alvaro Alonso, Seth Ament, Peter Anderson, Pramod Anugu, Deborah Applebaum-Bowden, Kristin Ardlie, Dan Arking, Donna K. Arnett, Allison Ashley-Koch, Stella Aslibekyan, Tim Assimes, Paul Auer, Dimitrios Avramopoulos, Najib Ayas, Adithya Balasubramanian, John Barnard, Kathleen Barnes, R. Graham Barr, Emily Barron-Casella, Lucas Barwick, Terri Beaty, Gerald Beck, Diane Becker, Lewis Becker, Rebecca Beer, Amber Beitelshees, Emelia Benjamin, Takis Benos, Marcos Bezerra, Larry Bielak, Joshua Bis, Thomas Blackwell, John Blangero, Eric Boerwinkle, Donald W. Bowden, Russell Bowler, Jennifer Brody, Ulrich Broeckel, Jai Broome, Deborah Brown, Karen Bunting, Esteban Burchard, Carlos Bustamante, Erin Buth, Brian Cade, Jonathan Cardwell, Vincent Carey, Julie Carrier, April Carson, Cara Carty, Richard Casaburi, Juan P. Casas Romero, James Casella, Peter Castaldi, Mark Chaffin, Christy Chang, Yi-Cheng Chang, Daniel Chasman, Sameer Chavan, Bo-Juen Chen, Wei-Min Chen, Michael Cho, Seung Hoan Choi, Lee-Ming Chuang, Mina Chung, Ren-Hua Chung, Clary Clish, Suzy Comhair, Matthew Conomos, Elaine Cornell, Carolyn Crandall, James Crapo, L. Adrienne Cupples, Joanne Curran, Jeffrey Curtis, Brian Custer, Coleen Damcott, Dawood Darbar, Sean David, Colleen Davis, Michelle Daya, Mariza de Andrade, Lisa de las Fuentes, Paul de Vries, Michael DeBaun, Ranjan Deka, Dawn DeMeo, Scott Devine, Huyen Dinh, Harsha Doddapaneni, Qing Duan, Shannon Dugan-Perez, Ravi Duggirala, Jon Peter Durda, Susan K. Dutcher, Charles Eaton, Lynette Ekunwe, Adel El Boueiz, Patrick Ellinor, Leslie Emery, Serpil Erzurum, Charles Farber, Jesse Farek, Tasha Fingerlin, Matthew Flickinger, Myriam Fornage, Nora Franceschini, Chris Frazar, Mao Fu, Stephanie M. Fullerton, Lucinda Fulton, Stacey Gabriel, Weiniu Gan, Shanshan Gao, Margery Gass, Heather Geiger, Bruce Gelb, Mark Geraci, Soren Germer, Robert Gerszten, Auyon Ghosh, Richard Gibbs, Chris Gignoux, Mark Gladwin, David Glahn, Stephanie Gogarten, Da-Wei Gong, Harald Goring, Sharon Graw, Kathryn J. Gray, Daniel Grine, Colin Gross, C. Charles Gu, Yue Guan, Namrata Gupta, David M. Haas, Jeff Haessler, Michael Hall, Yi Han, Patrick Hanly, Daniel Harris, Nicola L. Hawley, Jiang He, Ben Heavner, Susan Heckbert, Ryan Hernandez, David Herrington, Craig Hersh, Bertha Hidalgo, James Hixson, Brian Hobbs, John Hokanson, Elliott Hong, Karin Hoth, Chao (Agnes) Hsiung, Jianhong Hu, Yi-Jen Hung, Haley Huston, Chii Min Hwu, Marguerite Ryan Irvin, Rebecca Jackson, Cashell Jaquish, Jill Johnsen, Andrew Johnson, Craig Johnson, Rich Johnston, Kimberly Jones, Hyun Min Kang, Robert Kaplan, Sharon Kardia, Shannon Kelly, Eimear Kenny, Michael Kessler, Alyna Khan, Ziad Khan, Wonji Kim, John Kimoff, Greg Kinney, Barbara Konkle, Charles Kooperberg, Holly Kramer, Christoph Lange, Ethan Lange, Leslie Lange, Cathy Laurie, Cecelia Laurie, Meryl LeBoff, Jiwon Lee, Sandra Lee, Wen-Jane Lee, Jonathon LeFaive, David Levine, Dan Levy, Joshua Lewis, Xiaohui Li, Yun Li, Henry Lin, Honghuang Lin, Xihong Lin, Simin Liu, Yu Liu, Ruth J.F. Loos, Steven