Genetic Modulation of Lipid Profiles following Lifestyle Modification or Metformin Treatment: The Diabetes Prevention Program

Toni I. Pollin, Tamara Isakova, Kathleen A. Jablonski, Paul I.W. de Bakker, Andrew Taylor, Jarred McAteer, Qing Pan, Edward S. Horton, Linda M. Delahanty, David Altshuler, Alan R. Shuldiner, Ronald B. Goldberg, Jose C. Florez, Paul W. Franks, George A. Bray, Iris W. Culbert, Catherine M. Champagne, Barbara Eberhardt, Frank Greenway, Fonda G. GuilloryApril A. Herbert, Michael L. Jeffirs, Betty M. Kennedy, Jennifer C. Lovejoy, Laura H. Morris, Lee E. Melancon, Donna Ryan, Deborah A. Sanford, Kenneth G. Smith, Lisa L. Smith, Julia A. St. Amant, Richard T. Tulley, Paula C. Vicknair, Donald Williamson, Jeffery J. Zachwieja, Kenneth S. Polonsky, Janet Tobian, David Ehrmann, Margaret J. Matulik, Bart Clark, Kirsten Czech, Catherine DeSandre, Ruthanne Hilbrich, Wylie McNabb, Ann R. Semenske, Jose F. Caro, Pamela G. Watson, Barry J. Goldstein, Kellie A. Smith, Jewel Mendoza, Renee Liberoni, Constance Pepe, John Spandorfer, Richard P. Donahue, Ronald B. Goldberg, Ronald Prineas, Patricia Rowe, Jeanette Calles, Paul Cassanova-Romero, Hermes J. Florez, Anna Giannella, Lascelles Kirby, Carmen Larreal, Valerie McLymont, Jadell Mendez, Juliet Ojito, Arlette Perry, Patrice Saab, Steven M. Haffner, Maria G. Montez, Carlos Lorenzo, Arlene Martinez, Richard F. Hamman, Patricia V. Nash, Lisa Testaverde, Denise R. Anderson, Larry B. Ballonoff, Alexis Bouffard, B. Ned Calonge, Lynne Delve, Martha Farago, James O. Hill, Shelley R. Hoyer, Bonnie T. Jortberg, Dione Lenz, Marsha Miller, David W. Price, Judith G. Regensteiner, Helen Seagle, Carissa M. Smith, Sheila C. Steinke, Brent VanDorsten, Edward S. Horton, Kathleen E. Lawton, Ronald A. Arky, Marybeth Bryant, Jacqueline P. Burke, Enrique Caballero, Karen M. Callaphan, Om P. Ganda, Therese Franklin, Sharon D. Jackson, Alan M. Jacobsen, Alan M. Jacobsen, Lyn M. Kula, Margaret Kocal, Maureen A. Malloy, Maryanne Nicosia, Cathryn F. Oldmixon, Jocelyn Pan, Marizel Quitingon, Stacy Rubtchinsky, Ellen W. Seely, Dana Schweizer, Donald Simonson, Fannie Smith, Caren G. Solomon, James Warram, Steven E. Kahn, Brenda K. Montgomery, Wilfred Fujimoto, Robert H. Knopp, Edward W. Lipkin, Michelle Marr, Dace Trence, Abbas E. Kitabchi, Mary E. Murphy, William B. Applegate, Michael Bryer-Ash, Sandra L. Frieson, Raed Imseis, Helen Lambeth, Lynne C. Lichtermann, Hooman Oktaei, Lily M.K. Rutledge, Amy R. Sherman, Clara M. Smith, Judith E. Soberman, Beverly Williams-Cleaves, Boyd E. Metzger, Mariana K. Johnson, Catherine Behrends, Michelle Cook, Marian Fitzgibbon, Mimi M. Giles, Deloris Heard, Cheryl K.H. Johnson, Diane Larsen, Anne Lowe, Megan Lyman, David McPherson, Mark E. Molitch, Thomas Pitts, Renee Reinhart, Susan Roston, Pamela A. Schinleber, David M. Nathan, Charles McKitrick, Heather Turgeon, Kathy Abbott, Ellen Anderson, Laurie Bissett, Enrico Cagliero, Jose C. Florez, Linda Delahanty, Valerie Goldman, Alexandra Poulos, Jerrold M. Olefsky, Mary Lou Carrion-Petersen, Elizabeth Barrett-Connor, Steven V. Edelman, Robert R. Henry, Javiva Horne, Simona Szerdi Janesch, Diana Leos, Sundar Mudaliar, William Polonsky, Jean Smith, Karen Vejvoda, F. Xavier Pi-Sunyer, Jane E. Lee, David B. Allison, Nancy J. Aronoff, Jill P. Crandall, Sandra T. Foo, Carmen Pal, Kathy Parkes, Mary Beth Pena, Ellen S. Rooney, Gretchen E.H. van Wye, Kristine A. Viscovich, David G. Marrero, Melvin J. Prince, Susie M. Kelly, Yolanda F. Dotson, Edwin S. Fineberg, John C. Guare, Angela M. Hadden, James M. Ignaut, Marcia L. Jackson, Marion S. Kirkman, Kieren J. Mather, Beverly D. Porter, Paris J. Roach, Nancy D. Rowland, Madelyn L. Wheeler, Robert E. Ratner, Gretchen Youssef, Sue Shapiro, Catherine