Meta-analyses of the association of G6PC2 allele variants with elevated fasting glucose and type 2 diabetes

Objective: 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). Design: Meta-analysis Data sources: PubMed, Web of Knowledge and Embase databases. Study selection: Full text articles of studies that identified an association of G6PC2 with T2D and elevated FG. Patient involvement: 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. Statistical analysis: 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. Results: 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). Conclusions: 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.