Etiology of HDL Cholesterol ("The Upenn High HDL Research Study")
Penn CVI Scientific Director for Translational / Clinical Research
CVI Program Unit Administrator (Director):
Prevention / Atherosclerosis / Lipids
The Rader laboratory is focused on two major themes: 1) novel pathways regulating lipid and lipoprotein metabolism and atherosclerosis inspired by unbiased studies of human genetics; 2) factors regulating the structure and function of high density lipoproteins and the process of reverse cholesterol transport and their relationship to atherosclerosis. A variety of basic cell and molecular laboratory techniques, mouse models, and translational research approaches are used in addressing these questions.
Some examples of ongoing projects are:
1) The roles of sortilin (gene SORT1) and tribbles-1 (gene TRIB1) in lipoprotein metabolism and atherosclerosis. Variants at the SORT1 locus are among the most strongly associated with LDL cholesterol and (coronary artery disease) in the human genome, and variants at the TRIB1 locus are significantly associated with all major plasma lipid traits and CAD. A variety of tissue-specific deleted mouse models, gene targeting in iPS cells with differentiation to hepatocytes, and cell biologic and biochemical approaches are being employed.
2) Functional genomics and mechanistic studies of a number of additional genes at loci significantly associated with lipid and metabolic traits, CAD, or other cardiovascular traits. Most of these genes harbor rare coding variants associated with these traits. In addition to elucidating fundamental mechanisms by which the protein influences relevant biology, the influence of specific mutations on protein structure and function are being explored.
3) Molecular regulation of HDLmetabolism and reverse cholesterol transport using cells, mice, and humans
4) Deep phenotyping of humans with low-frequency and rare variants in genes influencing lipid and cardiovascular traits, including the generation of iPS cells and differentiation to a variety of relevant cell types
Michael S. Kelly
11th floor, Smilow Center for Translational Research
9th floor Maloney Building, Hospital of The University of Pennsylvania
Research Associate Professors:
Marina Cuchel, MD PhD
Research Assistant Professors:
Yanqing (Anna) Gong, PhD
Nicholas Hand, PhD
Sissel Lund-Katz, PhD
Michael C. Phillips, PhD
Senior Research Investigators:
Jeffrey Billheimer, PhD
John Millar, PhD
Athanasia (Nancy) Skoura, PhD
Nicholas Lyssenko, PhD
Sony Tuteja, PharmD
Deepti Abbey, PhD
Ezimamaka Ajufo, MD
Robert Bauer, PhD
Xin Bi, PhD
Donna Conlon, PhD
Marie Guerraty, MD/PhD
Ali Javaheri, MD/PhD
Sylvia Nürnberg, PhD
Evanthia Pashos, PhD
Swapnil Shewale, PhD
Doris Duke Fellow:
Jian Cui, MD
Marjolein van den Boogert
Hye In Kim
Stephanie DerOhannessian, MB
Dawn Marchadier, MS
H. Shanker Rao, MS
Wei Zhao, MS
Susannah Elwyn, MS
Mayda Hernandez, MS
Amrith Rodrigues, MS
Maosen Sun, MD/PhD
Aisha Wilson, MLAS
Clinical Research Personnel:
Amanda Baer, MBA
Marjorie Risman, MS
Clinical Research Coordinators:
Masako Ueda, MD
Clinical Research Assistants:
The Etiology of HDL Cholesterol (“The Upenn High HDL Research Study”)
Name of Study:
The Etiology of HDL Cholesterol (“The Upenn High HDL Research Study”)
Daniel J. Rader, MD
2690 subjects in 1196 families as of January 28, 2013
What is HDL?
The letters HDL stand for high density lipoprotein. It is known as the “good cholesterol” because a high HDL level can protect against heart disease and stroke.
The purpose of this study is to identify genes that are associated with HDL and influence coronary artery disease. Data from blood samples and health histories of individuals with high HDL levels and their family members are used to assess the relationship between these genes and HDL cholesterol. The long term goal of investigating these genes is the development of new therapies to prevent coronary artery disease.
