Abstract
BackgroundThe endoplasmic reticulum enzyme glucose-6-phosphatase catalyzes the common terminal reaction in the gluconeogenic/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.ResultsWe analyzed the evolutionary history of G6Pase genes. Results indicated that the three paralogs originated during early vertebrate evolution and that negative selection was the major force shaping diversity at these genes in mammals. Nonetheless, site-wise estimation of evolutionary rates at corresponding sites revealed weak correlations, suggesting that mammalian G6Pases have evolved different structural features over time. We also detected pervasive positive selection at mammalian G6PC2. Most selected residues localize in the C-terminal protein region, where several human variants associated with FG levels also map. This region was re-sequenced in ~560 subjects from Saudi Arabia, 185 of whom suffering from type 2 diabetes (T2D). 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 were conditioned on rs560887, previously identified in a GWAS for FG. Two haplotypes were significantly associated with T2D with an opposite effect direction.ConclusionsWe detected pervasive positive selection at mammalian G6PC2 genes and we suggest that distinct haplotypes at the G6PC2 locus modulate susceptibility to T2D.
Highlights
The endoplasmic reticulum enzyme glucose-6-phosphatase catalyzes the common terminal reaction in the gluconeogenic/glycogenolytic pathways and plays a central role in glucose homeostasis
G6PC2 is expressed in pancreatic islets where its function is still incompletely understood [1, 2]. g6pc2−/− mice display a reduction in blood glucose levels after a 6 h fast, whereas plasma insulin and glucagon concentrations are unaffected [1, 2]
The data we report preliminary, may help reconcile the contrasting results obtained for rs560887 on type 2 diabetes (T2D) risk, as its effect might depend on haplotype context and may vary in different populations depending on linkage disequilibrium (LD) between rs560887 and other functional variants
Summary
The endoplasmic reticulum enzyme glucose-6-phosphatase catalyzes the common terminal reaction in the gluconeogenic/glycogenolytic pathways and plays a central role in glucose homeostasis. SCN4 patients are susceptible to bacterial infections and may display additional non immunologic symptoms In both humans and in the knock-out mouse model, G6PC3 only marginally contributes to the regulation of blood glucose levels or hepatic glycogen content [1, 2]. Common and rare variants in G6PC2 have been associated with fasting glucose (FG) levels and with decreased insulin secretion during glucose tolerance tests [3,4,5,6,7,8,9] This observation led to the suggestion that G6PC2 may regulate the pulsatility of insulin secretion [1, 2]
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