Common missense variant in the glucokinase regulatory protein gene is associated with increased plasma triglyceride and C-reactive protein but lower fasting glucose concentrations.
OBJECTIVE
Using the genome-wide association approach, we recently identified the glucokinase regulatory protein gene (GCKR, rs780094) region as a novel quantitative trait locus for plasma triglyceride concentration in Europeans. Here, we sought to study the association of GCKR variants with metabolic phenotypes, including measures of glucose homeostasis, to evaluate the GCKR locus in samples of non-European ancestry and to fine- map across the associated genomic interval.


METHODS
We performed association studies in 12 independent cohorts comprising >45,000 individuals representing several ancestral groups (whites from Northern and Southern Europe, whites from the U.S., African Americans from the U.S., Hispanics of Caribbean origin, and Chinese, Malays, and Asian Indians from Singapore). We conducted genetic fine-mapping across the approximately 417-kb region of linkage disequilibrium spanning GCKR and 16 other genes on chromosome 2p23 by imputing untyped HapMap single nucleotide polymorphisms (SNPs) and genotyping 104 SNPs across the associated genomic interval.


RESULTS
We provide comprehensive evidence that GCKR rs780094 is associated with opposite effects on fasting plasma triglyceride (P(meta) = 3 x 10(-56)) and glucose (P(meta) = 1 x 10(-13)) concentrations. In addition, we confirmed recent reports that the same SNP is associated with C-reactive protein (CRP) level (P = 5 x 10(-5)). Both fine-mapping approaches revealed a common missense GCKR variant (rs1260326, Pro446Leu, 34% frequency, r(2) = 0.93 with rs780094) as the strongest association signal in the region.


CONCLUSIONS
These findings point to a molecular mechanism in humans by which higher triglycerides and CRP can be coupled with lower plasma glucose concentrations and position GCKR in central pathways regulating both hepatic triglyceride and glucose metabolism.
Orho-Melander
Marju
M
Department of Clinical Sciences, University Hospital Malmö, Clinical Research Center, Lund University, Malmö, Sweden. marju.orho-melander@med.lu.se
Melander
Olle
O
Guiducci
Candace
C
Perez-Martinez
Pablo
P
Corella
Dolores
D
Roos
Charlotta
C
Tewhey
Ryan
R
Rieder
Mark J
MJ
Hall
Jennifer
J
Abecasis
Goncalo
G
Tai
E Shyong
ES
Welch
Cullan
C
Arnett
Donna K
DK
Lyssenko
Valeriya
V
Lindholm
Eero
E
Saxena
Richa
R
de Bakker
Paul I W
PI
Burtt
Noel
N
Voight
Benjamin F
BF
Hirschhorn
Joel N
JN
Tucker
Katherine L
KL
Hedner
Thomas
T
Tuomi
Tiinamaija
T
Isomaa
Bo
B
Eriksson
Karl-Fredrik
KF
Taskinen
Marja-Riitta
MR
Wahlstrand
Björn
B
Hughes
Thomas E
TE
Parnell
Laurence D
LD
Lai
Chao-Qiang
CQ
Berglund
Göran
G
Peltonen
Leena
L
Vartiainen
Erkki
E
Jousilahti
Pekka
P
Havulinna
Aki S
AS
Salomaa
Veikko
V
Nilsson
Peter
P
Groop
Leif
L
Altshuler
David
D
Ordovas
Jose M
JM
Kathiresan
Sekar
S
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D001786:Blood Glucose / Q000378:metabolism*; D002097:C-Reactive Protein / Q000378:metabolism*; D005215:Fasting / Q000097:blood; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D014280:Triglycerides / Q000097:blood*
D048868:Adaptor Proteins, Signal Transducing; D001786:Blood Glucose; C485100:GCKR protein, human; D014280:Triglycerides; D002097:C-Reactive Protein