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 language | English (US) |
|---|---|
| Article number | e1002895 |
| Journal | PLoS genetics |
| Volume | 8 |
| Issue number | 8 |
| DOIs | |
| State | Published - Aug 1 2012 |
| Externally published | Yes |
ASJC Scopus subject areas
- Ecology, Evolution, Behavior and Systematics
- Molecular Biology
- Genetics
- Genetics(clinical)
- Cancer Research
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In: PLoS genetics, Vol. 8, No. 8, e1002895, 01.08.2012.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Genetic Modulation of Lipid Profiles following Lifestyle Modification or Metformin Treatment
T2 - The Diabetes Prevention Program
AU - Pollin, Toni I.
AU - Isakova, Tamara
AU - Jablonski, Kathleen A.
AU - de Bakker, Paul I.W.
AU - Taylor, Andrew
AU - McAteer, Jarred
AU - Pan, Qing
AU - Horton, Edward S.
AU - Delahanty, Linda M.
AU - Altshuler, David
AU - Shuldiner, Alan R.
AU - Goldberg, Ronald B.
AU - Florez, Jose C.
AU - Franks, Paul W.
AU - Bray, George A.
AU - Culbert, Iris W.
AU - Champagne, Catherine M.
AU - Eberhardt, Barbara
AU - Greenway, Frank
AU - Guillory, Fonda G.
AU - Herbert, April A.
AU - Jeffirs, Michael L.
AU - Kennedy, Betty M.
AU - Lovejoy, Jennifer C.
AU - Morris, Laura H.
AU - Melancon, Lee E.
AU - Ryan, Donna
AU - Sanford, Deborah A.
AU - Smith, Kenneth G.
AU - Smith, Lisa L.
AU - St. Amant, Julia A.
AU - Tulley, Richard T.
AU - Vicknair, Paula C.
AU - Williamson, Donald
AU - Zachwieja, Jeffery J.
AU - Polonsky, Kenneth S.
AU - Tobian, Janet
AU - Ehrmann, David
AU - Matulik, Margaret J.
AU - Clark, Bart
AU - Czech, Kirsten
AU - DeSandre, Catherine
AU - Hilbrich, Ruthanne
AU - McNabb, Wylie
AU - Semenske, Ann R.
AU - Caro, Jose F.
AU - Watson, Pamela G.
AU - Goldstein, Barry J.
AU - Smith, Kellie A.
AU - Mendoza, Jewel
AU - Liberoni, Renee
AU - Pepe, Constance
AU - Spandorfer, John
AU - Donahue, Richard P.
AU - Prineas, Ronald
AU - Rowe, Patricia
AU - Calles, Jeanette
AU - Cassanova-Romero, Paul
AU - Florez, Hermes J.
AU - Giannella, Anna
AU - Kirby, Lascelles
AU - Larreal, Carmen
AU - McLymont, Valerie
AU - Mendez, Jadell
AU - Ojito, Juliet
AU - Perry, Arlette
AU - Saab, Patrice
AU - Haffner, Steven M.
AU - Montez, Maria G.
AU - Lorenzo, Carlos
AU - Martinez, Arlene
AU - Hamman, Richard F.
AU - Nash, Patricia V.
AU - Testaverde, Lisa
AU - Anderson, Denise R.
AU - Ballonoff, Larry B.
AU - Bouffard, Alexis
AU - Calonge, B. Ned
AU - Delve, Lynne
AU - Farago, Martha
AU - Hill, James O.
AU - Hoyer, Shelley R.
AU - Jortberg, Bonnie T.
AU - Lenz, Dione
AU - Miller, Marsha
AU - Price, David W.
AU - Regensteiner, Judith G.
AU - Seagle, Helen
AU - Smith, Carissa M.
AU - Steinke, Sheila C.
AU - VanDorsten, Brent
AU - Horton, Edward S.
AU - Lawton, Kathleen E.
AU - Arky, Ronald A.
AU - Bryant, Marybeth
AU - Burke, Jacqueline P.
AU - Caballero, Enrique
AU - Callaphan, Karen M.
AU - Ganda, Om P.
