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
Keenan T, Zhao W, Rasheed A, Ho WK, Malik R, Felix JF, Young R, Shah N, Samuel M, Sheikh N, Mucksavage ML, Shah O, Li J, Morley M, Laser A, Mallick NH, Zaman KS, Ishaq M, Rasheed SZ, Memon FU, Ahmed F, Hanif B, Lakhani MS, Fahim M, Ishaq M, Shardha NK, Ahmed N, Mahmood K, Iqbal W, Akhtar S, Raheel R, O'Donnell CJ, Hengstenberg C, März W, Kathiresan S, Samani N, Goel A, Hopewell JC, Chambers J, Cheng YC, Sharma P, Yang Q, Rosand J, Boncoraglio GB, Kazmi SU, Hakonarson H, Köttgen A, Kalogeropoulos A, Frossard: Causal Assessment of Serum Urate Levels in Cardiometabolic Diseases Through a Mendelian Randomization Study. J Am Coll Cardiol 67 (4): 407-416,2016.
Nurnberg ST, Zhang H, Hand NJ, Bauer RC, Saleheen D, Reilly MP, Rader DJ: From Loci to Biology: Functional Genomics of Genome-Wide Association for Coronary Disease. Circ Res 118 (4): 586-606,2016.
454. Pattaro C, Teumer A, Gorski M, Chu AY, Li M, Mijatovic V, Garnaas M, Tin A, Sorice R, Li Y, Taliun D, Olden M, Foster M, Yang Q, Chen MH, Pers TH, Johnson AD, Ko YA, Fuchsberger C, Tayo B, Nalls M, Feitosa MF, Isaacs A, Dehghan A, d'Adamo P, Adeyemo A, Dieffenbach AK, Zonderman AB, Nolte IM, van der Most PJ, Wright AF, Shuldiner AR, Morrison AC, Hofman A, Smith AV, Dreisbach AW, Franke A, Uitterlinden AG, Metspalu A, Tonjes A, Lupo A, Robino A, Johansson Å, Demirkan A, Kollerits B, Freedman BI, Ponte B: Genetic associations at 53 loci highlight cell types and biologica pathways relevant for kidney function. Nat Commun : 7,2016.
Clapham KR, Chu AY, Wessel J, Natarajan P, Flannick J, Rivas MA, Sartori S, Mehran R, Baber U, Fuster V, Scott RA, Rader DJ, Boehnke M, McCarthy MI, Altshuler DM, Kathiresan S, Peloso GM.: A null mutation in ANGPTL8 does not associate with either plasma glucose or type 2 diabetes in humans. BMC Endocr Disord 16 (1): 7,2016.
Kastelein JJ, Nissen SE, Rader DJ, Hovingh GK, Wang MD, Shen T, Krueger KA: Safety and efficacy of LY3015014, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9): a randomized, placebo-controlled Phase 2 study. Eur Heart J. : 2016.
Ibrahim S, Somanathan S, Billheimer J, Wilson JM, Rader DJ: Stable Liver-specific Expression of Human IDOL in Humanized Mice Raises Plasma Cholesterol. Cardiovasc Res. : 2016.
Wolf JH, Holmes MV, Fouraschen S, Keating BJ, Baker T, Emond J, Rader DJ, Shaked A, Olthoff KM: Serum lipid expression correlates with function and regeneration following living donor liver transplantation. Liver Transpl 22 (1): 103-101,2016.
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. : 2015.
Voight BF, Rader DJ: Human genetics shines a light on ischaemic stroke. Lancet Neurol. : 2015.
Khera AV, Millar JS, Ruotolo G, Wang MD, Rader DJ: Potent peroxisome proliferator-activated receptor-a agonist treatment increases cholesterol efflux capacity in humans with the metabolic syndrome. Eur Heart J 36 (42): 3020-3022,2015.
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