A note to people who have already participated and their families:
If you have already provided a blood sample for this study since 1998, thank you very much! Your help is invaluable. If you have high HDL cholesterol, we are asking that you speak to your relatives who have not yet participated. We are interested in receiving samples from your parents, children and siblings. If a participant’s child also participated, or plans to participate, we would also like to receive a sample from the child’s other parent.
If it is possible to receive samples that would give us samples from two parents and at least one child, whether you are the child or one of the parents, your family’s participation would be especially valuable and welcome.
A note to potential new participants:
If you and your family have NOT participated in the study, but you have been told you have high HDL (for example you are a man with an HDL value above 75 mg/dL or a woman with an HDL above 90 mg/dL) you may also be eligible to participate.
For more information about the study, or to arrange participation, contact the research coordinator:
local telephone number: 215-746-8342
toll free telephone number: 1-888-81HEART (1-888-814-3278).
What does participating in this study involve?
Participants are asked to provide a small blood sample and complete a short health questionnaire. We use the blood sample to measure cholesterol levels and to isolate DNA for the genetic research. DNA is the part of your blood sample that holds genetic information. Participants receive the results of their lipid panel (cholesterol results).
A participant can either:
Come to our research clinic at the Hospital of the University of Pennsylvania for a brief visit to provide a blood sample.
Receive by mail a kit containing all the necessary materials for the blood draw. The kit can be taken to a local laboratory or doctor’s office and the blood sample can then be shipped to us at our expense in packaging we provide. If a participant is charged for having blood drawn, we can reimburse the charge. We can also assist in finding a location for the blood draw.
The study has been recruiting participants since 1998, and the investigators have already made some significant findings using the data already collected.
A specific protein, endothelial lipase, breaks down HDL cholesterol particles. The following three articles used data from this study to explore the relationship between endothelial lipase and HDL:
1. deLemos AS, Wolfe ML, Long CJ, Sivapackianathan R, Rader DJ. (2002) Identification of genetic variants in endothelial lipase in persons with elevated high-density lipoprotein cholesterol. Circulation. 2002;106(11):1321-6.
Shortly after the initial discovery of the endothelial lipase gene, we sequenced the gene in subjects with high HDL levels. We identified six variants of endothelial lipase that may have contributed to the individuals' elevated HDL concentration.
2. Edmondson AC, Brown RJ, Kathiresan S, Cupples LA, Demissie S, Manning AK, Jensen MK, Rimm EB, Wang J, Rodrigues A, Bamba V, Khetarpal SA, Wolfe ML, Derohannessian S, Li M, Reilly MP, Aberle J, Evans D, Hegele RA, Rader DJ. (2009) Loss-of-function variants in endothelial lipase are a cause of elevated HDL cholesterol in humans. J. Clin. Invest. 119: 1042-1050.
We identified that healthy people with high HDL also have mutations in their endothelial lipase protein that makes the protein unable to break down HDL cholesterol particles. Our results suggest that new drugs that stop endothelial lipase from breaking down HDL cholesterol particles will increase HDL levels and may reduce heart disease. However, further studies on the effect of the endothelial lipase mutations in heart disease are needed.
3. Brown RJ, Edmondson AC, Griffon N, Hill TB, Fuki IV, Badellino KO, Li M, Wolfe ML, Reilly MP, Rader DJ (2009) A naturally occurring variant of endothelial lipase associated with elevated HDL exhibits impaired synthesis. J Lipid Res.
We identified a version of the endothelial lipase that is present in some individuals of African descent that results in a person having lower levels of endothelial lipase protein and higher levels of HDL.
4. He J, Wang K, Edmondson AC, Rader DJ, Li C, Li M. (2010) Gene-based interaction analysis by incorporating external linkage disequilibrium information. Eur J Hum Genet. 1-9
We developed a new statistical method to identify genes that interact with each other. The Upenn High HDL Research Study was used to show how this new method works and identified the genes CETP and BCAT1 interacting with each other.