AU - Franklin, Therese
AU - Jackson, Sharon D.
AU - Jacobsen, Alan M.
AU - Jacobsen, Alan M.
AU - Kula, Lyn M.
AU - Kocal, Margaret
AU - Malloy, Maureen A.
AU - Nicosia, Maryanne
AU - Oldmixon, Cathryn F.
AU - Pan, Jocelyn
AU - Quitingon, Marizel
AU - Rubtchinsky, Stacy
AU - Seely, Ellen W.
AU - Schweizer, Dana
AU - Simonson, Donald
AU - Smith, Fannie
AU - Solomon, Caren G.
AU - Warram, James
AU - Kahn, Steven E.
AU - Montgomery, Brenda K.
AU - Fujimoto, Wilfred
AU - Knopp, Robert H.
AU - Lipkin, Edward W.
AU - Marr, Michelle
AU - Trence, Dace
AU - Kitabchi, Abbas E.
AU - Murphy, Mary E.
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AU - Bryer-Ash, Michael
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AU - Lambeth, Helen
AU - Lichtermann, Lynne C.
AU - Oktaei, Hooman
AU - Rutledge, Lily M.K.
AU - Sherman, Amy R.
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AU - Soberman, Judith E.
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AU - Metzger, Boyd E.
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AU - Behrends, Catherine
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AU - Fitzgibbon, Marian
AU - Giles, Mimi M.
AU - Heard, Deloris
AU - Johnson, Cheryl K.H.
AU - Larsen, Diane
AU - Lowe, Anne
AU - Lyman, Megan
AU - McPherson, David
AU - Molitch, Mark E.
AU - Pitts, Thomas
AU - Reinhart, Renee
AU - Roston, Susan
AU - Schinleber, Pamela A.
AU - Nathan, David M.
AU - McKitrick, Charles
AU - Turgeon, Heather
AU - Abbott, Kathy
AU - Anderson, Ellen
AU - Bissett, Laurie
AU - Cagliero, Enrico
AU - Florez, Jose C.
AU - Delahanty, Linda
AU - Goldman, Valerie
AU - Poulos, Alexandra
AU - Olefsky, Jerrold M.
AU - Carrion-Petersen, Mary Lou
AU - Barrett-Connor, Elizabeth
AU - Edelman, Steven V.
AU - Henry, Robert R.
AU - Horne, Javiva
AU - Janesch, Simona Szerdi
AU - Leos, Diana
AU - Mudaliar, Sundar
AU - Polonsky, William
AU - Smith, Jean
AU - Vejvoda, Karen
AU - Pi-Sunyer, F. Xavier
AU - Lee, Jane E.
AU - Allison, David B.
AU - Aronoff, Nancy J.
AU - Crandall, Jill P.
AU - Foo, Sandra T.
AU - Pal, Carmen
AU - Parkes, Kathy
AU - Pena, Mary Beth
AU - Rooney, Ellen S.
AU - van Wye, Gretchen E.H.
AU - Viscovich, Kristine A.
AU - Marrero, David G.
AU - Prince, Melvin J.
AU - Kelly, Susie M.
AU - Dotson, Yolanda F.
AU - Fineberg, Edwin S.
AU - Guare, John C.
AU - Hadden, Angela M.
AU - Ignaut, James M.
AU - Jackson, Marcia L.
AU - Kirkman, Marion S.
AU - Mather, Kieren J.
AU - Porter, Beverly D.
AU - Roach, Paris J.
AU - Rowland, Nancy D.
AU - Wheeler, Madelyn L.
AU - Ratner, Robert E.
AU - Youssef, Gretchen
AU - Shapiro, Sue
AU - Bavido-Arrage, Catherine
AU - Boggs, Geraldine
AU - Bronsord, Marjorie
AU - Brown, Ernestine
AU - Cheatham, Wayman W.
AU - Cola, Susan
AU - Evans, Cindy
AU - Gibbs, Peggy
AU - Kellum, Tracy
AU - Levatan, Claresa
AU - Nair, Asha K.
AU - Passaro, Maureen
AU - Uwaifo, Gabriel
AU - Saad, Mohammed F.