Lubitz, Kathryn Lunetta, James Luo, Ulysses Magalang, Michael Mahaney, Barry Make, Ani Manichaikul, Alisa Manning, JoAnn Manson, Lisa Martin, Melissa Marton, Susan Mathai, Rasika Mathias, Susanne May, Patrick McArdle, Merry-Lynn McDonald, Sean McFarland, Stephen McGarvey, Daniel McGoldrick, Caitlin McHugh, Becky McNeil, Hao Mei, James Meigs, Vipin Menon, Luisa Mestroni, Ginger Metcalf, Deborah A. Meyers, Emmanuel Mignot, Julie Mikulla, Nancy Min, Mollie Minear, Ryan L. Minster, Braxton D. Mitchell, Matt Moll, Zeineen Momin, May E. Montasser, Courtney Montgomery, Donna Muzny, Josyf C. Mychaleckyj, Girish Nadkarni, Rakhi Naik, Take Naseri, Sergei Nekhai, Sarah C. Nelson, Bonnie Neltner, Caitlin Nessner, Deborah Nickerson, Osuji Nkechinyere, Kari North, Jeff O’Connell, Tim O’Connor, Heather Ochs-Balcom, Geoffrey Okwuonu, Allan Pack, David T. Paik, Nicholette Palmer, James Pankow, George Papanicolaou, Cora Parker, Gina Peloso, Juan Manuel Peralta, Marco Perez, James Perry, Ulrike Peters, Patricia Peyser, Lawrence S. Phillips, Jacob Pleiness, Toni Pollin, Wendy Post, Julia Powers Becker, Meher Preethi Boorgula, Michael Preuss, Bruce Psaty, Pankaj Qasba, Dandi Qiao, Zhaohui Qin, Nicholas Rafaels, Laura Raffield, Mahitha Rajendran, Vasan S. Ramachandran, D.C. Rao, Laura Rasmussen-Torvik, Aakrosh Ratan, Susan Redline, Robert Reed, Catherine Reeves, Elizabeth Regan, Alex Reiner, Muagututi’a Sefuiva Reupena, Ken Rice, Stephen Rich, Rebecca Robillard, Nicolas Robine, Dan Roden, Carolina Roselli, Jerome Rotter, Ingo Ruczinski, Alexi Runnels, Pamela Russell, Sarah Ruuska, Kathleen Ryan, Ester Cerdeira Sabino, Danish Saleheen, Shabnam Salimi, Sejal Salvi, Steven Salzberg, Kevin Sandow, Vijay G. Sankaran, Jireh Santibanez, Karen Schwander, David Schwartz, Frank Sciurba, Christine Seidman, Jonathan Seidman, Frédéric Sériès, Vivien Sheehan, Stephanie L. Sherman, Amol Shetty, Aniket Shetty, Wayne Hui-Heng Sheu, M. Benjamin Shoemaker, Brian Silver, Edwin Silverman, Robert Skomro, Albert Vernon Smith, Jennifer Smith, Josh Smith, Nicholas Smith, Tanja Smith, Sylvia Smoller, Beverly Snively, Michael Snyder, Tamar Sofer, Nona Sotoodehnia, Adrienne M. Stilp, Garrett Storm, Elizabeth Streeten, Jessica Lasky Su, Yun Ju Sung, Jody Sylvia, Adam Szpiro, Daniel Taliun, Hua Tang, Margaret Taub, Matthew Taylor, Simeon Taylor, Marilyn Telen, Timothy A. Thornton, Machiko Threlkeld, Lesley Tinker, David Tirschwell, Sarah Tishkoff, Hemant Tiwari, Catherine Tong, Russell Tracy, Michael Tsai, Dhananjay Vaidya, David Van Den Berg, Peter VandeHaar, Scott Vrieze, Tarik Walker, Robert Wallace, Avram Walts, Fei Fei Wang, Heming Wang, Jiongming Wang, Karol Watson, Jennifer Watt, Daniel E. Weeks, Joshua Weinstock, Bruce Weir, Scott T. Weiss, Lu-Chen Weng, Jennifer Wessel, Cristen Willer, Kayleen Williams, L. Keoki Williams, Carla Wilson, James Wilson, Lara Winterkorn, Quenna Wong, Joseph Wu, Huichun Xu, Lisa Yanek, Ivana Yang, Ketian Yu, Seyedeh Maryam Zekavat, Yingze Zhang, Snow Xueyan Zhao, Wei Zhao, Xiaofeng Zhu, Michael Zody, and Sebastian Zoellner