5. Teslovich TM, Musunuru K, Smith AV, Edmondson AC, Stylianou IM, Koseki M, Pirruccello JP, Ripatti S, Chasman DI, Willer CJ, Johansen CT, Fouchier SW, Isaacs A, Peloso GM, Barbalic M, Ricketts SL, Bis JC, Aulchenko YS, Thorleifsson G, Feitosa MF, Chambers J, Orho-Melander M, Melander O, Johnson T, Li X, Guo X, Li M, Shin Cho Y, Jin Go M, Jin Kim Y, Lee JY, Park T, Kim K, Sim X, Twee-Hee Ong R, Croteau-Chonka DC, Lange LA, Smith JD, Song K, Hua Zhao J, Yuan X, Luan J, Lamina C, Ziegler A, Zhang W, Zee RY, Wright AF, Witteman JC, Wilson JF, Willemsen G, Wichmann HE, Whitfield JB, Waterworth DM, Wareham NJ, Waeber G, Vollenweider P, Voight BF, Vitart V, Uitterlinden AG, Uda M, Tuomilehto J, Thompson JR, Tanaka T, Surakka I, Stringham HM, Spector TD, Soranzo N, Smit JH, Sinisalo J, Silander K, Sijbrands EJ, Scuteri A, Scott J, Schlessinger D, Sanna S, Salomaa V, Saharinen J, Sabatti C, Ruokonen A, Rudan I, Rose LM, Roberts R, Rieder M, Psaty BM, Pramstaller PP, Pichler I, Perola M, Penninx BW, Pedersen NL, Pattaro C, Parker AN, Pare G, Oostra BA, O'Donnell CJ, Nieminen MS, Nickerson DA, Montgomery GW, Meitinger T, McPherson R, McCarthy MI, McArdle W, Masson D, Martin NG, Marroni F, Mangino M, Magnusson PK, Lucas G, Luben R, Loos RJ, Lokki ML, Lettre G, Langenberg C, Launer LJ, Lakatta EG, Laaksonen R, Kyvik KO, Kronenberg F, König IR, Khaw KT, Kaprio J, Kaplan LM, Johansson A, Jarvelin MR, Cecile J W Janssens A, Ingelsson E, Igl W, Kees Hovingh G, Hottenga JJ, Hofman A, Hicks AA, Hengstenberg C, Heid IM, Hayward C, Havulinna AS, Hastie ND, Harris TB, Haritunians T, Hall AS, Gyllensten U, Guiducci C, Groop LC, Gonzalez E, Gieger C, Freimer NB, Ferrucci L, Erdmann J, Elliott P, Ejebe KG, Döring A, Dominiczak AF, Demissie S, Deloukas P, de Geus EJ, de Faire U, Crawford G, Collins FS, Chen YD, Caulfield MJ, Campbell H, Burtt NP, Bonnycastle LL, Boomsma DI, Boekholdt SM, Bergman RN, Barroso I, Bandinelli S, Ballantyne CM, Assimes TL, Quertermous T, Altshuler D, Seielstad M, Wong TY, Tai ES, Feranil AB, Kuzawa CW, Adair LS, Taylor HA Jr, Borecki IB, Gabriel SB, Wilson JG, Holm H, Thorsteinsdottir U, Gudnason V, Krauss RM, Mohlke KL, Ordovas JM, Munroe PB, Kooner JS, Tall AR, Hegele RA, Kastelein JJ, Schadt EE, Rotter JI, Boerwinkle E, Strachan DP, Mooser V, Stefansson K, Reilly MP, Samani NJ, Schunkert H, Cupples LA, Sandhu MS, Ridker PM, Rader DJ, van Duijn CM, Peltonen L, Abecasis GR, Boehnke M, Kathiresan S. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466
We collaborated with many different studies to study the genetics of plasma lipids in >100,000 individuals. We identified 95 different regions of the human genome that contribute to determining levels of total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides and showed genetic contributions to cholesterol levels in people of European, East Asian, South Asian, and African American ancestry. This knowledge will help us to better understand the biology of cholesterol metabolism and identify new drug targets to prevent heart disease.
Local telephone number: 215-746-8342
Toll free telephone number: 1-888-81HEART (1-888-814-3278)
Stroes E, Guyton JR, Lepor N, Civeira F, Gaudet D, Watts GF, Baccara-Dinet MT, Lecorps G, Manvelian G, Farnier M; ODYSSEY CHOICE II Investigators. : Efficacy and Safety of Alirocumab 150 mg Every 4 Weeks in Patients With Hypercholesterolemia Not on Statin Therapy: The ODYSSEY CHOICE II Study. J Am Heart Assoc 5(9): 407-416, Sep 2016.