Bavido-Arrage, Geraldine Boggs, Marjorie Bronsord, Ernestine Brown, Wayman W. Cheatham, Susan Cola, Cindy Evans, Peggy Gibbs, Tracy Kellum, Claresa Levatan, Asha K. Nair, Maureen Passaro, Gabriel Uwaifo, Mohammed F. Saad, Maria Budget, Sujata Jinagouda, Khan Akbar, Claudia Conzues, Perpetua Magpuri, Kathy Ngo, Amer Rassam, Debra Waters, Kathy Xapthalamous, Julio V. Santiago, Samuel Dagogo-Jack, Neil H. White, Samia Das, Ana Santiago, Angela Brown, Edwin Fisher, Emma Hurt, Tracy Jones, Michelle Kerr, Lucy Ryder, Cormarie Wernimont, Christopher D. Saudek, Vanessa Bradley, Emily Sullivan, Tracy Whittington, Caroline Abbas, Frederick L. Brancati, Jeanne M. Clark, Jeanne B. Charleston, Janice Freel, Katherine Horak, Dawn Jiggetts, Deloris Johnson, Hope Joseph, Kimberly Loman, Henry Mosley, Richard R. Rubin, Alafia Samuels, Kerry J. Stewart, Paula Williamson, David S. Schade, Karwyn S. Adams, Carolyn Johannes, Leslie F. Atler, Patrick J. Boyle, Mark R. Burge, Janene L. Canady, Lisa Chai, Ysela Gonzales, Doris A. Hernandez-McGinnis, Patricia Katz, Carolyn King, Amer Rassam, Sofya Rubinchik, Willette Senter, Debra Waters, Harry Shamoon, Janet O. Brown, Elsie Adorno, Liane Cox, Jill Crandall, Helena Duffy, Samuel Engel, Allison Friedler, Crystal J. Howard-Century, Stacey Kloiber, Nadege Longchamp, Helen Martinez, Dorothy Pompi, Jonathan Scheindlin, Elissa Violino, Elizabeth Walker, Judith Wylie-Rosett, Elise Zimmerman, Joel Zonszein, Trevor Orchard, Rena R. Wing, Gaye Koenning, M. Kaye Kramer, Susan Barr, Miriam Boraz, Lisa Clifford, Rebecca Culyba, Marlene Frazier, Ryan Gilligan, Susan Harrier, Louann Harris, Susan Jeffries, Andrea Kriska, Qurashia Manjoo, Monica Mullen, Alicia Noel, Amy Otto, Linda Semler, Cheryl F. Smith, Marie Smith, Elizabeth Venditti, Valarie Weinzierl, Katherine V. Williams, Tara Wilson, Richard F. Arakaki, Renee W. Latimer, Narleen K. Baker-Ladao, Ralph Beddow, Lorna Dias, Jillian Inouye, Marjorie K. Mau, Kathy Mikami, Pharis Mohideen, Sharon K. Odom, Raynette U. Perry, William C. Knowler, Norman Cooeyate, Mary A. Hoskin, Carol A. Percy, Kelly J. Acton, Vickie L. Andre, Rosalyn Barber, Shandiin Begay, Peter H. Bennett, Mary Beth Benson, Evelyn C. Bird, Brenda A. Broussard, Marcella Chavez, Tara Dacawyma, Matthew S. Doughty, Roberta Duncan, Cyndy Edgerton, Jacqueline M. Ghahate, Justin Glass, Martia Glass, Dorothy Gohdes, Wendy Grant, Robert L. Hanson, Ellie Horse, Louise E. Ingraham, Merry Jackson, Priscilla Jay, Roylen S. Kaskalla, David Kessler, Kathleen M. Kobus, Jonathan Krakoff, Catherine Manus, Sara Michaels, Tina Morgan, Yolanda Nashboo, Julie A. Nelson, Steven Poirier, Evette Polczynski, Mike Reidy, Jeanine Roumain, Debra Rowse, Sandra Sangster, Janet Sewenemewa, Darryl Tonemah, Charlton Wilson, Michelle Yazzie, Raymond Bain, Sarah Fowler, Tina Brenneman, Solome Abebe, Julie Bamdad, Jackie Callaghan, Sharon L. Edelstein, Yuping Gao, Kristina L. Grimes, Nisha Grover, Lori Haffner, Steve Jones, Tara L. Jones, Richard Katz, John M. Lachin, Pamela Mucik, Robert Orlosky, James Rochon, Alla Sapozhnikova, Hanna Sherif, Charlotte Stimpson, Marinella Temprosa, Fredricka Walker-Murray, Santica Marcovina, Greg Strylewicz, F. Alan Aldrich, Dan O'Leary, Elizabeth Stamm, Pentti Rautaharju, Ronald J. Prineas, Teresa Alexander, Charles Campbell, Sharon Hall, Yabing Li, Margaret Mills, Nancy Pemberton, Farida Rautaharju, Zhuming Zhang, Elizabeth Mayer-Davis, Robert R. Moran, Ted Ganiats, Kristin David, Andrew J. Sarkin, R. Eastman, Judith Fradkin, Sanford Garfield, Edward Gregg, Ping Zhang, William Herman, Jose C. Florez, David Altshuler, Paul I.W. de Bakker, Paul W. Franks, Robert L. Hanson, Kathleen Jablonski, William C. Knowler, Jarred B. McAteer, Toni I. Pollin, Alan R. Shuldiner