Subjects
Adult, Male, Proteomics, Aging, Whole genome sequence analysis, Proteome, Clinical Sciences, Black People, Disease, Computational biology, race and ethnicity, Cardiorespiratory Medicine and Haematology, Cardiovascular, Article, proteomics, cardiovascular disease, Physiology (medical), Genetics, 2.1 Biological and endogenous factors, Humans, Medicine, Aetiology, Lung, Heart Disease - Coronary Heart Disease, and Blood Institute TOPMed (Trans-Omics for Precision Medicine) Consortium†, business.industry, Prevention, Human Genome, National Heart, Genomics, Blood proteins, Genetic architecture, Heart Disease, Good Health and Well Being, Cardiovascular System & Hematology, Cardiovascular Diseases, Public Health and Health Services, Female, Cardiology and Cardiovascular Medicine, business, Biotechnology, Genome-Wide Association Study
Abstract

Background: Plasma proteins are critical mediators of cardiovascular processes and are the targets of many drugs. Previous efforts to characterize the genetic architecture of the plasma proteome have been limited by a focus on individuals of European descent and leveraged genotyping arrays and imputation. Here we describe whole genome sequence analysis of the plasma proteome in individuals with greater African ancestry, increasing our power to identify novel genetic determinants. Methods: Proteomic profiling of 1301 proteins was performed in 1852 Black adults from the Jackson Heart Study using aptamer-based proteomics (SomaScan). Whole genome sequencing association analysis was ascertained for all variants with minor allele count ≥5. Results were validated using an alternative, antibody-based, proteomic platform (Olink) as well as replicated in the Multi-Ethnic Study of Atherosclerosis and the HERITAGE Family Study (Health, Risk Factors, Exercise Training and Genetics). Results: We identify 569 genetic associations between 479 proteins and 438 unique genetic regions at a Bonferroni-adjusted significance level of 3.8×10 -11 . These associations include 114 novel locus-protein relationships and an additional 217 novel sentinel variant-protein relationships. Novel cardiovascular findings include new protein associations at the APOE gene locus including ZAP70 (sentinel single nucleotide polymorphism [SNP] rs7412-T, β=0.61±0.05, P =3.27×10 -30 ) and MMP-3 (β=-0.60±0.05, P =1.67×10 -32 ), as well as a completely novel pleiotropic locus at the HPX gene, associated with 9 proteins. Further, the associations suggest new mechanisms of genetically mediated cardiovascular disease linked to African ancestry; we identify a novel association between variants linked to APOL1-associated chronic kidney and heart disease and the protein CKAP2 (rs73885319-G, β=0.34±0.04, P =1.34×10 -17 ) as well as an association between ATTR amyloidosis and RBP4 levels in community-dwelling individuals without heart failure. Conclusions: Taken together, these results provide evidence for the functional importance of variants in non-European populations, and suggest new biological mechanisms for ancestry-specific determinants of lipids, coagulation, and myocardial function.

Published
2022

25. Different cutoffs of hypertension, risk of incident diabetes and progression of insulin resistance: A prospective cohort study

Author

Jung-Nan Wei, Chung-Yi Yang, Jou-Wei Lin, Yenh-Chen Hsein, Lee-Ming Chuang, Shyang-Rong Shih, Wan-Chen Wu, Hung-Yuan Li, Mao-Shin Lin, Chia-Hung Lin, Kang-Chih Fan, Cyue-Huei Hua, and Chi-Tai Fang

Subjects
Medicine (General), medicine.medical_specialty, Cutoffs, Hypertension risk, 03 medical and health sciences, R5-920, 0302 clinical medicine, Insulin resistance, Internal medicine, Diabetes mellitus, Diabetes Mellitus, medicine, Humans, Prospective Studies, Oral glucose tolerance, Risk factor, Prospective cohort study, business.industry, General Medicine, Guideline, medicine.disease, 030220 oncology & carcinogenesis, Hypertension, 030211 gastroenterology & hepatology, Insulin Resistance, business
Abstract

