Aeron Small
University of Pennsylvania
Network
Latest external collaboration on country level. Dive into details by clicking on the dots.
Publication
Featured researches published by Aeron Small.
The New England Journal of Medicine | 2017
Frederick E. Dewey; Viktoria Gusarova; Richard L. Dunbar; Colm O’Dushlaine; Omri Gottesman; Shane McCarthy; Cristopher V. Van Hout; Shannon Bruse; Hayes M. Dansky; Joseph B. Leader; Michael F. Murray; Marylyn D. Ritchie; H. Lester Kirchner; Lukas Habegger; Alex Lopez; John S. Penn; An Zhao; Weiping Shao; Neil Stahl; Andrew J. Murphy; Sara C. Hamon; Aurelie Bouzelmat; Rick Zhang; Brad Shumel; Robert Pordy; Daniel A. Gipe; Gary A. Herman; Wayne H-H Sheu; I-Te Lee; Kae-Woei Liang
BACKGROUND Loss‐of‐function variants in the angiopoietin‐like 3 gene (ANGPTL3) have been associated with decreased plasma levels of triglycerides, low‐density lipoprotein (LDL) cholesterol, and high‐density lipoprotein (HDL) cholesterol. It is not known whether such variants or therapeutic antagonism of ANGPTL3 are associated with a reduced risk of atherosclerotic cardiovascular disease. METHODS We sequenced the exons of ANGPTL3 in 58,335 participants in the DiscovEHR human genetics study. We performed tests of association for loss‐of‐function variants in ANGPTL3 with lipid levels and with coronary artery disease in 13,102 case patients and 40,430 controls from the DiscovEHR study, with follow‐up studies involving 23,317 case patients and 107,166 controls from four population studies. We also tested the effects of a human monoclonal antibody, evinacumab, against Angptl3 in dyslipidemic mice and against ANGPTL3 in healthy human volunteers with elevated levels of triglycerides or LDL cholesterol. RESULTS In the DiscovEHR study, participants with heterozygous loss‐of‐function variants in ANGPTL3 had significantly lower serum levels of triglycerides, HDL cholesterol, and LDL cholesterol than participants without these variants. Loss‐of‐function variants were found in 0.33% of case patients with coronary artery disease and in 0.45% of controls (adjusted odds ratio, 0.59; 95% confidence interval, 0.41 to 0.85; P=0.004). These results were confirmed in the follow‐up studies. In dyslipidemic mice, inhibition of Angptl3 with evinacumab resulted in a greater decrease in atherosclerotic lesion area and necrotic content than a control antibody. In humans, evinacumab caused a dose‐dependent placebo‐adjusted reduction in fasting triglyceride levels of up to 76% and LDL cholesterol levels of up to 23%. CONCLUSIONS Genetic and therapeutic antagonism of ANGPTL3 in humans and of Angptl3 in mice was associated with decreased levels of all three major lipid fractions and decreased odds of atherosclerotic cardiovascular disease. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT01749878.)
Proceedings of the National Academy of Sciences of the United States of America | 2015
Jianhe Huang; Tao Wang; Alexander C. Wright; Jifu Yang; Su Zhou; Li Li; Jisheng Yang; Aeron Small; Michael S. Parmacek
Significance Smooth muscle cells (SMCs) play critical roles in maintaining organismal homeostasis. Myocardin is a muscle-restricted transcriptional coactivator previously implicated in development of the heart and vasculature. To define myocardin-mediated functions during postnatal development, we generated mice harboring an inducible, SMC-restricted mutation in the Myocd gene. Myocardin mutant mice exhibit profound derangements in arterial structure and in the gastrointestinal and genitourinary tracts. Myocd deletion leads to the loss of the contractile SMC phenotype, triggering cell-autonomous ER stress, autophagy, and apoptosis. These data reveal that myocardin is required for maintenance, homeostasis, and ultimately survival of vascular and visceral SMCs during postnatal development. These findings provide unanticipated insights into the pathogenesis of thoracic aortic aneurysm and dissection and gastrointestinal and genitourinary syndromes. Myocardin is a muscle-restricted transcriptional coactivator that activates a serum response factor (SRF)-dependent gene program required for cardiogenesis and embryonic survival. To identify myocardin-dependent functions in smooth muscle cells (SMCs) during postnatal development, mice harboring a SMC-restricted conditional, inducible Myocd null mutation were generated and characterized. Tamoxifen-treated SMMHC-CreERT2/MyocdF/F conditional mutant mice die within 6 mo of Myocd gene deletion, exhibiting profound derangements in the structure of great arteries as well as the gastrointestinal and genitourinary tracts. Conditional mutant mice develop arterial aneurysms, dissection, and rupture, recapitulating pathology observed in heritable forms of thoracic aortic aneurysm and dissection (TAAD). SMCs populating arteries of Myocd conditional mutant mice modulate their phenotype by down-regulation of SMC contractile genes and up-regulation of extracellular matrix proteins. Surprisingly, this is accompanied by SMC autonomous activation of endoplasmic reticulum (ER) stress and autophagy, which over time progress to programmed cell death. Consistent with these observations, Myocd conditional mutant mice develop remarkable dilation of the stomach, small intestine, bladder, and ureters attributable to the loss of visceral SMCs disrupting the muscularis mucosa. Taken together, these data demonstrate that during postnatal development, myocardin plays a unique, and important, role required for maintenance and homeostasis of the vasculature, gastrointestinal, and genitourinary tracts. The loss of myocardin in SMCs triggers ER stress and autophagy, which transitions to apoptosis, revealing evolutionary conservation of myocardin function in SMCs and cardiomyocytes.
