Introduction: The endoplasmic reticulum enzyme glucose-6-phosphatase catalyzes the common terminal reaction in the gluconeogenic and glycogenolytic pathways and plays a central role in glucose homeostasis. In most mammals, different G6PC subunits are encoded by three paralogous genes (G6PC, G6PC2, and G6PC3). Mutations in G6PC and G6PC3 are responsible for human Mendelian diseases, whereas variants in G6PC2 are associated with fasting glucose (FG) levels.
Methods: We analyzed the evolutionary history of G6Pase genes in mammals. Results indicated that negative selection was the major force shaping diversity at these genes. Nonetheless, site-wise estimation of evolutionary rates at corresponding sites revealed weak correlations, suggesting that G6Pases have evolved different structural features over time. We also detected pervasive positive selection at mammalian G6PC2 genes. Most selected residues are located in the C-terminal protein region, where several human variants associated with FG levels also map. This region was thus re-sequenced in a cohort of ~560 subjects from Saudi Arabia, 185 of whom suffering from type 2 diabetes (T2D).
Results: The frequency of rare missense and nonsense variants was not significantly different in T2D and controls. Association analysis with two common missense variants (V219L and S342C) revealed a weak but significant association for both SNPs when analyses where conditioned on rs560887, previously identified in a GWAS for FG. Two haplotypes were significantly associated with T2D with an opposite effect direction.
Conclusion: These results, although preliminary, suggest that distinct haplotypes at the G6PC2 locus modulate susceptibility to T2D.
20 - 23 May 2017
European Society of Endocrinology