Ginsberg HN, Rader DJ, Raal FJ, Guyton JR, Baccara-Dinet MT, Lorenzato C, Pordy R, Stroes E. : Efficacy and Safety of Alirocumab in Patients with Heterozygous Familial Hypercholesterolemia and LDL-C of 160 mg/dl or Higher. Cardiovasc Drugs Ther Sep 2016 Notes: Epub ahead of print.
Saleheen D, Rader DJ, Voight BF: Disentangling the Causal Association of Plasma Lipid Traits and Type 2 Diabetes Using Human Genetics. JAMA Cardiol Aug 2016 Notes: Epub ahead of print.
Mansouri B, Kivelevitch D, Natarajan B, Joshi AA, Ryan C, Benjegerdes K, Schussler JM, Rader DJ, Reilly MP, Menter A, Mehta NN. : Comparison of Coronary Artery Calcium Scores Between Patients With Psoriasis and Type 2 Diabetes. JAMA Dermatol Aug 2016 Notes: Epub ahead of print.
Herzog E, Pragst I, Waelchli M, Gille A, Schenk S, Mueller-Cohrs J, Diditchenko S, Zanoni P, Cuchel M, Seubert A, Rader DJ, Wright SD : Reconstituted high-density lipoprotein can elevate plasma alanine aminotransferase by transient depletion of hepatic cholesterol: role of the phospholipid component. J Appl Toxicol 36(8): 1038-1047, Aug 2016.
Khetarpal SA, Schjoldager KT, Christoffersen C, Raghavan A, Edmondson AC, Reutter HM, Ahmed B, Ouazzani R, Peloso GM, Vitali C, Zhao W, Somasundara AV, Millar JS, Park Y, Fernando G, Livanov V, Choi S, Noé E, Patel P, Ho SP; Myocardial Infarction Exome Sequencing Study, Kirchgessner TG, Wandall HH, Hansen L, Bennett EP, Vakhrushev SY, Saleheen D, Kathiresan S, Brown CD, Abou Jamra R, LeGuern E, Clausen H, Rader DJ. : Loss of Function of GALNT2 Lowers High-Density Lipoproteins in Humans, Nonhuman Primates, and Rodents. Cell Metab 24(2): 234-245, Aug 2016.
Beheshtian A, Shitole SG, Segal AZ, Leifer D, Tracy RP, Rader DJ, Devereux RB, Kizer JR : Lipoprotein (a) level, apolipoprotein (a) size, and risk of unexplained ischemic stroke in young and middle-aged adults. Atherosclerosis 253: 47-53, Aug 2016 Notes: Epub ahead of print.
Javaheri A, Molina M, Zamani P, Rodrigues A, Novak E, Chambers S, Stutman P, Maslanek W, Williams M, Lilly SM, Heeger P, Sayegh MH, Chandraker A, Briscoe DM, Daly KP, Starling R, Ikle D, Christie J, Rame JE, Goldberg LR, Billheimer J, Rader DJ : Cholesterol efflux capacity of high-density lipoprotein correlates with survival and allograft vasculopathy in cardiac transplant recipients. J Heart Lung Transplant Jul 2016 Notes: Epub ahead of print.
Daugherty A, Hegele RA, Mackman N, Rader DJ, Schmidt AM, Weber C: Complying With the National Institutes of Health Guidelines and Principles for Rigor and Reproducibility: Refutations. Arterioscler Thromb Vasc Biol 36(7): 1303-1304, Jul 2016.
Patel AP, Peloso GM, Pirruccello JP, Johansen CT, Dubé JB, Larach DB, Ban MR, Dallinge-Thie GM, Gupta N, Boehnke M, Abecasis GR, Kastelein JJ, Hovingh GK, Hegele RA, Rader DJ, Kathiresan S : Targeted exonic sequencing of GWAS loci in the high extremes of the plasma lipids distribution. Atherosclerosis 250: 63=68, Jul 2016.
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Last updated: 09/22/2016
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