Background/Purpose: Hypertension is a risk factor of incident diabetes. In 2017, the ACC/AHA updated the definition of hypertension to above 130/80 mmHg, while the 2018 ESC/ESH guideline and the JNC7 criteria remained the cutoff of 140/90 mmHg. This study was aimed to investigate how different cutoffs of hypertension affect the association of hypertension to incident diabetes and the progression of insulin resistance. Methods: A total of 1177 subjects without diabetes at baseline were followed for 4.5 years. Diabetes was diagnosed by the results of oral glucose tolerance tests and hemoglobin A1c, or if anti-diabetic agents were used. Results: Hypertension by both criteria was associated with incident diabetes. Change of HOMA2-IR every 5 years (ΔHOMA2-IR/5 yr) was higher in subjects with hypertension than those without (adjusted p = 0.044). Subjects with treated hypertension had the highest risk of diabetes (HR 2.98, p

Published
2022

26. Muscle Microcirculatory Responses to Incremental Exercises Are Correlated with Peak Oxygen Uptake in Individuals With and Without Type 2 Diabetes Mellitus

Author

Yan-Jhen Lu, Ssu-Yuan Chen, Ying-Chuen Lai, Pakaratee Chaiyawat, Yuan-Hung Chao, Lee-Ming Chuang, Tiffany Ting-Fang Shih, and Hsing-Kuo Wang

Subjects
Oxygen, Oxygen Consumption, Diabetes Mellitus, Type 2, Endocrinology, Diabetes and Metabolism, Microcirculation, Muscles, Internal Medicine, Exercise Test, Humans, Middle Aged, Muscle, Skeletal
Published
2022

30. Cluster Analysis of Cardiovascular Phenotypes in Patients With Type 2 Diabetes and Established Atherosclerotic Cardiovascular Disease: A Potential Approach to Precision Medicine

Author

Darren K. McGuire, Shaun G. Goodman, Robert G. Josse, Abhinav Sharma, Cynthia M. Westerhout, Jacob A. Udell, Keith D. Kaufman, Eric D. Peterson, Lee-Ming Chuang, John B. Buse, Rury R. Holman, Giuseppe Ambrosio, Renato D. Lopes, Justin A. Ezekowitz, Paul W. Armstrong, Jennifer B. Green, and Yinggan Zheng

Subjects
Male, medicine.medical_specialty, Cardiovascular and Metabolic Risk, Endocrinology, Diabetes and Metabolism, Type 2 diabetes, Coronary artery disease, Risk Factors, Diabetes mellitus, Internal medicine, Internal Medicine, medicine, Cluster Analysis, Humans, Myocardial infarction, Precision Medicine, Advanced and Specialized Nursing, Unstable angina, Proportional hazards model, business.industry, Hazard ratio, medicine.disease, Phenotype, Diabetes Mellitus, Type 2, Cardiovascular Diseases, Sitagliptin, Female, business, medicine.drug
Abstract

OBJECTIVE Phenotypic heterogeneity among patients with type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease (ASCVD) is ill defined. We used cluster analysis machine-learning algorithms to identify phenotypes among trial participants with T2DM and ASCVD. RESEARCH DESIGN AND METHODS We used data from the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) study (n = 14,671), a cardiovascular outcome safety trial comparing sitagliptin with placebo in patients with T2DM and ASCVD (median follow-up 3.0 years). Cluster analysis using 40 baseline variables was conducted, with associations between clusters and the primary composite outcome (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina) assessed by Cox proportional hazards models. We replicated the results using the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial. RESULTS Four distinct phenotypes were identified: cluster I included Caucasian men with a high prevalence of coronary artery disease; cluster II included Asian patients with a low BMI; cluster III included women with noncoronary ASCVD disease; and cluster IV included patients with heart failure and kidney dysfunction. The primary outcome occurred, respectively, in 11.6%, 8.6%, 10.3%, and 16.8% of patients in clusters I to IV. The crude difference in cardiovascular risk for the highest versus lowest risk cluster (cluster IV vs. II) was statistically significant (hazard ratio 2.74 [95% CI 2.29–3.29]). Similar phenotypes and outcomes were identified in EXSCEL. CONCLUSIONS In patients with T2DM and ASCVD, cluster analysis identified four clinically distinct groups. Further cardiovascular phenotyping is warranted to inform patient care and optimize clinical trial designs.

