Susceptibility to type 2 diabetes may be modulated by haplotypes in G6PC2, a target of positive selection.
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. 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.



We 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.



We detected pervasive positive selection at mammalian G6PC2 genes and we suggest that distinct haplotypes at the G6PC2 locus modulate susceptibility to T2D.
Biomarker research program, Biochemistry Department, College of Science, King Saud Universiy, Riyadh, 11451, Kingdom of Saudi Arabia.|Prince Mutaib Chair for Biomarkers of Osteoporosis Research, King Saud University, Riyadh, 11451, Kingdom of Saudi Arabia.
Nasser M
NM
Al-Daghri
Scientific Institute IRCCS E.MEDEA, Bosisio Parini, 23842, Italy.
Chiara
C
Pontremoli
Scientific Institute IRCCS E.MEDEA, Bosisio Parini, 23842, Italy.
Rachele
R
Cagliani
Scientific Institute IRCCS E.MEDEA, Bosisio Parini, 23842, Italy.
Diego
D
Forni
Biomarker research program, Biochemistry Department, College of Science, King Saud Universiy, Riyadh, 11451, Kingdom of Saudi Arabia.|Prince Mutaib Chair for Biomarkers of Osteoporosis Research, King Saud University, Riyadh, 11451, Kingdom of Saudi Arabia.
Majed S
MS
Alokail
Biomarker research program, Biochemistry Department, College of Science, King Saud Universiy, Riyadh, 11451, Kingdom of Saudi Arabia.|Prince Mutaib Chair for Biomarkers of Osteoporosis Research, King Saud University, Riyadh, 11451, Kingdom of Saudi Arabia.
Omar S
OS
Al-Attas
Biomarker research program, Biochemistry Department, College of Science, King Saud Universiy, Riyadh, 11451, Kingdom of Saudi Arabia.|Prince Mutaib Chair for Biomarkers of Osteoporosis Research, King Saud University, Riyadh, 11451, Kingdom of Saudi Arabia.
Shaun
S
Sabico
Scientific Institute IRCCS E.MEDEA, Bosisio Parini, 23842, Italy.
Stefania
S
Riva
Department of Physiopathology and Transplantation, University of Milan, via F.lli Cervi 93, Segrate, 20090, Milan, Italy. mario.clerici@unimi.it.|Don Gnocchi Foundation, ONLUS, Milan, 20148, Italy. mario.clerici@unimi.it.
Mario
M
Clerici
Scientific Institute IRCCS E.MEDEA, Bosisio Parini, 23842, Italy.
Manuela
M
Sironi
D000328:Adult; D000368:Aged; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D019143:Evolution, Molecular; D005260:Female; D005952:Glucose-6-Phosphatase / Q000235:genetics* / Q000378:metabolism; D006239:Haplotypes; D006801:Humans; D007448:Invertebrates / Q000201:enzymology / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D012529:Saudi Arabia; D017422:Sequence Analysis, DNA; D014714:Vertebrates / Q000235:genetics; D055815:Young Adult
D005952:Glucose-6-Phosphatase; C492194:G6PC2 protein, human
Association analysis; G6PC; G6PC2; G6PC3; Natural selection; Type 2 diabetes