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PLoS One. 2012;7(9):e44424. doi: 10.1371/journal.pone.0044424. Epub 2012 Sep 11.

Effects of genetic variants previously associated with fasting glucose and insulin in the Diabetes Prevention Program.

Collaborators (424)

Bray GA, Culbert IW, Champagne CM, Eberhardt B, Greenway F, Guillory FG, Herbert AA, Jeffirs ML, Kennedy BM, Lovejoy JC, Morris LH, Melancon LE, Ryan D, Sanford DA, Smith KG, Smith LL, St Amant JA, Tulley RT, Vicknair PC, Williamson D, Zachwieja JJ, Polonsky KS, Tobian J, Ehrmann D, Matulik MJ, Clark B, Czech K, DeSandre C, Hilbrich R, McNabb W, Semenske AR, Caro JF, Watson PG, Goldstein BJ, Smith KA, Mendoza J, Liberoni R, Pepe C, Spandorfer J, Donahue RP, Goldberg RB, Prineas R, Rowe P, Calles J, Cassanova-Romero P, Florez HJ, Giannella A, Kirby L, Larreal C, McLymont V, Mendez J, Ojito J, Perry A, Saab P, Haffner SM, Montez MG, Lorenzo C, Martinez A, Hamman RF, Nash PV, Testaverde L, Anderson DR, Ballonoff LB, Bouffard A, Calonge B, Delve L, Farago M, Hill JO, Hoyer SR, Jortberg BT, Lenz D, Miller M, Price DW, Regensteiner JG, Seagle H, Smith CM, Steinke SC, VanDorsten B, Horton ES, Lawton KE, Arky RA, Bryant M, Burke JP, Caballero E, Callaphan KM, Ganda OP, Franklin T, Jackson SD, Jacobsen AM, Kula LM, Kocal M, Malloy MA, Nicosia M, Oldmixon CF, Pan J, Quitingon M, Rubtchinsky S, Seely EW, Schweizer D, Simonson D, Smith F, Solomon CG, Warram J, Kahn SE, Montgomery BK, Fujimoto W, Knopp RH, Lipkin EW, Marr M, Trence D, Kitabchi AE, Murphy ME, Applegate WB, Bryer-Ash M, Frieson SL, Imseis R, Lambeth H, Lichtermann LC, Oktaei H, Rutledge LM, Sherman AR, Smith CM, Soberman JE, Williams-Cleaves B, Metzger BE, Johnson MK, Behrends C, Cook M, Fitzgibbon M, Giles MM, Heard D, Johnson CK, Larsen D, Lowe A, Lyman M, McPherson D, Molitch ME, Pitts T, Reinhart R, Roston S, Schinleber PA, Nathan DM, McKitrick C, Turgeon H, Abbott K, Anderson E, Bissett L, Cagliero E, Florez JC, Delahanty L, Goldman V, Poulos A, Olefsky JM, Carrion-Petersen ML, Barrett-Connor E, Edelman SV, Henry RR, Horne J, Janesch SS, Leos D, Mudaliar S, Polonsky W, Smith J, Vejvoda K, Pi-Sunyer F, Lee JE, Allison DB, Aronoff NJ, Crandall JP, Foo ST, Pal C, Parkes K, Pena MB, Rooney ES, Van Wye GE, Viscovich KA, Marrero DG, Prince MJ, Kelly SM, Dotson YF, Fineberg ES, Guare JC, Hadden AM, Ignaut JM, Jackson ML, Kirkman MS, Mather KJ, Porter BD, Roach PJ, Rowland ND, Wheeler ML, Ratner RE, Youssef G, Shapiro S, Bavido-Arrage C, Boggs G, Bronsord M, Brown E, Cheatham WW, Cola S, Evans C, Gibbs P, Kellum T, Levatan C, Nair AK, Passaro M, Uwaifo G, Saad MF, Budget M, Jinagouda S, Akbar K, Conzues C, Magpuri P, Ngo K, Rassam A, Waters D, Xapthalamous K, Santiago JV, Dagogo-Jack S, White NH, Das S, Santiago A, Brown A, Fisher E, Hurt E, Jones T, Kerr M, Ryder L, Wernimont C, Saudek CD, Bradley V, Sullivan E, Whittington T, Abbas C, Brancati FL, Clark JM, Charleston JB, Freel J, Horak K, Jiggetts D, Johnson D, Joseph H, Loman K, Mosley H, Rubin RR, Samuels A, Stewart KJ, Williamson P, Schade DS, Adams KS, Johannes C, Atler LF, Boyle PJ, Burge MR, Canady JL, Chai L, Gonzales Y, Hernandez-McGinnis DA, Katz P, King C, Rassam A, Rubinchik S, Senter W, Waters D, Shamoon H, Brown JO, Adorno E, Cox L, Crandall J, Duffy H, Engel S, Friedler A, Howard-Century CJ, Kloiber S, Longchamp N, Martinez H, Pompi D, Scheindlin J, Violino E, Walker E, Wylie-Rosett J, Zimmerman E, Zonszein J, Orchard T, Wing RR, Koenning G, Kramer M, Barr S, Boraz M, Clifford L, Culyba R, Frazier M, Gilligan R, Harrier S, Harris L, Jeffries S, Kriska A, Manjoo Q, Mullen M, Noel A, Otto A, Semler L, Smith CF, Smith M, Venditti E, Weinzierl V, Williams KV, Wilson T, Arakaki RF, Latimer RW, Baker-Ladao NK, Beddow R, Dias L, Inouye J, Mau MK, Mikami K, Mohideen P, Odom SK, Perry RU, Knowler WC, Cooeyate N, Hoskin MA, Percy CA, Acton KJ, Andre VL, Barber R, Begay S, Bennett PH, Benson MB, Bird EC, Broussard BA, Chavez M, Dacawyma T, Doughty MS, Duncan R, Edgerton C, Ghahate JM, Glass J, Glass M, Gohdes D, Grant W, Hanson RL, Horse E, Ingraham LE, Jackson M, Jay P, Kaskalla RS, Kessler D, Kobus KM, Krakoff J, Manus C, Michaels S, Morgan T, Nashboo Y, Nelson JA, Poirier S, Polczynski E, Reidy M, Roumain J, Rowse D, Sangster S, Sewenemewa J, Tonemah D, Wilson C, Yazzie M, Bain R, Fowler S, Brenneman T, Abebe S, Bamdad J, Callaghan J, Edelstein SL, Gao Y, Grimes KL, Grover N, Haffner L, Jones S, Jones TL, Katz R, Lachin JM, Mucik P, Orlosky R, Rochon J, Sapozhnikova A, Sherif H, Stimpson C, Temprosa M, Walker-Murray F, Marcovina S, Strylewicz G, Aldrich F, O'Leary D, Stamm E, Rautaharju P, Prineas RJ, Alexander T, Campbell C, Hall S, Li Y, Mills M, Pemberton N, Rautaharju F, Zhang Z, Mayer-Davis E, Moran RR, Ganiats T, David K, Sarkin AJ, Eastman R, Fradkin J, Garfield S, Gregg E, Zhang P, Herman WH, Florez JC, Altshuler D, de Bakker PI, Franks PW, Hanson RL, Jablonski K, Knowler WC, McAteer JB, Pollin TI, Shuldiner AR.

