Aldons J. Lusis, Ph.D.
Professor, Medicine, Human Genetics, Microbiology, Immunology & Molecular Genetics
Vice Chair, Human Genetics
Member, Brain Research Institute, CTSI, Center for Duchenne Muscular Dystrophy, Genetics & Genomics GPB Home Area, JCCC Cancer and Stem Cell Biology Program Area, Molecular Pharmacology GPB Home Area, Molecular, Cellular & Integrative Physiology GPB Home Area, Workforce Development
Faculty, Cardiology, BWF-IT-MD, Center for Metabolic Disease Prevention
Atherosclerosis, the primary cause of heart disease and stroke, has an important genetic component, but the genes contributing to the common forms of the disease are largely unknown. Studies in humans have been hampered by the etiologic complexity of atherosclerosis. One approach to the problem involves studies in mouse models, which are more amenable to genetic dissection of complex traits. The genes and pathways identified in mice can them be tested in human populations.
Familial combined hyperlipidemia (FCH), characterized by elevated levels of triglyceride and cholesterol, is a common cause of early heart disease. Studies of a mouse model of FCH (Castellani et al. Nature Genetics, 1998) implicates the thioredoxin system, the primary regulator of cellular redox states, in the control of lipid metabolism in liver and muscle. The hyperlipidemia mouse has a defect in a gene, designated Hyplip1, that encodes a thioredoxin-binding protein. A locus contributing to FCH on human chromosome 1q contains the ortholog of the Hyplip1 gene, and we are investigating whether variations of the gene may contribute to the human disorder.
As yet, human studies have not succeeded in identifying genetic factors in atherosclerosis that act by affecting vascular cell functions, a major problem being the difficulty of accurately evaluating the severity of disease by noninvasive techniques. Using genetic studies in mice, we have identified at least two pathways in atherosclerosis that affect cellular functions. Genetic variations affecting these pathways in mice can completely block the development of lesions, even on the background of extreme hyperlipidemia resulting from mutations of apolipoprotein E or the low density lipoprotein receptor. One of the pathways influences endothelial cell responses to oxidized lipoproteins, while the other appears to control interactions with blood cells. Neither pathway has significant effects on cholesterol metabolism, blood pressure or other common risk factors. We are searching for the underlying genes using a combination biochemical, genetic and genomics approaches.
Jake Lusis received his Ph.D. in Biophysics from Oregon State University. He was a postdoctoral fellow with Kenneth Paigen in the Molecular Biology Department, Roswell Park Memorial Institute, Buffalo, NY. Since 1979, he has been on the faculty at the University of California, Los Angeles, where he is presently Professor in the Departments of Microbiology and Medicine. He has a secondary appointment in the Department of Human Genetics, where he is also Vice Chairman. He has served on advisory panels for the National Institutes of Health, the American Heart Association, and various private companies and organizations. Presently, he serves on the Board of Scientific Counselors, NHLBI. Among his awards are the Bristol-Myers Squibb Award for Distinguished Achievement in Research, the American Heart Association Duff Award, and the NAVBO Benditt Award.
Wang JJ, Rau C, Avetisyan R, Ren S, Romay MC, Stolin G, Gong KW, Wang Y, Lusis AJ. Genetic dissection of cardiac remodeling in an isoproterenol-induced heart failure mouse model. PLoS Genet. 2016; 12:e1006038.
Pillai Indulekha C L, Li Shen, Romay Milagros, Lam Larry, Lu Yan, Huang Jie, Dillard Nathaniel, Zemanova Marketa, Rubbi Liudmilla, Wang Yibin, Lee Jason, Xia Ming, Liang Owen, Xie Ya-Hong, Pellegrini Matteo, Lusis Aldons J, Deb Arjun Cardiac Fibroblasts Adopt Osteogenic Fates and Can Be Targeted to Attenuate Pathological Heart Calcification. Cell stem cell. 2016; .
Rau Christoph D, Romay Milagros C, Tuteryan Mary, Wang Jessica J-C, Santolini Marc, Ren Shuxun, Karma Alain, Weiss James N, Wang Yibin, Lusis Aldons J Systems Genetics Approach Identifies Gene Pathways and Adamts2 as Drivers of Isoproterenol-Induced Cardiac Hypertrophy and Cardiomyopathy in Mice. Cell systems. 2016; .
Wang Jessica Jen-Chu, Rau Christoph, Avetisyan Rozeta, Ren Shuxun, Romay Milagros C, Stolin Gabriel, Gong Ke Wei, Wang Yibin, Lusis Aldons J Genetic Dissection of Cardiac Remodeling in an Isoproterenol-Induced Heart Failure Mouse Model. PLoS genetics. 2016; 12(7): e1006038.
