Dataset Information

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.

ABSTRACT: 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.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.Genetic analyses provide evidence for a strong contribution of the promoter SNPs to FPG variability at the G6PC2 locus (rs13431652: ? = 0.075, P = 3.6 × 10(-35); rs573225 ? = 0.073 P = 3.6 × 10(-34)), in addition to rs560887 (? = 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.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.

SUBMITTER: Bouatia-Naji N

PROVIDER: S-EPMC3279535 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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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.

Bouatia-Naji Nabila N Bonnefond Amélie A Baerenwald Devin A DA Marchand Marion M Bugliani Marco M Marchetti Piero P Pattou François F Printz Richard L RL Flemming Brian P BP Umunakwe Obi C OC Conley Nicholas L NL Vaxillaire Martine M Lantieri Olivier O Balkau Beverley B Marre Michel M Lévy-Marchal Claire C Elliott Paul P Jarvelin Marjo-Riitta MR Meyre David D Dina Christian C Oeser James K JK Froguel Philippe P O'Brien Richard M RM

Diabetes 20100709 10

<h4>Objective</h4>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.<h4>Research design and methods</h4>We genotyped 9,532 normal FPG participants (FPG <6.1 mmol/ ...[more]

PMID: 20622168

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Project description:To collectively evaluate the association of glucose-6-phosphatase catalytic unit 2 (G6PC2) allele variants with elevated fasting glucose (FG) and type 2 diabetes (T2D).Meta-analysis.PubMed, Web of Knowledge and Embase databases.Full text articles of studies that identified an association of G6PC2 with T2D and elevated FG.There was no T2D patient involvement in the analyses on the association of FG with G6PC2, there were T2D patients and non-diabetes patient involvement in the analyses on the association of T2D with G6PC2.Random-effects meta-analyses were used to calculate the pool effect sizes. I2 metric and H2 tests were used to calculate the heterogeneity. Begg's funnel plot and Egger's linear regression test were done to assess publication bias.Of the 423 studies identified, 21 were eligible and included. Data on three loci (rs560887, rs16856187 and rs573225) were available. The G allele at rs560887 in three ethnicities, the C allele at rs16856187 and the A allele at rs573225 all had a positive association with elevated FG. Per increment of G allele at rs560887 and A allele at rs573225 resulted in a FG 0.070 mmol/l and 0.075 mmol/l higher (ß (95% CI) = 0.070 (0.060, 0.079), p = 4.635e-50 and 0.075 (0.065, 0.085), p = 5.856e-48, respectively). With regard to the relationship of rs16856187 and FG, an increase of 0.152 (95% CI: 0.034-0.270; p = 0.011) and 0.317 (95% CI: 0.193-0.442, p = 6.046e-07) was found in the standardized mean difference (SMD) of FG for the AC and CC genotypes, respectively, when compared with the AA reference genotype. However, the G-allele of rs560887 in Caucasians under the additive model and the C-allele of rs16856187 under the allele and dominant models were associated with a decreased risk of T2D (OR (95% CI) = 0.964 (0.947, 0.981), p = 0.570e-4; OR (95% CI) = 0.892 (0.832, 0.956), p = 0.001; and OR (95% CI) = 0.923(0.892, 0.955), p = 5.301e-6, respectively).Our meta-analyses demonstrate that all three allele variants of G6PC2 (rs560887, rs16856187 and rs573225) are associated with elevated FG, with two variants (rs560887 in the Caucasians subgroup and rs16856187 under the allele and dominant model) being associated with T2D as well. Further studies utilizing larger sample sizes and different ethnic populations are needed to extend and confirm these findings.

Dataset Information

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.

Publications

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.

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