The New England Journal of Medicine | 2018
Noura S. Abul-Husn; Xiping Cheng; Alexander H. Li; Yurong Xin; Claudia Schurmann; Panayiotis Stevis; Y. Liu; Julia Kozlitina; Stefan Stender; G. Craig Wood; Ann N. Stepanchick; Matthew D. Still; Shane McCarthy; Colm O’Dushlaine; Jonathan S. Packer; Suganthi Balasubramanian; Nehal Gosalia; David Esopi; Sun Y. Kim; Semanti Mukherjee; Alexander E. Lopez; Erin D. Fuller; John Penn; Xin Chu; Jonathan Z. Luo; Uyenlinh L. Mirshahi; David J. Carey; Christopher D. Still; Michael Feldman; Aeron Small
BACKGROUND Elucidation of the genetic factors underlying chronic liver disease may reveal new therapeutic targets. METHODS We used exome sequence data and electronic health records from 46,544 participants in the DiscovEHR human genetics study to identify genetic variants associated with serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Variants that were replicated in three additional cohorts (12,527 persons) were evaluated for association with clinical diagnoses of chronic liver disease in DiscovEHR study participants and two independent cohorts (total of 37,173 persons) and with histopathological severity of liver disease in 2391 human liver samples. RESULTS A splice variant (rs72613567:TA) in HSD17B13, encoding the hepatic lipid droplet protein hydroxysteroid 17‐beta dehydrogenase 13, was associated with reduced levels of ALT (P=4.2×10‐12) and AST (P=6.2×10‐10). Among DiscovEHR study participants, this variant was associated with a reduced risk of alcoholic liver disease (by 42% [95% confidence interval {CI}, 20 to 58] among heterozygotes and by 53% [95% CI, 3 to 77] among homozygotes), nonalcoholic liver disease (by 17% [95% CI, 8 to 25] among heterozygotes and by 30% [95% CI, 13 to 43] among homozygotes), alcoholic cirrhosis (by 42% [95% CI, 14 to 61] among heterozygotes and by 73% [95% CI, 15 to 91] among homozygotes), and nonalcoholic cirrhosis (by 26% [95% CI, 7 to 40] among heterozygotes and by 49% [95% CI, 15 to 69] among homozygotes). Associations were confirmed in two independent cohorts. The rs72613567:TA variant was associated with a reduced risk of nonalcoholic steatohepatitis, but not steatosis, in human liver samples. The rs72613567:TA variant mitigated liver injury associated with the risk‐increasing PNPLA3 p.I148M allele and resulted in an unstable and truncated protein with reduced enzymatic activity. CONCLUSIONS A loss‐of‐function variant in HSD17B13 was associated with a reduced risk of chronic liver disease and of progression from steatosis to steatohepatitis. (Funded by Regeneron Pharmaceuticals and others.)
Nature Communications | 2018
Viktoria Gusarova; Colm O’Dushlaine; Tanya M. Teslovich; Peter N. Benotti; Tooraj Mirshahi; Omri Gottesman; Cristopher V. Van Hout; Michael F. Murray; Anubha Mahajan; Jonas B. Nielsen; Lars G. Fritsche; Anders Berg Wulff; Daniel F. Gudbjartsson; Marketa Sjögren; Connor A. Emdin; Robert A. Scott; Wen-Jane Lee; Aeron Small; Lydia Kwee; Om Prakash Dwivedi; Rashmi B. Prasad; Shannon Bruse; Alexander E. Lopez; John S. Penn; Anthony Marcketta; Joseph B. Leader; Christopher D. Still; H. Lester Kirchner; Uyenlinh L. Mirshahi; Amr H. Wardeh
Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85–0.92, p = 6.3 × 10−10), lower fasting glucose, and greater insulin sensitivity. Predicted loss-of-function variants are associated with lower odds of T2D among 32,015 cases and 84,006 controls (odds ratio 0.71, 95% confidence interval 0.49–0.99, p = 0.041). Functional studies in Angptl4-deficient mice confirm improved insulin sensitivity and glucose homeostasis. In conclusion, genetic inactivation of ANGPTL4 is associated with improved glucose homeostasis and reduced risk of T2D.Genetic variation in ANGPTL4 is associated with lipid traits. Here, the authors find that predicted loss-of-function variants in ANGPTL4 are associated with glucose homeostasis and reduced risk of type 2 diabetes and that Angptl4−/− mice on a high-fat diet show improved insulin sensitivity.
