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A Single-Nucleotide Polymorphism in a Methylatable Foxa2 Binding Site of the G6PC2 Promoter Is Associated With Insulin Secretion In Vivo and Increased Promoter Activity In Vitro

OBJECTIVE—The G6PC2 gene encoding islet-specific glucose-6-phosphatase related protein (IGRP) has a common promoter variant, rs573225 (−231G/A), located within a Foxa binding site. We tested the cis-regulatory effects of rs573225 on promoter activity and its association with insulin response to oral...

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Autores principales: Dos Santos, Christine, Bougnères, Pierre, Fradin, Delphine
Formato: Texto
Lenguaje:English
Publicado: American Diabetes Association 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2628624/
https://www.ncbi.nlm.nih.gov/pubmed/18984742
http://dx.doi.org/10.2337/db08-0587
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author Dos Santos, Christine
Bougnères, Pierre
Fradin, Delphine
author_facet Dos Santos, Christine
Bougnères, Pierre
Fradin, Delphine
author_sort Dos Santos, Christine
collection PubMed
description OBJECTIVE—The G6PC2 gene encoding islet-specific glucose-6-phosphatase related protein (IGRP) has a common promoter variant, rs573225 (−231G/A), located within a Foxa binding site. We tested the cis-regulatory effects of rs573225 on promoter activity and its association with insulin response to oral glucose. RESEARCH DESIGN AND METHODS—Functional effects of rs573225 were explored in transfected INS-1 and HIT-T β-cell lines. A total of 734 young obese subjects of European ancestry were genotyped for rs573225. Insulin and glucose levels were measured in response to oral glucose, and the insulinogenic index (IGI) of insulin secretion was calculated. RESULTS—In vitro, the G allele showed a higher affinity for binding Foxa2 transcription factor and increased G6PC2 promoter activity. Foxa2 binding is modified if the C adjacent to the G allele is methylated. IGI was associated with rs573225 by linear regression analysis and was 30% greater in AA or AG than in GG obese children. rs573225 was also associated with fasting glucose. CONCLUSIONS—rs573225 is a functional cis-regulatory (epi)-single-nucleotide polymorphism (SNP) of G6PC2 associated with glucose-insulin homeostasis in obese children, likely to explain the results of recent genome-wide association studies in nondiabetic adults.
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spelling pubmed-26286242010-02-01 A Single-Nucleotide Polymorphism in a Methylatable Foxa2 Binding Site of the G6PC2 Promoter Is Associated With Insulin Secretion In Vivo and Increased Promoter Activity In Vitro Dos Santos, Christine Bougnères, Pierre Fradin, Delphine Diabetes Genetics OBJECTIVE—The G6PC2 gene encoding islet-specific glucose-6-phosphatase related protein (IGRP) has a common promoter variant, rs573225 (−231G/A), located within a Foxa binding site. We tested the cis-regulatory effects of rs573225 on promoter activity and its association with insulin response to oral glucose. RESEARCH DESIGN AND METHODS—Functional effects of rs573225 were explored in transfected INS-1 and HIT-T β-cell lines. A total of 734 young obese subjects of European ancestry were genotyped for rs573225. Insulin and glucose levels were measured in response to oral glucose, and the insulinogenic index (IGI) of insulin secretion was calculated. RESULTS—In vitro, the G allele showed a higher affinity for binding Foxa2 transcription factor and increased G6PC2 promoter activity. Foxa2 binding is modified if the C adjacent to the G allele is methylated. IGI was associated with rs573225 by linear regression analysis and was 30% greater in AA or AG than in GG obese children. rs573225 was also associated with fasting glucose. CONCLUSIONS—rs573225 is a functional cis-regulatory (epi)-single-nucleotide polymorphism (SNP) of G6PC2 associated with glucose-insulin homeostasis in obese children, likely to explain the results of recent genome-wide association studies in nondiabetic adults. American Diabetes Association 2009-02 /pmc/articles/PMC2628624/ /pubmed/18984742 http://dx.doi.org/10.2337/db08-0587 Text en Copyright © 2009, American Diabetes Association Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
spellingShingle Genetics
Dos Santos, Christine
Bougnères, Pierre
Fradin, Delphine
A Single-Nucleotide Polymorphism in a Methylatable Foxa2 Binding Site of the G6PC2 Promoter Is Associated With Insulin Secretion In Vivo and Increased Promoter Activity In Vitro
title A Single-Nucleotide Polymorphism in a Methylatable Foxa2 Binding Site of the G6PC2 Promoter Is Associated With Insulin Secretion In Vivo and Increased Promoter Activity In Vitro
title_full A Single-Nucleotide Polymorphism in a Methylatable Foxa2 Binding Site of the G6PC2 Promoter Is Associated With Insulin Secretion In Vivo and Increased Promoter Activity In Vitro
title_fullStr A Single-Nucleotide Polymorphism in a Methylatable Foxa2 Binding Site of the G6PC2 Promoter Is Associated With Insulin Secretion In Vivo and Increased Promoter Activity In Vitro
title_full_unstemmed A Single-Nucleotide Polymorphism in a Methylatable Foxa2 Binding Site of the G6PC2 Promoter Is Associated With Insulin Secretion In Vivo and Increased Promoter Activity In Vitro
title_short A Single-Nucleotide Polymorphism in a Methylatable Foxa2 Binding Site of the G6PC2 Promoter Is Associated With Insulin Secretion In Vivo and Increased Promoter Activity In Vitro
title_sort single-nucleotide polymorphism in a methylatable foxa2 binding site of the g6pc2 promoter is associated with insulin secretion in vivo and increased promoter activity in vitro
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2628624/
https://www.ncbi.nlm.nih.gov/pubmed/18984742
http://dx.doi.org/10.2337/db08-0587
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