Bennett Brian J, Davis Richard C, Civelek Mete, Orozco Luz, Wu Judy, Qi Hannah, Pan Calvin, Sevag Packard RenÃ© R, Eskin Eleazar, Yan Mujing, Kirchgessner Todd, Wang Zeneng, Li Xinmin, Gregory Jill C, Hazen Stanley L, Gargalovic Peter S, Lusis Aldons J Correction: Genetic Architecture of Atherosclerosis in Mice: A Systems Genetics Analysis of Common Inbred Strains. PLoS genetics. 2016; 12(3): e1005913.
Zhu Weifei, Gregory Jill C, Org Elin, Buffa Jennifer A, Gupta Nilaksh, Wang Zeneng, Li Lin, Fu Xiaoming, Wu Yuping, Mehrabian Margarete, Sartor R Balfour, McIntyre Thomas M, Silverstein Roy L, Tang W H Wilson, DiDonato Joseph A, Brown J Mark, Lusis Aldons J, Hazen Stanley L Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk. Cell. 2016; 165(1): 111-24.
Org Elin, Parks Brian W, Joo Jong Wha J, Emert Benjamin, Schwartzman William, Kang Eun Yong, Mehrabian Margarete, Pan Calvin, Knight Rob, Gunsalus Robert, Drake Thomas A, Eskin Eleazar, Lusis Aldons J Genetic and environmental control of host-gut microbiota interactions. Genome research. 2015; 25(10): 1558-69.
Hui Simon T, Parks Brian W, Org Elin, Norheim Frode, Che Nam, Pan Calvin, Castellani Lawrence W, Charugundla Sarada, Dirks Darwin L, Psychogios Nikolaos, Neuhaus Isaac, Gerszten Robert E, Kirchgessner Todd, Gargalovic Peter S, Lusis Aldons J The genetic architecture of NAFLD among inbred strains of mice. eLife. 2015; 4: e05607.
Parks Brian W, Sallam Tamer, Mehrabian Margarete, Psychogios Nikolas, Hui Simon T, Norheim Frode, Castellani Lawrence W, Rau Christoph D, Pan Calvin, Phun Jennifer, Zhou Zhenqi, Yang Wen-Pin, Neuhaus Isaac, Gargalovic Peter S, Kirchgessner Todd G, Graham Mark, Lee Richard, Tontonoz Peter, Gerszten Robert E, Hevener Andrea L, Lusis Aldons J Genetic architecture of insulin resistance in the mouse. Cell metabolism. 2015; 21(2): 334-46.
Parks Brian W, Nam Elizabeth, Org Elin, Kostem Emrah, Norheim Frode, Hui Simon T, Pan Calvin, Civelek Mete, Rau Christoph D, Bennett Brian J, Mehrabian Margarete, Ursell Luke K, He Aiqing, Castellani Lawrence W, Zinker Bradley, Kirby Mark, Drake Thomas A, Drevon Christian A, Knight Rob, Gargalovic Peter, Kirchgessner Todd, Eskin Eleazar, Lusis Aldons J Genetic control of obesity and gut microbiota composition in response to high-fat, high-sucrose diet in mice. Cell metabolism. 2013; 17(1): 141-52.
Bennett Brian J, de Aguiar Vallim Thomas Q, Wang Zeneng, Shih Diana M, Meng Yonghong, Gregory Jill, Allayee Hooman, Lee Richard, Graham Mark, Crooke Rosanne, Edwards Peter A, Hazen Stanley L, Lusis Aldons J Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell metabolism. 2013; 17(1): 49-60.
Orozco Luz D, Bennett Brian J, Farber Charles R, Ghazalpour Anatole, Pan Calvin, Che Nam, Wen Pingzi, Qi Hong Xiu, Mutukulu Adonisa, Siemers Nathan, Neuhaus Isaac, Yordanova Roumyana, Gargalovic Peter, Pellegrini Matteo, Kirchgessner Todd, Lusis Aldons J Unraveling inflammatory responses using systems genetics and gene-environment interactions in macrophages. Cell. 2012; 151(3): 658-70.
Romanoski Casey E, Che Nam, Yin Fen, Mai Nguyen, Pouldar Delila, Civelek Mete, Pan Calvin, Lee Sangderk, Vakili Ladan, Yang Wen-Pin, Kayne Paul, Mungrue Imran N, Araujo Jesus A, Berliner Judith A, Lusis Aldons J Network for activation of human endothelial cells by oxidized phospholipids: a critical role of heme oxygenase 1. Circulation research. 2011; 109(5): e27-41.