Published
2021

31. Whole genome sequence analysis of blood lipid levels in >66,000 individuals

Author

Akhil Pampana, Xiuqing Guo, Tanika N. Kelly, Yii-Der Ida Chen, Charles Kooperberg, Chii-Min Hwu, Mariaelisa Graff, Jiang He, Xihao Li, Patrick T. Ellinor, Joshua C. Bis, Kari E. North, Nancy L. Heard-Costa, Joseph Park, Stacey Gabriel, Joanne E. Curran, Braxton D. Mitchell, Lee-Ming Chuang, Ravindranath Duggirala, Jerome I. Rotter, Robert C. Kaplan, Soren Germer, Pradeep Natarajan, Take Naseri, Xihong Lin, Susan K. Dutcher, Stella Aslibekyan, Ryan W. Kim, Daniel J. Rader, Richard A. Gibbs, Myriam Fornage, Eric Boerwinkle, Bertha Hidalgo, Muagututi’a S. Reupena, Deborah A. Nickerson, Zhe Wang, Donald W. Bowden, Yuxuan Wang, Alanna C. Morrison, Stephen S. Rich, David Zhang, Gina M. Peloso, Xiaohui Li, Martin Lisa, Lisa de las Fuentes, Zilin Li, Alexander P. Reiner, Jennifer A. Brody, Lisa R. Yanek, Marguerite R. Irvin, Bruce M. Psaty, Bao Wei, Preuss Michael, Leslie A. Lange, John T. Wilkins, Russell P. Tracy, Paul S. de Vries, Wei Zhao, Rasika A. Mathias, Susan Redline, Xiao Sun, Kent D. Taylor, Barry I. Freedman, Ani Manichaikul, Donna K. Arnett, Nicholette D. Palmer, Cristen J. Willer, Steven A. Lubitz, Sharon L.R. Kardia, L. Adrienne Cupples, Ramachandran S. Vasan, May E. Montasser, Ren-Hua Chung, Margaret Sunitha Selvaraj, Jeffrey R. O'Connell, Ruth J. F. Loos, Jennifer A. Smith, John Blangero, Brian G. Kral, Karine A. Viaud Martinez, Stephen T. McGarvey, Adolfo Correa, Michael Y. Tsai, Patricia A. Peyser, and Brian E. Cade

Subjects
Genetics, Whole genome sequencing, Genome Scan, Blood lipids, Biology, medicine.disease, Genome, symbols.namesake, Mendelian inheritance, symbols, medicine, lipids (amino acids, peptides, and proteins), Allele, Gene, Dyslipidemia
Abstract

Plasma lipids are heritable modifiable causal factors for coronary artery disease, the leading cause of death globally. Despite the well-described monogenic and polygenic bases of dyslipidemia, limitations remain in discovery of lipid-associated alleles using whole genome sequencing, partly due to limited sample sizes, ancestral diversity, and interpretation of potential clinical significance. Increasingly larger whole genome sequence datasets with plasma lipids coupled with methodologic advances enable us to more fully catalog the allelic spectrum for lipids. Here, among 66,329 ancestrally diverse (56% non-European ancestry) participants, we associate 428M variants from deep-coverage whole genome sequences with plasma lipids. Approximately 400M of these variants were not studied in prior lipids genetic analyses. We find multiple lipid-related genes strongly associated with plasma lipids through analysis of common and rare coding variants. We additionally discover several significantly associated rare non-coding variants largely at Mendelian lipid genes. Notably, we detect rareLDLRintronic variants associated with markedly increased LDL-C, similar to rareLDLRexonic variants. In conclusion, we conducted a systematic whole genome scan for plasma lipids expanding the alleles linked to lipids for multiple ancestries and characterize a clinically-relevant rare non-coding variant model for lipids.

Published
2021

32. The impact of glucose tolerance state on seropositivity rate after hepatitis B vaccination

Author

Maria Mercedes Chang Villacreses, Rudruidee Karnchanasorn, Horng-Yih Ou, Raynald Samoa, Lee-Ming Chuang, and Ken C. Chiu

