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

Nasser M Al-Daghri, Chiara Pontremoli, Rachele Cagliani, Diego Forni, Majed S Alokail, Omar S Al-Attas, Shaun Sabico, Stefania Riva, Mario Clerici, Manuela Sironi

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

BACKGROUND: 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.

RESULTS: 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.

CONCLUSIONS: We detected pervasive positive selection at mammalian G6PC2 genes and we suggest that distinct haplotypes at the G6PC2 locus modulate susceptibility to T2D.

Original languageEnglish
Pages (from-to)43
JournalBMC Evolutionary Biology
Volume17
Issue number1
DOIs
Publication statusPublished - Feb 7 2017

Fingerprint

diabetes
noninsulin-dependent diabetes mellitus
haplotypes
glucose
fasting
gene
genes
mammals
glucose-6-phosphatase
mammal
Saudi Arabia
endoplasmic reticulum
homeostasis
phosphatase
vertebrates
mutation
vertebrate
history
loci
enzyme

Keywords

  • Adult
  • Aged
  • Animals
  • Diabetes Mellitus, Type 2
  • Evolution, Molecular
  • Female
  • Glucose-6-Phosphatase
  • Haplotypes
  • Humans
  • Invertebrates
  • Male
  • Middle Aged
  • Phylogeny
  • Polymorphism, Single Nucleotide
  • Saudi Arabia
  • Sequence Analysis, DNA
  • Vertebrates
  • Young Adult
  • Journal Article

Cite this

Susceptibility to type 2 diabetes may be modulated by haplotypes in G6PC2, a target of positive selection. / Al-Daghri, Nasser M; Pontremoli, Chiara; Cagliani, Rachele; Forni, Diego; Alokail, Majed S; Al-Attas, Omar S; Sabico, Shaun; Riva, Stefania; Clerici, Mario; Sironi, Manuela.

In: BMC Evolutionary Biology, Vol. 17, No. 1, 07.02.2017, p. 43.

Research output: Contribution to journalArticle

Al-Daghri, Nasser M ; Pontremoli, Chiara ; Cagliani, Rachele ; Forni, Diego ; Alokail, Majed S ; Al-Attas, Omar S ; Sabico, Shaun ; Riva, Stefania ; Clerici, Mario ; Sironi, Manuela. / Susceptibility to type 2 diabetes may be modulated by haplotypes in G6PC2, a target of positive selection. In: BMC Evolutionary Biology. 2017 ; Vol. 17, No. 1. pp. 43.
@article{4aa4005ac3af4b0c94da80e267b677f9,
title = "Susceptibility to type 2 diabetes may be modulated by haplotypes in G6PC2, a target of positive selection",
abstract = "BACKGROUND: 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.RESULTS: 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.CONCLUSIONS: We detected pervasive positive selection at mammalian G6PC2 genes and we suggest that distinct haplotypes at the G6PC2 locus modulate susceptibility to T2D.",
keywords = "Adult, Aged, Animals, Diabetes Mellitus, Type 2, Evolution, Molecular, Female, Glucose-6-Phosphatase, Haplotypes, Humans, Invertebrates, Male, Middle Aged, Phylogeny, Polymorphism, Single Nucleotide, Saudi Arabia, Sequence Analysis, DNA, Vertebrates, Young Adult, Journal Article",
author = "Al-Daghri, {Nasser M} and Chiara Pontremoli and Rachele Cagliani and Diego Forni and Alokail, {Majed S} and Al-Attas, {Omar S} and Shaun Sabico and Stefania Riva and Mario Clerici and Manuela Sironi",
year = "2017",
month = "2",
day = "7",
doi = "10.1186/s12862-017-0897-z",
language = "English",
volume = "17",
pages = "43",
journal = "BMC Evolutionary Biology",
issn = "1471-2148",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - Susceptibility to type 2 diabetes may be modulated by haplotypes in G6PC2, a target of positive selection

AU - Al-Daghri, Nasser M

AU - Pontremoli, Chiara

AU - Cagliani, Rachele

AU - Forni, Diego

AU - Alokail, Majed S

AU - Al-Attas, Omar S

AU - Sabico, Shaun

AU - Riva, Stefania

AU - Clerici, Mario

AU - Sironi, Manuela

PY - 2017/2/7

Y1 - 2017/2/7

N2 - BACKGROUND: 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.RESULTS: 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.CONCLUSIONS: We detected pervasive positive selection at mammalian G6PC2 genes and we suggest that distinct haplotypes at the G6PC2 locus modulate susceptibility to T2D.

AB - BACKGROUND: 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.RESULTS: 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.CONCLUSIONS: We detected pervasive positive selection at mammalian G6PC2 genes and we suggest that distinct haplotypes at the G6PC2 locus modulate susceptibility to T2D.

KW - Adult

KW - Aged

KW - Animals

KW - Diabetes Mellitus, Type 2

KW - Evolution, Molecular

KW - Female

KW - Glucose-6-Phosphatase

KW - Haplotypes

KW - Humans

KW - Invertebrates

KW - Male

KW - Middle Aged

KW - Phylogeny

KW - Polymorphism, Single Nucleotide

KW - Saudi Arabia

KW - Sequence Analysis, DNA

KW - Vertebrates

KW - Young Adult

KW - Journal Article

U2 - 10.1186/s12862-017-0897-z

DO - 10.1186/s12862-017-0897-z

M3 - Article

VL - 17

SP - 43

JO - BMC Evolutionary Biology

JF - BMC Evolutionary Biology

SN - 1471-2148

IS - 1

ER -