Wang Zeneng, Klipfell Elizabeth, Bennett Brian J, Koeth Robert, Levison Bruce S, Dugar Brandon, Feldstein Ariel E, Britt Earl B, Fu Xiaoming, Chung Yoon-Mi, Wu Yuping, Schauer Phil, Smith Jonathan D, Allayee Hooman, Tang W H Wilson, DiDonato Joseph A, Lusis Aldons J, Hazen Stanley L Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011; 472(7341): 57-63.
Farber Charles R, Bennett Brian J, Orozco Luz, Zou Wei, Lira Ana, Kostem Emrah, Kang Hyun Min, Furlotte Nicholas, Berberyan Ani, Ghazalpour Anatole, Suwanwela Jaijam, Drake Thomas A, Eskin Eleazar, Wang Q Tian, Teitelbaum Steven L, Lusis Aldons J Mouse genome-wide association and systems genetics identify Asxl2 as a regulator of bone mineral density and osteoclastogenesis. PLoS genetics. 2011; 7(4): e1002038.
Bennett Brian J, Farber Charles R, Orozco Luz, Kang Hyun Min, Ghazalpour Anatole, Siemers Nathan, Neubauer Michael, Neuhaus Isaac, Yordanova Roumyana, Guan Bo, Truong Amy, Yang Wen-pin, He Aiqing, Kayne Paul, Gargalovic Peter, Kirchgessner Todd, Pan Calvin, Castellani Lawrence W, Kostem Emrah, Furlotte Nicholas, Drake Thomas A, Eskin Eleazar, Lusis Aldons J A high-resolution association mapping panel for the dissection of complex traits in mice. Genome research. 2010; 20(2): 281-90.
Meng Haijin, Vera Iset, Che Nam, Wang Xuping, Wang Susanna S, Ingram-Drake Leslie, Schadt Eric E, Drake Thomas A, Lusis Aldons J Identification of Abcc6 as the major causal gene for dystrophic cardiac calcification in mice through integrative genomics. Proceedings of the National Academy of Sciences of the United States of America. 2007; 104(11): 4530-5.
Schadt Eric E, Lamb John, Yang Xia, Zhu Jun, Edwards Steve, Guhathakurta Debraj, Sieberts Solveig K, Monks Stephanie, Reitman Marc, Zhang Chunsheng, Lum Pek Yee, Leonardson Amy, Thieringer Rolf, Metzger Joseph M, Yang Liming, Castle John, Zhu Haoyuan, Kash Shera F, Drake Thomas A, Sachs Alan, Lusis Aldons J An integrative genomics approach to infer causal associations between gene expression and disease. Nature genetics. 2005; 37(7): 710-7.
Bodnar Jackie S, Chatterjee Aurobindo, Castellani Lawrence W, Ross David A, Ohmen Jeffrey, Cavalcoli James, Wu Chenyan, Dains Katherine M, Catanese Joe, Chu Michael, Sheth Sonal S, Charugundla Kanti, Demant Peter, West David B, de Jong Pieter, Lusis Aldons J Positional cloning of the combined hyperlipidemia gene Hyplip1. Nature genetics. 2002; 30(1): 110-6.
Shih D M, Gu L, Xia Y R, Navab M, Li W F, Hama S, Castellani L W, Furlong C E, Costa L G, Fogelman A M, Lusis A J Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis. Nature. 1998; 394(6690): 284-7.
Warden C H, Hedrick C C, Qiao J H, Castellani L W, Lusis A J Atherosclerosis in transgenic mice overexpressing apolipoprotein A-II. Science (New York, N.Y.). 1993; 261(5120): 469-72.
Rajavashisth T B, Andalibi A, Territo M C, Berliner J A, Navab M, Fogelman A M, Lusis A J Induction of endothelial cell expression of granulocyte and macrophage colony-stimulating factors by modified low-density lipoproteins. Nature. 1990; 344(6263): 254-7.
Kirchgessner T G, Chuat J C, Heinzmann C, Etienne J, Guilhot S, Svenson K, Ameis D, Pilon C, d’Auriol L, Andalibi A Organization of the human lipoprotein lipase gene and evolution of the lipase gene family. Proceedings of the National Academy of Sciences of the United States of America. 1989; 86(24): 9647-51.
Lusis A J, West R, Mehrabian M, Reuben M A, LeBoeuf R C, Kaptein J S, Johnson D F, Schumaker V N, Yuhasz M P, Schotz M C Cloning and expression of apolipoprotein B, the major protein of low and very low density lipoproteins. Proceedings of the National Academy of Sciences of the United States of America. 1985; 82(14): 4597-601.
Lusis A J, Taylor B A, Wangenstein R W, LeBoeuf R C Genetic control of lipid transport in mice. II. Genes controlling structure of high density lipoproteins.The Journal of biological chemistry. 1983; 258(8): 5071-8.