TY - JOUR
T1 - New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk
AU - Dupuis, Josee
AU - Langenberg, Claudia
AU - Prokopenko, Inga
AU - Saxena, Richa
AU - Soranzo, Nicole
AU - Jackson, Anne U.
AU - Wheeler, Eleanor
AU - Glazer, Nicole L.
AU - Bouatia-Naji, Nabila
AU - Gloyn, Anna L.
AU - Lindgren, Cecilia M.
AU - Magi, Reedik
AU - Morris, Andrew P.
AU - Randall, Joshua
AU - Johnson, Toby
AU - Elliott, Paul
AU - Rybin, Denis
AU - Thorleifsson, Gudmar
AU - Steinthorsdottir, Valgerdur
AU - Henneman, Peter
AU - Grallert, Harald
AU - Dehghan, Abbas
AU - Hottenga, Jouke Jan
AU - Franklin, Christopher S.
AU - Navarro, Pau
AU - Song, Kijoung
AU - Goel, Anuj
AU - Perry, John R. B.
AU - Egan, Josephine M.
AU - Lajunen, Taina
AU - Grarup, Niels
AU - Sparso, Thomas
AU - Doney, Alex
AU - Voight, Benjamin F.
AU - Stringham, Heather M.
AU - Li, Man
AU - Kanoni, Stavroula
AU - Shrader, Peter
AU - Cavalcanti-Proenca, Christine
AU - Kumari, Meena
AU - Qi, Lu
AU - Timpson, Nicholas J.
AU - Ben-Shlomo, Yoav
AU - Day, Ian N. M.
AU - Johnson, Paul R. V.
AU - Kivimaki, Mika
AU - Lawlor, Debbie A.
AU - Smith, George Davey
AU - Palmer, Lyle J.
AU - Ebrahim, Shah
AU - DIAGRAM Consortium
AU - GIANT Consortium
AU - Global BPgen Consortium
AU - Anders Hamsten Procardis Consortiu
AU - MAGIC Investigators
PY - 2010/2
Y1 - 2010/2
N2 - Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.
AB - Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.
KW - GENOME-WIDE ASSOCIATION
KW - BETA-CELL DYSFUNCTION
KW - PLASMA-GLUCOSE
KW - INSULIN-SECRETION
KW - TRIGLYCERIDE LEVELS
KW - ESSENTIAL COMPONENTS
KW - MODEL ASSESSMENT
KW - COMMON VARIANTS
KW - CIRCADIAN CLOCK
KW - DISEASE RISK
U2 - 10.1038/ng.520
DO - 10.1038/ng.520
M3 - Article (Academic Journal)
C2 - 20081858
VL - 42
SP - 105-U32
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 2
ER -