Author information

1
Center for Human Genetic Research and Diabetes Research Center, Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts, United States of America. jcflorez@partners.org

Abstract

Common genetic variants have been recently associated with fasting glucose and insulin levels in white populations. Whether these associations replicate in pre-diabetes is not known. We extended these findings to the Diabetes Prevention Program, a clinical trial in which participants at high risk for diabetes were randomized to placebo, lifestyle modification or metformin for diabetes prevention. We genotyped previously reported polymorphisms (or their proxies) in/near G6PC2, MTNR1B, GCK, DGKB, GCKR, ADCY5, MADD, CRY2, ADRA2A, FADS1, PROX1, SLC2A2, GLIS3, C2CD4B, IGF1, and IRS1 in 3,548 Diabetes Prevention Program participants. We analyzed variants for association with baseline glycemic traits, incident diabetes and their interaction with response to metformin or lifestyle intervention. We replicated associations with fasting glucose at MTNR1B (P<0.001), G6PC2 (P = 0.002) and GCKR (P = 0.001). We noted impaired β-cell function in carriers of glucose-raising alleles at MTNR1B (P<0.001), and an increase in the insulinogenic index for the glucose-raising allele at G6PC2 (P<0.001). The association of MTNR1B with fasting glucose and impaired β-cell function persisted at 1 year despite adjustment for the baseline trait, indicating a sustained deleterious effect at this locus. We also replicated the association of MADD with fasting proinsulin levels (P<0.001). We detected no significant impact of these variants on diabetes incidence or interaction with preventive interventions. The association of several polymorphisms with quantitative glycemic traits is replicated in a cohort of high-risk persons. These variants do not have a detectable impact on diabetes incidence or response to metformin or lifestyle modification in the Diabetes Prevention Program.

PMID:
22984506
PMCID:
PMC3439414
DOI:
10.1371/journal.pone.0044424
[Indexed for MEDLINE]
Free PMC Article

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