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.
Chen
Wei-Min
WM
Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia, USA.
Erdos
Michael R
MR
Jackson
Anne U
AU
Saxena
Richa
R
Sanna
Serena
S
Silver
Kristi D
KD
Timpson
Nicholas J
NJ
Hansen
Torben
T
Orrù
Marco
M
Grazia Piras
Maria
M
Bonnycastle
Lori L
LL
Willer
Cristen J
CJ
Lyssenko
Valeriya
V
Shen
Haiqing
H
Kuusisto
Johanna
J
Ebrahim
Shah
S
Sestu
Natascia
N
Duren
William L
WL
Spada
Maria Cristina
MC
Stringham
Heather M
HM
Scott
Laura J
LJ
Olla
Nazario
N
Swift
Amy J
AJ
Najjar
Samer
S
Mitchell
Braxton D
BD
Lawlor
Debbie A
DA
Smith
George Davey
GD
Ben-Shlomo
Yoav
Y
Andersen
Gitte
G
Borch-Johnsen
Knut
K
Jørgensen
Torben
T
Saramies
Jouko
J
Valle
Timo T
TT
Buchanan
Thomas A
TA
Shuldiner
Alan R
AR
Lakatta
Edward
E
Bergman
Richard N
RN
Uda
Manuela
M
Tuomilehto
Jaakko
J
Pedersen
Oluf
O
Cao
Antonio
A
Groop
Leif
L
Mohlke
Karen L
KL
Laakso
Markku
M
Schlessinger
David
D
Collins
Francis S
FS
Altshuler
David
D
Abecasis
Gonçalo R
GR
Boehnke
Michael
M
Scuteri
Angelo
A
Watanabe
Richard M
RM
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