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@article{Bouatia-Naji:2010:10.2337/db10-0389,
author = {Bouatia-Naji, N and Bonnefond, A and Baerenwald, DA and Marchand, M and Bugliani, M and Marchetti, P and Pattou, F and Printz, RL and Flemming, BP and Umunakwe, OC and Conley, NL and Vaxillaire, M and Lantieri, O and Balkau, B and Marre, M and Levy-Marchal, C and Elliott, P and Jarvelin, M-R and Meyre, D and Dina, C and Oeser, JK and Froguel, P and O'Brien, RM},
doi = {10.2337/db10-0389},
journal = {Diabetes},
pages = {2662--2671},
title = {Genetic and functional assessment of the role of the rs13431652-A and rs573225-A alleles in the G6PC2 promoter that are strongly associated with elevated fasting glucose levels},
url = {http://dx.doi.org/10.2337/db10-0389},
volume = {59},
year = {2010}
}

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TY  - JOUR
AB  - OBJECTIVE Genome-wide association studies have identified a single nucleotide polymorphism (SNP), rs560887, located in a G6PC2 intron that is highly correlated with variations in fasting plasma glucose (FPG). G6PC2 encodes an islet-specific glucose-6-phosphatase catalytic subunit. This study examines the contribution of two G6PC2 promoter SNPs, rs13431652 and rs573225, to the association signal.RESEARCH DESIGN AND METHODS We genotyped 9,532 normal FPG participants (FPG <6.1 mmol/l) for three G6PC2 SNPs, rs13431652 (distal promoter), rs573225 (proximal promoter), rs560887 (3rd intron). We used regression analyses adjusted for age, sex, and BMI to assess the association with FPG and haplotype analyses to assess comparative SNP contributions. Fusion gene and gel retardation analyses characterized the effect of rs13431652 and rs573225 on G6PC2 promoter activity and transcription factor binding.RESULTS Genetic analyses provide evidence for a strong contribution of the promoter SNPs to FPG variability at the G6PC2 locus (rs13431652: β = 0.075, P = 3.6 × 10−35; rs573225 β = 0.073 P = 3.6 × 10−34), in addition to rs560887 (β = 0.071, P = 1.2 × 10−31). The rs13431652-A and rs573225-A alleles promote increased NF-Y and Foxa2 binding, respectively. The rs13431652-A allele is associated with increased FPG and elevated promoter activity, consistent with the function of G6PC2 in pancreatic islets. In contrast, the rs573225-A allele is associated with elevated FPG but reduced promoter activity.CONCLUSIONS Genetic and in situ functional data support a potential role for rs13431652, but not rs573225, as a causative SNP linking G6PC2 to variations in FPG, though a causative role for rs573225 in vivo cannot be ruled out.
AU  - Bouatia-Naji,N
AU  - Bonnefond,A
AU  - Baerenwald,DA
AU  - Marchand,M
AU  - Bugliani,M
AU  - Marchetti,P
AU  - Pattou,F
AU  - Printz,RL
AU  - Flemming,BP
AU  - Umunakwe,OC
AU  - Conley,NL
AU  - Vaxillaire,M
AU  - Lantieri,O
AU  - Balkau,B
AU  - Marre,M
AU  - Levy-Marchal,C
AU  - Elliott,P
AU  - Jarvelin,M-R
AU  - Meyre,D
AU  - Dina,C
AU  - Oeser,JK
AU  - Froguel,P
AU  - O'Brien,RM
DO  - 10.2337/db10-0389
EP  - 2671
PY  - 2010///
SN  - 0012-1797
SP  - 2662
TI  - Genetic and functional assessment of the role of the rs13431652-A and rs573225-A alleles in the G6PC2 promoter that are strongly associated with elevated fasting glucose levels
T2  - Diabetes
UR  - http://dx.doi.org/10.2337/db10-0389
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000283205700041&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - https://diabetes.diabetesjournals.org/content/59/10/2662
UR  - http://hdl.handle.net/10044/1/85668
VL  - 59
ER  -

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