Variations in the G6PC2/ABCB11 genomic region are associated with fasting glucose levels.
Identifying the genetic variants that regulate fasting glucose concentrations may further our understanding of the pathogenesis of diabetes. We therefore investigated the association of fasting glucose levels with SNPs in 2 genome-wide scans including a total of 5,088 nondiabetic individuals from Finland and Sardinia. We found a significant association between the SNP rs563694 and fasting glucose concentrations (P = 3.5 x 10(-7)). This association was further investigated in an additional 18,436 nondiabetic individuals of mixed European descent from 7 different studies. The combined P value for association in these follow-up samples was 6.9 x 10(-26), and combining results from all studies resulted in an overall P value for association of 6.4 x 10(-33). Across these studies, fasting glucose concentrations increased 0.01-0.16 mM with each copy of the major allele, accounting for approximately 1% of the total variation in fasting glucose. The rs563694 SNP is located between the genes glucose-6-phosphatase catalytic subunit 2 (G6PC2) and ATP-binding cassette, subfamily B (MDR/TAP), member 11 (ABCB11). Our results in combination with data reported in the literature suggest that G6PC2, a glucose-6-phosphatase almost exclusively expressed in pancreatic islet cells, may underlie variation in fasting glucose, though it is possible that ABCB11, which is expressed primarily in liver, may also contribute to such variation.
Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia, USA.
Wei-Min
WM
Chen
Michael R
MR
Erdos
Anne U
AU
Jackson
Richa
R
Saxena
Serena
S
Sanna
Kristi D
KD
Silver
Nicholas J
NJ
Timpson
Torben
T
Hansen
Marco
M
Orrù
Maria
M
Grazia Piras
Lori L
LL
Bonnycastle
Cristen J
CJ
Willer
Valeriya
V
Lyssenko
Haiqing
H
Shen
Johanna
J
Kuusisto
Shah
S
Ebrahim
Natascia
N
Sestu
William L
WL
Duren
Maria Cristina
MC
Spada
Heather M
HM
Stringham
Laura J
LJ
Scott
Nazario
N
Olla
Amy J
AJ
Swift
Samer
S
Najjar
Braxton D
BD
Mitchell
Debbie A
DA
Lawlor
George Davey
GD
Smith
Yoav
Y
Ben-Shlomo
Gitte
G
Andersen
Knut
K
Borch-Johnsen
Torben
T
Jørgensen
Jouko
J
Saramies
Timo T
TT
Valle
Thomas A
TA
Buchanan
Alan R
AR
Shuldiner
Edward
E
Lakatta
Richard N
RN
Bergman
Manuela
M
Uda
Jaakko
J
Tuomilehto
Oluf
O
Pedersen
Antonio
A
Cao
Leif
L
Groop
Karen L
KL
Mohlke
Markku
M
Laakso
David
D
Schlessinger
Francis S
FS
Collins
David
D
Altshuler
Gonçalo R
GR
Abecasis
Michael
M
Boehnke
Angelo
A
Scuteri
Richard M
RM
Watanabe
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D001786:Blood Glucose / Q000032:analysis*; D005215:Fasting / Q000097:blood; D005387:Finland; D005500:Follow-Up Studies; D005787:Gene Frequency; D005838:Genotype; D005952:Glucose-6-Phosphatase / Q000235:genetics*; D006801:Humans; D007558:Italy; D015810:Linkage Disequilibrium; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics
C093491:ABCB11 protein, human; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D001786:Blood Glucose; D005952:Glucose-6-Phosphatase; C492194:G6PC2 protein, human