AU - Budget, Maria
AU - Jinagouda, Sujata
AU - Akbar, Khan
AU - Conzues, Claudia
AU - Magpuri, Perpetua
AU - Ngo, Kathy
AU - Rassam, Amer
AU - Waters, Debra
AU - Xapthalamous, Kathy
AU - Santiago, Julio V.
AU - Dagogo-Jack, Samuel
AU - White, Neil H.
AU - Das, Samia
AU - Santiago, Ana
AU - Brown, Angela
AU - Fisher, Edwin
AU - Hurt, Emma
AU - Jones, Tracy
AU - Kerr, Michelle
AU - Ryder, Lucy
AU - Wernimont, Cormarie
AU - Saudek, Christopher D.
AU - Bradley, Vanessa
AU - Sullivan, Emily
AU - Whittington, Tracy
AU - Abbas, Caroline
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AU - Clark, Jeanne M.
AU - Charleston, Jeanne B.
AU - Freel, Janice
AU - Horak, Katherine
AU - Jiggetts, Dawn
AU - Johnson, Deloris
AU - Joseph, Hope
AU - Loman, Kimberly
AU - Mosley, Henry
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AU - Samuels, Alafia
AU - Stewart, Kerry J.
AU - Williamson, Paula
AU - Schade, David S.
AU - Adams, Karwyn S.
AU - Johannes, Carolyn
AU - Atler, Leslie F.
AU - Boyle, Patrick J.
AU - Burge, Mark R.
AU - Canady, Janene L.
AU - Chai, Lisa
AU - Gonzales, Ysela
AU - Hernandez-McGinnis, Doris A.
AU - Katz, Patricia
AU - King, Carolyn
AU - Rassam, Amer
AU - Rubinchik, Sofya
AU - Senter, Willette
AU - Waters, Debra
AU - Shamoon, Harry
AU - Brown, Janet O.
AU - Adorno, Elsie
AU - Cox, Liane
AU - Crandall, Jill
AU - Duffy, Helena
AU - Engel, Samuel
AU - Friedler, Allison
AU - Howard-Century, Crystal J.
AU - Kloiber, Stacey
AU - Longchamp, Nadege
AU - Martinez, Helen
AU - Pompi, Dorothy
AU - Scheindlin, Jonathan
AU - Violino, Elissa
AU - Walker, Elizabeth
AU - Wylie-Rosett, Judith
AU - Zimmerman, Elise
AU - Zonszein, Joel
AU - Orchard, Trevor
AU - Wing, Rena R.
AU - Koenning, Gaye
AU - Kramer, M. Kaye
AU - Barr, Susan
AU - Boraz, Miriam
AU - Clifford, Lisa
AU - Culyba, Rebecca
AU - Frazier, Marlene
AU - Gilligan, Ryan
AU - Harrier, Susan
AU - Harris, Louann
AU - Jeffries, Susan
AU - Kriska, Andrea
AU - Manjoo, Qurashia
AU - Mullen, Monica
AU - Noel, Alicia
AU - Otto, Amy
AU - Semler, Linda
AU - Smith, Cheryl F.
AU - Smith, Marie
AU - Venditti, Elizabeth
AU - Weinzierl, Valarie
AU - Williams, Katherine V.
AU - Wilson, Tara
AU - Arakaki, Richard F.
AU - Latimer, Renee W.
AU - Baker-Ladao, Narleen K.
AU - Beddow, Ralph
AU - Dias, Lorna
AU - Inouye, Jillian
AU - Mau, Marjorie K.
AU - Mikami, Kathy
AU - Mohideen, Pharis
AU - Odom, Sharon K.
AU - Perry, Raynette U.
AU - Knowler, William C.
AU - Cooeyate, Norman
AU - Hoskin, Mary A.
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AU - Begay, Shandiin
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AU - Benson, Mary Beth
AU - Bird, Evelyn C.
AU - Broussard, Brenda A.
AU - Chavez, Marcella
AU - Dacawyma, Tara
AU - Doughty, Matthew S.
