Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge.
Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies (n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci (n = 6,958-30,620). We identify variants at the GIPR locus associated with 2-h glucose level (rs10423928, beta (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 x 10(-15)). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 x 10(-17); ratio of insulin to glucose area under the curve, P = 1.3 x 10(-16)) and diminished incretin effect (n = 804; P = 4.3 x 10(-4)). We also identified variants at ADCY5 (rs2877716, P = 4.2 x 10(-16)), VPS13C (rs17271305, P = 4.1 x 10(-8)), GCKR (rs1260326, P = 7.1 x 10(-11)) and TCF7L2 (rs7903146, P = 4.2 x 10(-10)) associated with 2-h glucose. Of the three newly implicated loci (GIPR, ADCY5 and VPS13C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09-1.15, P = 4.8 x 10(-18)).
Saxena
Richa
R
Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Hivert
Marie-France
MF
Langenberg
Claudia
C
Tanaka
Toshiko
T
Pankow
James S
JS
Vollenweider
Peter
P
Lyssenko
Valeriya
V
Bouatia-Naji
Nabila
N
Dupuis
Josée
J
Jackson
Anne U
AU
Kao
W H Linda
WH
Li
Man
M
Glazer
Nicole L
NL
Manning
Alisa K
AK
Luan
Jian'an
J
Stringham
Heather M
HM
Prokopenko
Inga
I
Johnson
Toby
T
Grarup
Niels
N
Boesgaard
Trine W
TW
Lecoeur
Cécile
C
Shrader
Peter
P
O'Connell
Jeffrey
J
Ingelsson
Erik
E
Couper
David J
DJ
Rice
Kenneth
K
Song
Kijoung
K
Andreasen
Camilla H
CH
Dina
Christian
C
Köttgen
Anna
A
Le Bacquer
Olivier
O
Pattou
François
F
Taneera
Jalal
J
Steinthorsdottir
Valgerdur
V
Rybin
Denis
D
Ardlie
Kristin
K
Sampson
Michael
M
Qi
Lu
L
van Hoek
Mandy
M
Weedon
Michael N
MN
Aulchenko
Yurii S
YS
Voight
Benjamin F
BF
Grallert
Harald
H
Balkau
Beverley
B
Bergman
Richard N
RN
Bielinski
Suzette J
SJ
Bonnefond
Amelie
A
Bonnycastle
Lori L
LL
Borch-Johnsen
Knut
K
Böttcher
Yvonne
Y
Brunner
Eric
E
Buchanan
Thomas A
TA
Bumpstead
Suzannah J
SJ
Cavalcanti-Proença
Christine
C
Charpentier
Guillaume
G
Chen
Yii-Der Ida
YD
Chines
Peter S
PS
Collins
Francis S
FS
Cornelis
Marilyn
M
J Crawford
Gabriel
G
Delplanque
Jerome
J
Doney
Alex
A
Egan
Josephine M
JM
Erdos
Michael R
MR
Firmann
Mathieu
M
Forouhi
Nita G
NG
Fox
Caroline S
CS
Goodarzi
Mark O
MO
Graessler
Jürgen
J
Hingorani
Aroon
A
Isomaa
Bo
B
Jørgensen
Torben
T
Kivimaki
Mika
M
Kovacs
Peter
P
Krohn
Knut
K
Kumari
Meena
M
Lauritzen
Torsten
T
Lévy-Marchal
Claire
C
Mayor
Vladimir
V
McAteer
Jarred B
JB
Meyre
David
D
Mitchell
Braxton D
BD
Mohlke
Karen L
KL
Morken
Mario A
MA
Narisu
Narisu
N
Palmer
Colin N A
CN
Pakyz
Ruth
R
Pascoe
Laura
L
Payne
Felicity
F
Pearson
Daniel
D
Rathmann
Wolfgang
W
Sandbaek
Annelli
A
Sayer
Avan Aihie
AA
Scott
Laura J
LJ
Sharp
Stephen J
SJ
Sijbrands
Eric
E
Singleton
Andrew
A
Siscovick
David S
DS
Smith
Nicholas L
NL
Sparsø
Thomas
T
Swift
Amy J
AJ
Syddall
Holly
H
Thorleifsson
Gudmar
G
Tönjes
Anke
A
Tuomi
Tiinamaija
T
Tuomilehto
Jaakko
J
Valle
Timo T
TT
Waeber
Gérard
G
Walley
Andrew
A
Waterworth
Dawn M
DM
Zeggini
Eleftheria
E
Zhao
Jing Hua
JH
Illig
Thomas
T
Wichmann
H Erich
HE
Wilson
James F
JF
van Duijn
Cornelia
C
Hu
Frank B
FB
Morris
Andrew D
AD
Frayling
Timothy M
TM
Hattersley
Andrew T
AT
Thorsteinsdottir
Unnur
U
Stefansson
Kari
K
Nilsson
Peter
P
Syvänen
Ann-Christine
AC
Shuldiner
Alan R
AR
Walker
Mark
M
Bornstein
Stefan R
SR
Schwarz
Peter
P
Williams
Gordon H
GH
Nathan
David M
DM
Kuusisto
Johanna
J
Laakso
Markku
M
Cooper
Cyrus
C
Marmot
Michael
M
Ferrucci
Luigi
L
Mooser
Vincent
V
Stumvoll
Michael
M
Loos
Ruth J F
RJ
Altshuler
David
D
Psaty
Bruce M
BM
Rotter
Jerome I
JI
Boerwinkle
Eric
E
Hansen
Torben
T
Pedersen
Oluf
O
Florez
Jose C
JC
McCarthy
Mark I
MI
Boehnke
Michael
M
Barroso
Inês
I
Sladek
Robert
R
Froguel
Philippe
P
Meigs
James B
JB
Groop
Leif
L
Wareham
Nicholas J
NJ
Watanabe
Richard M
RM
D000262:Adenylyl Cyclases / Q000235:genetics; D015992:Body Mass Index; D003718:Denmark; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D056426:Genetic Loci / Q000235:genetics; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006801:Humans; D054795:Incretins / Q000235:genetics; D007328:Insulin / Q000378:metabolism*; D008297:Male; D015201:Meta-Analysis as Topic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011964:Receptors, Gastrointestinal Hormone / Q000235:genetics* / Q000378:metabolism
D054795:Incretins; D007328:Insulin; D011506:Proteins; D012333:RNA, Messenger; D011964:Receptors, Gastrointestinal Hormone; C495324:VPS13C protein, human; C041086:gastric inhibitory polypeptide receptor; D000262:Adenylyl Cyclases; D005947:Glucose