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Weight-loss interventions generally improve lipid profiles and reduce cardiovascular disease risk, but effects are variable and may depend on genetic factors. We performed a genetic association analysis of data from 2,993 participants in the Diabetes Prevention Program to test the hypotheses that a genetic risk score (GRS) based on deleterious alleles at 32 lipid-associated single-nucleotide polymorphisms modifies the effects of lifestyle and/or metformin interventions on lipid levels and nuclear magnetic resonance (NMR) lipoprotein subfraction size and number. Twenty-three loci previously associated with fasting LDL-C, HDL-C, or triglycerides replicated (P = 0.04-1×10-17). Except for total HDL particles (r = -0.03, P = 0.26), all components of the lipid profile correlated with the GRS (partial {pipe}r{pipe} = 0.07-0.17, P = 5×10-5-1×10-19). The GRS was associated with higher baseline-adjusted 1-year LDL cholesterol levels (β = +0.87, SEE±0.22 mg/dl/allele, P = 8×10-5, Pinteraction = 0.02) in the lifestyle intervention group, but not in the placebo (β = +0.20, SEE±0.22 mg/dl/allele, P = 0.35) or metformin (β = -0.03, SEE±0.22 mg/dl/allele, P = 0.90; Pinteraction = 0.64) groups. Similarly, a higher GRS predicted a greater number of baseline-adjusted small LDL particles at 1 year in the lifestyle intervention arm (β = +0.30, SEE±0.012 ln nmol/L/allele, P = 0.01, Pinteraction = 0.01) but not in the placebo (β = -0.002, SEE±0.008 ln nmol/L/allele, P = 0.74) or metformin (β = +0.013, SEE±0.008 nmol/L/allele, P = 0.12; Pinteraction = 0.24) groups. Our findings suggest that a high genetic burden confers an adverse lipid profile and predicts attenuated response in LDL-C levels and small LDL particle number to dietary and physical activity interventions aimed at weight loss.

Original languageEnglish (US)
Article numbere1002895
JournalPLoS genetics
Volume8
Issue number8
DOIs
StatePublished - Aug 1 2012

    Fingerprint

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Pollin, T. I., Isakova, T., Jablonski, K. A., de Bakker, P. I. W., Taylor, A., McAteer, J., Pan, Q., Horton, E. S., Delahanty, L. M., Altshuler, D., Shuldiner, A. R., Goldberg, R. B., Florez, J. C., Franks, P. W., Bray, G. A., Culbert, I. W., Champagne, C. M., Eberhardt, B., Greenway, F., ... Shuldiner, A. R. (2012). Genetic Modulation of Lipid Profiles following Lifestyle Modification or Metformin Treatment: The Diabetes Prevention Program. PLoS genetics, 8(8), [e1002895]. https://doi.org/10.1371/journal.pgen.1002895