G-allele of intronic rs10830963 in MTNR1B confers increased risk of impaired fasting glycemia and type 2 diabetes through an impaired glucose-stimulated insulin release: studies involving 19,605 Europeans.
OBJECTIVE
Genome-wide association studies have identified several variants within the MTNR1B locus that are associated with fasting plasma glucose (FPG) and type 2 diabetes. We refined the association signal by direct genotyping and examined for associations of the variant displaying the most independent effect on FPG with isolated impaired fasting glycemia (i-IFG), isolated impaired glucose tolerance (i-IGT), type 2 diabetes, and measures of insulin release and peripheral and hepatic insulin sensitivity.


METHODS
We examined European-descent participants in the Inter99 study (n = 5,553), in a sample of young healthy Danes (n = 372), in Danish twins (n = 77 elderly and n = 97 young), in additional Danish type 2 diabetic patients (n = 1,626) and control subjects (n = 505), in the Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study (n = 4,656), in the North Finland Birth Cohort 86 (n = 5,258), and in the Haguenau study (n = 1,461).


RESULTS
The MTNR1B intronic variant, rs10830963, carried most of the effect on FPG and showed the strongest association with FPG (combined P = 5.3 x 10(-31)) and type 2 diabetes. The rs10830963 G-allele increased the risk of i-IFG (odds ratio [OR] 1.64, P = 5.5 x 10(-11)) but not i-IGT. The G-allele was associated with a decreased insulin release after oral and intravenous glucose challenges (P < 0.01) but not after injection of tolbutamide. In elderly twins, the G-allele associated with hepatic insulin resistance (P = 0.017).


CONCLUSIONS
The G-allele of MTNR1B rs10830963 increases risk of type 2 diabetes through a state of i-IFG and not through i-IGT. The same allele associates with estimates of beta-cell dysfunction and hepatic insulin resistance.
Sparsø
Thomas
T
Steno Diabetes Center, Gentofte, Denmark. tspr@steno.dk.
Bonnefond
Amélie
A
Andersson
Ehm
E
Bouatia-Naji
Nabila
N
Holmkvist
Johan
J
Wegner
Lise
L
Grarup
Niels
N
Gjesing
Anette P
AP
Banasik
Karina
K
Cavalcanti-Proença
Christine
C
Marchand
Marion
M
Vaxillaire
Martine
M
Charpentier
Guillaume
G
Jarvelin
Marjo-Riitta
MR
Tichet
Jean
J
Balkau
Beverley
B
Marre
Michel
M
Lévy-Marchal
Claire
C
Faerch
Kristine
K
Borch-Johnsen
Knut
K
Jørgensen
Torben
T
Madsbad
Sten
S
Poulsen
Pernille
P
Vaag
Allan
A
Dina
Christian
C
Hansen
Torben
T
Pedersen
Oluf
O
Froguel
Philippe
P