Subjects
Multidisciplinary, Nutrition Surveys
Abstract

Immunization is recommended for people with diabetes mellitus (DM), but little information is available on their seropositivity rates. To determine the impact of glucose tolerance state on seropositivity rate after hepatitis B vaccination, we included 7645 adult participants from the National Health and Nutrition Examination Survey 2005–2016 who reported three doses of hepatitis B vaccine and were seropositive for anti-hepatitis B surface antibody (≥ 12.0 mIU/mL), after exclusion of those positive for anti-hepatitis B core antibody and/or hepatitis B surface antigen. We classified the states of glucose tolerance as normal glucose tolerance (NGT, 61.68%), abnormal glucose tolerance (AGT, 26.02%), or DM (13.30%). We observed a stepwise decline in hepatitis B seropositivity rate from NGT (53.64%) to AGT (45.52%) to DM (28.84%) (P

Published
2021

33. Dynamin-2 Phosphorylation as A Critical Regulatory Target of Bin1 and GSK3α for Endocytosis in Muscle

Author

Wei-Chun Tang, Hui-Kang Liu, Yi-Cheng Chang, Ya-Wen Liu, Mei-Chun Chuang, Lee-Ming Chuang, Bi-Chang Chen, Julie Loh, and Jessica Laiman

Subjects
Cell signaling, Chemistry, Endocytic cycle, medicine, Myocyte, Centronuclear myopathy, medicine.symptom, medicine.disease, Myopathy, Endocytosis, Cell biology, Dynamin, Proto-oncogene tyrosine-protein kinase Src
Abstract

Tight regulation of endocytosis ensures accurate control of cellular signaling and membrane dynamics, which are crucial for tissue morphogenesis and functions. Mutations of Bin1 and dynamin-2 (Dyn2), proteins that generate membrane curvature and sever endocytic invaginations, respectively, cause progressive hereditary myopathy. Here, we show that Bin1 inhibits Dyn2 via direct interaction of its SRC Homology 3 (SH3) domain with the proline-rich domain (PRD) of Dyn2. Phosphorylation of S848 of Dyn2 by GSK3α, a kinase downstream of insulin signaling, relieves Dyn2 from the inhibition of Bin1 and promotes endocytosis in muscle. Mutations of Bin1 associated with centronuclear myopathy disrupt its inhibition of Dyn2, thereby exaggerating Dyn2 fission activity and causing excessive fragmentation of T-tubules in the muscle cells. Our work reveals how Bin1-Dyn2 interaction fine-tunes membrane remodeling at the molecular level, and lay the foundation for future exploration of endocytic regulation and hereditary muscle diseases.

Published
2021

34. The Role of Hemoglobin A1C in Diabetes Screening and Diabetic Retinopathy

Author

Raynald Samoa, Rudruidee Karnchanasorn, Ken C. Chiu, Lee-Ming Chuang, Horng Yih Ou, and Maria Mercedes Chang Villacreses

Subjects
medicine.medical_specialty, National Health and Nutrition Examination Survey, endocrine system diseases, diagnosis, specificity, Gastroenterology, Article, Diabetes mellitus, Internal medicine, retinopathy, medicine, business.industry, nutritional and metabolic diseases, General Medicine, Diabetic retinopathy, medicine.disease, sensitivity, Predictive value, Diabetes screening, Cohort, diabetes mellitus, Medicine, Hemoglobin, business, Retinopathy
Abstract

Hemoglobin A1C (A1C) is used in various settings. Its performance has not been evaluated systemically. We compared A1C in diagnosis of diabetes with fasting plasma glucose (FPG) and 2-h postchallenged plasma glucose (2hPG) parameters in a cross-sectional cohort in the United Stated. Adult subjects (≥20 years) were identified from the National Health and Nutrition Examination Survey 2005–2016 without a history of diabetes who had BMI, A1C, FPG, and 2hPG (n = 10,416). For comparisons, we calculated the sample weighted prevalence, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) with subgroup analyses. For the retinopathy study, diabetic subjects with established diabetes who responded to the question of diabetic retinopathy were evaluated (n = 3907). Compared to the FPG/2hPG criteria, A1C ≥ 48 mmol/mol (6.5%) had a low sensitivity at 25.90%, with specificity 99.70%, PPV 84.70%, and NPV 95.70%. Subgroup analyses revealed a lower sensitivity in males (24.52%), the lowest in non-Hispanic White (21.35%), in the third decade (14.32%), and in the BMI &lt, 22.50 kg/m2 group (7.21%). The prevalence of self-reported diabetic retinopathy increased drastically with an inflection point at A1C 48 mmol/mol (6.5%) from 11.52% to 18.32% (p &lt, 0.0001). A1C ≥ 48 mmol/mol (6.5%) should be cautiously used to diagnose diabetes in certain subgroups due to very low sensitivity in certain groups. With the confirmation of the association of increasing self-reported diabetic retinopathy with A1C ≥ 48 mmol/mol (6.5%), the current A1C cutoff is an acceptable value with the understanding of especially low sensitivity in certain subgroups.

