Description of Research Expertise:
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
11th floor, Smilow Center for Translational Research
9th floor Maloney Building, Hospital of The University of Pennsylvania
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): 407-416,2016.
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 : 2016.
Saleheen D, Rader DJ, Voight BF: Disentangling the Causal Association of Plasma Lipid Traits and Type 2 Diabetes Using Human Genetics. JAMA Cardiol : 2016.
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 : 2016.
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): 1038-1047,2016.
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): 234-245,2016.
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 : 47-53,2016.
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 : 2016.
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): 1303-1304,2016.
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=68,2016.
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