Arteriosclerosis, Thrombosis, and Vascular Biology | 2017
Aeron Small; Daniel Kiss; Jay Giri; Saif Anwaruddin; Hasan K. Siddiqi; Marie Guerraty; Julio A. Chirinos; Giovanni Ferrari; Daniel J. Rader
Calcific aortic valve disease (CAVD) is a highly prevalent cardiovascular disorder accounting for a rising economic and social burden on aging populations. In spite of continuing study on the pathophysiology of disease, there remain no medical therapies to prevent the progression of CAVD. The discovery of biomarkers represents a potentially complementary approach in stratifying risk and timing of intervention in CAVD and has the advantage of providing insight into causal factors for the disease. Biomarkers have been studied extensively in atherosclerotic cardiovascular disease, with success as additive for clinical and scientific purposes. Similar research in CAVD is less robust; however, the available studies of biomarkers in CAVD show promise for enhanced clinical decision making and identification of causal factors for the disease. This comprehensive review summarizes available established and novel biomarkers in CAVD, their contributions toward an understanding of pathophysiology, their potential clinical utility, and provides an outline to direct future research in the field.
Clinical Chemistry | 2017
Aeron Small; Nehal N. Mehta; Daniel J. Rader
The potential for new therapies that might delay the onset of life-threatening cardiovascular events has motivated a continued interest in the identification of novel predictive circulating biomarkers for cardiovascular disease (CVD).2 While a number of biomarkers [such as C-reactive protein (CRP), d-dimer, fibrinogen, and B-type natriuretic peptide] demonstrate a strong positive association with future risk of CVD events, they have modest incremental predictive power when added to clinical risk factors (1). There remains interest in the discovery of new biomarkers of CVD risk that are uncorrelated to existing markers and provide complementary information on the biological mechanisms determining cardiovascular risk. Emerging technologies such as nuclear magnetic resonance (NMR) spectroscopy enable the comprehensive study of yet-undescribed biological territories and serve as rich ground for the discovery of new and potentially informative circulating molecules in the blood. The serum “glycome” is a fascinating example of an emerging paradigm for the discovery of new biomarkers to characterize disease risk and pathophysiology. The glycome represents the totality of posttranslational modifications of secreted proteins by enzymatic glycosylation. Glycosylated proteins and their sugar moieties called glycans are key to a variety of important cellular processes, but they have historically been difficult to measure, owing in part to low plasma concentrations. In 2015, LabCorp developed a spectral deconvolution algorithm to qualify additional signals derived from lipoprotein particle analyses originating from the N- acetyl methyl group protons of mobile glycan residues (2). This composite signal, designated “GlycA,” is thought to represent a composite of glycoproteins involved in the biology of inflammation, most prominently α1 …
Arteriosclerosis, Thrombosis, and Vascular Biology | 2017
Aeron Small; Daniel Kiss; Jay Giri; Saif Anwaruddin; Hasan K. Siddiqi; Marie Guerraty; Julio A. Chirinos; Giovanni Ferrari; Daniel J. Rader
WOS | 2017
Wei Zhao; Asif Rasheed; Emmi Tikkanen; Jung-Jin Lee; Adam S. Butterworth; Joanna M. M. Howson; Themistocles L. Assimes; Rajiv Chowdhury; Marju Orho-Melander; Scott M. Damrauer; Aeron Small; Senay Asma; Minako Imamura; Toshimasa Yamauch; John Chambers; Peng Chen; Bishwa Raj Sapkota; Nabi Shah; Sehrish Jabeen; Praveen Surendran; Yingchang Lu; Weihua Zhang; Atif Imran; Shahid Abbas; Faisal Majeed; Kevin Trindade; Nadeem Qamar; Nadeem Hayyat Mallick; Zia Yaqoob; Tahir Saghir
Journal of Biomedical Informatics | 2017
Aeron Small; Daniel Kiss; Yevgeny Zlatsin; David L. Birtwell; Heather Williams; Marie Guerraty; Yuchi Han; Saif Anwaruddin; John H. Holmes; Julio A. Chirinos; Robert L. Wilensky; Jay Giri; Daniel J. Rader
Circulation | 2017
Hao Yu Chen; Benjamin J Cairns; Line Dufresne; Hannah Burr; Athithan Ambikkumar; Aeron Small; Albert Nguyen; Johan Ljungberg; Ulf Näslund; Bengt Johansson; Jian Rong; Dilrini Ranatunga; Rachel A. Whitmer; Vilmundur Gudnason; Christopher J. O'Donnell; Jerome I. Rotter; Wendy S. Post; Stefan Söderberg; Robert Clarke; J. Gustav Smith; Daniel J. Rader; Mark Lathrop; James C. Engert; George Thanassoulis