AU - Duncan, Roberta
AU - Edgerton, Cyndy
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AU - Glass, Justin
AU - Glass, Martia
AU - Gohdes, Dorothy
AU - Grant, Wendy
AU - Hanson, Robert L.
AU - Horse, Ellie
AU - Ingraham, Louise E.
AU - Jackson, Merry
AU - Jay, Priscilla
AU - Kaskalla, Roylen S.
AU - Kessler, David
AU - Kobus, Kathleen M.
AU - Krakoff, Jonathan
AU - Manus, Catherine
AU - Michaels, Sara
AU - Morgan, Tina
AU - Nashboo, Yolanda
AU - Nelson, Julie A.
AU - Poirier, Steven
AU - Polczynski, Evette
AU - Reidy, Mike
AU - Roumain, Jeanine
AU - Rowse, Debra
AU - Sangster, Sandra
AU - Sewenemewa, Janet
AU - Tonemah, Darryl
AU - Wilson, Charlton
AU - Yazzie, Michelle
AU - Bain, Raymond
AU - Fowler, Sarah
AU - Brenneman, Tina
AU - Abebe, Solome
AU - Bamdad, Julie
AU - Callaghan, Jackie
AU - Edelstein, Sharon L.
AU - Gao, Yuping
AU - Grimes, Kristina L.
AU - Grover, Nisha
AU - Haffner, Lori
AU - Jones, Steve
AU - Jones, Tara L.
AU - Katz, Richard
AU - Lachin, John M.
AU - Mucik, Pamela
AU - Orlosky, Robert
AU - Rochon, James
AU - Sapozhnikova, Alla
AU - Sherif, Hanna
AU - Stimpson, Charlotte
AU - Temprosa, Marinella
AU - Walker-Murray, Fredricka
AU - Marcovina, Santica
AU - Strylewicz, Greg
AU - Aldrich, F. Alan
AU - O'Leary, Dan
AU - Stamm, Elizabeth
AU - Rautaharju, Pentti
AU - Prineas, Ronald J.
AU - Alexander, Teresa
AU - Campbell, Charles
AU - Hall, Sharon
AU - Li, Yabing
AU - Mills, Margaret
AU - Pemberton, Nancy
AU - Rautaharju, Farida
AU - Zhang, Zhuming
AU - Mayer-Davis, Elizabeth
AU - Moran, Robert R.
AU - Ganiats, Ted
AU - David, Kristin
AU - Sarkin, Andrew J.
AU - Eastman, R.
AU - Fradkin, Judith
AU - Garfield, Sanford
AU - Gregg, Edward
AU - Zhang, Ping
AU - Herman, William
AU - Florez, Jose C.
AU - de Bakker, Paul I.W.
AU - Franks, Paul W.
AU - Hanson, Robert L.
AU - Jablonski, Kathleen
AU - Knowler, William C.
AU - McAteer, Jarred B.
AU - Pollin, Toni I.
AU - Shuldiner, Alan R.
N1 - Funding Information: TIP has been a consultant for Isis Pharmaceuticals. TI has received a research grant from NIDDK and honoraria from Shire and Genzyme and has been a consultant for Shire. KAJ (the DPP Genetics Program) has a research grant from NIH. DA has received a research grant from Pfizer and honoraria from academic non-profit (e.g. talks) and has been a consultant for Eisai, MPM Capital, and NanoString. ARS has a NIH research grant. RBG has a research grant from NIH for this study; speaker honoraria from Merck; other research support from Bristol Myers Squibb, GSK, and Roche; and small consultant activities. JCF has received consulting honoraria from Daiichi-Sankyo and AstraZeneca. PWF has received speaking honoraria from Novo Nordisk and other academic/non-profit organisations.
PY - 2012/8/1
Y1 - 2012/8/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84866155075&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84866155075&partnerID=8YFLogxK
U2 - 10.1371/journal.pgen.1002895
DO - 10.1371/journal.pgen.1002895
M3 - Article
C2 - 22951888
AN - SCOPUS:84866155075
SN - 1553-7390
VL - 8
JO - PLoS genetics
JF - PLoS genetics
IS - 8
M1 - e1002895
ER -