Published
2021

35. Cluster Analysis of Cardiovascular Phenotypes in Patients With Type 2 Diabetes and Established Atherosclerotic Cardiovascular Disease: A Potential Approach to Precision Medicine.

Author

Sharma, Abhinav, Yinggan Zheng, Ezekowitz, Justin A., Westerhout, Cynthia M., Udell, Jacob A., Goodman, Shaun G., Armstrong, Paul W., Buse, John B., Green, Jennifer B., Josse, Robert G., Kaufman, Keith D., McGuire, Darren K., Ambrosio, Giuseppe, Lee-Ming Chuang, Lopes, Renato D., Peterson, Eric D., Holman, Rury R., Zheng, Yinggan, and Chuang, Lee-Ming

Subjects
TYPE 2 diabetes, CLUSTER analysis (Statistics), CARDIOVASCULAR diseases, INDIVIDUALIZED medicine, PROPORTIONAL hazards models
Abstract

Objective: Phenotypic heterogeneity among patients with type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease (ASCVD) is ill defined. We used cluster analysis machine-learning algorithms to identify phenotypes among trial participants with T2DM and ASCVD.Research Design and Methods: We used data from the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) study (n = 14,671), a cardiovascular outcome safety trial comparing sitagliptin with placebo in patients with T2DM and ASCVD (median follow-up 3.0 years). Cluster analysis using 40 baseline variables was conducted, with associations between clusters and the primary composite outcome (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina) assessed by Cox proportional hazards models. We replicated the results using the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial.Results: Four distinct phenotypes were identified: cluster I included Caucasian men with a high prevalence of coronary artery disease; cluster II included Asian patients with a low BMI; cluster III included women with noncoronary ASCVD disease; and cluster IV included patients with heart failure and kidney dysfunction. The primary outcome occurred, respectively, in 11.6%, 8.6%, 10.3%, and 16.8% of patients in clusters I to IV. The crude difference in cardiovascular risk for the highest versus lowest risk cluster (cluster IV vs. II) was statistically significant (hazard ratio 2.74 [95% CI 2.29-3.29]). Similar phenotypes and outcomes were identified in EXSCEL.Conclusions: In patients with T2DM and ASCVD, cluster analysis identified four clinically distinct groups. Further cardiovascular phenotyping is warranted to inform patient care and optimize clinical trial designs. [ABSTRACT FROM AUTHOR]

Published
2022
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36. GSK3α phosphorylates dynamin-2 to promote GLUT4 endocytosis in muscle cells.

Author

Laiman, Jessica, Yen-Jung Hsu, Loh, Julie, Wei-Chun Tang, Mei-Chun Chuang, Hui-Kang Liu, Wei-Shun Yang, Bi-Chang Chen, Lee-Ming Chuang, Yi-Cheng Chang, and Ya-Wen Liu

Abstract

Insulin-stimulated translocation of glucose transporter 4 (GLUT4) to plasma membrane of skeletal muscle is critical for postprandial glucose uptake; however, whether the internalization of GLUT4 is also regulated by insulin signaling remains unclear. Here, we discover that the activity of dynamin-2 (Dyn2) in catalyzing GLUT4 endocytosis is negatively regulated by insulin signaling in muscle cells. Mechanistically, the fission activity of Dyn2 is inhibited by binding with the SH3 domain of Bin1. In the absence of insulin, GSK3α phosphorylates Dyn2 to relieve the inhibition of Bin1 and promotes endocytosis. Conversely, insulin signaling inactivates GSK3α and leads to attenuated GLUT4 internalization. Furthermore, the isoformspecific pharmacological inhibition of GSK3α significantly improves insulin sensitivity and glucose tolerance in diet-induced insulin-resistant mice. Together, we identify a new role of GSK3α in insulin-stimulated glucose disposal by regulating Dyn2-mediated GLUT4 endocytosis in muscle cells. These results highlight the isoform-specific function of GSK3α on membrane trafficking and its potential as a therapeutic target for metabolic disorders. [ABSTRACT FROM AUTHOR]

Published
2023
Full Text
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