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Diabetes. 2008 Sep;57(9):2503-10. doi: 10.2337/db08-0284. Epub 2008 Jun 10.

Extension of type 2 diabetes genome-wide association scan results in the diabetes prevention program.

Collaborators (402)

Bray GA, Culbert IW, Champagne CM, Eberhardt B, Greenway F, Guillory FG, Herbert AA, Jeffirs ML, Kennedy BM, Lovejoy JC, Morris LH, 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, Hillbrich 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 BN, 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, 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 FX, Lee JE, Allison DB, Aronoff N, 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 J, 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, Alter 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 MK, 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, Michales 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 S, 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 FA, Eastman R, Fradkin J, Garfield S, Florez JC, Altshuler D, de Bakker PI, Franks P, Hanson RL, Jablonski K, Knowler WC, McAteer J, Pollin TI, Shuldiner AR.

Author information

  • 1Center for Human Genetic Research, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.

Abstract

OBJECTIVE:

Genome-wide association scans (GWASs) have identified novel diabetes-associated genes. We evaluated how these variants impact diabetes incidence, quantitative glycemic traits, and response to preventive interventions in 3,548 subjects at high risk of type 2 diabetes enrolled in the Diabetes Prevention Program (DPP), which examined the effects of lifestyle intervention, metformin, and troglitazone versus placebo.

RESEARCH DESIGN AND METHODS:

We genotyped selected single nucleotide polymorphisms (SNPs) in or near diabetes-associated loci, including EXT2, CDKAL1, CDKN2A/B, IGF2BP2, HHEX, LOC387761, and SLC30A8 in DPP participants and performed Cox regression analyses using genotype, intervention, and their interactions as predictors of diabetes incidence. We evaluated their effect on insulin resistance and secretion at 1 year.

RESULTS:

None of the selected SNPs were associated with increased diabetes incidence in this population. After adjustments for ethnicity, baseline insulin secretion was lower in subjects with the risk genotype at HHEX rs1111875 (P = 0.01); there were no significant differences in baseline insulin sensitivity. Both at baseline and at 1 year, subjects with the risk genotype at LOC387761 had paradoxically increased insulin secretion; adjustment for self-reported ethnicity abolished these differences. In ethnicity-adjusted analyses, we noted a nominal differential improvement in beta-cell function for carriers of the protective genotype at CDKN2A/B after 1 year of troglitazone treatment (P = 0.01) and possibly lifestyle modification (P = 0.05).

CONCLUSIONS:

We were unable to replicate the GWAS findings regarding diabetes risk in the DPP. We did observe genotype associations with differences in baseline insulin secretion at the HHEX locus and a possible pharmacogenetic interaction at CDKNA2/B.

PMID:
18544707
[PubMed - indexed for MEDLINE]
PMCID:
PMC2518503
Free PMC Article
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