Diabetes
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Published online October 31, 2007
Diabetes 57:494-502, 2008
DOI: 10.2337/db07-1273
© 2008 by the American Diabetes Association
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
db07-1273v1
57/2/494    most recent
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Le Stunff, C.
Right arrow Articles by Bougnères, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Le Stunff, C.
Right arrow Articles by Bougnères, P.
Social Bookmarking
Add to CiteULike   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

Association Analysis Indicates That a Variant GATA-Binding Site in the PIK3CB Promoter Is a Cis-Acting Expression Quantitative Trait Locus for This Gene and Attenuates Insulin Resistance in Obese Children

Catherine Le Stunff1,2, Agnès Dechartres3, Virginie Mariot2, Chantal Lotton2, Cecelia Trainor4, Emanuele Miraglia Del Giudice5, David Meyre6, Ivan Bieche7, Ingrid Laurendeau7, Philippe Froguel6, Diana Zelenika8, Dani Fallin9, Mark Lathrop8, Paul-Henri Roméo10, and Pierre Bougnères1,2

1 Pediatric Endocrinology, Pôle d'Endocrinologie Enfants-Adultes Cochin-St Vincent de Paul, Assistance Publique-Hôspitaux de Paris, Hôpital Saint Vincent de Paul, Paris V University, Paris, France
2 Institut National de la Santé et de la Recherche Médicale (INSERM) U561, Hôpital Saint Vincent de Paul, Paris, France
3 Service de Biostatistique, Hôpital Necker, Paris, France
4 Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
5 Department of Pediatrics, Second University of Naples, Naples, Italy
6 Centre National de la Recherche Scientifique UMR8090, Pasteur Institute, Lille, France
7 INSERM U745, Faculty of Pharmacy, Paris V, Paris, France
8 Centre National de Génotypage, Genomic Center of the Commissariat de l’Energie Atomique, Evry, France
9 Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland
10 Institut de Radiobiologie Cellulaire et Moléculaire, Département des Sciences du Vivant of the Commissariat de l’Energie Atomique, Fontenay aux Roses, France

Address correspondence and reprint requests to Pierre Bougnères, Pediatric Endocrinology, Hôpital Saint Vincent de Paul, 82 Ave. Denfert Rochereau, 75014 Paris, France. E-mail: bougneres{at}paris5.inserm.fr

Abbreviations: EMSA, electromobility shift assay; eQTL, expression quantitative trait locus; eQTN, expression quantitative trait nucleotide; HOMA-IR, homeostasis model assessment of insulin resistance; INSERM, Institut National de la Santé et de la Recherche Médicale; IRS, insulin receptor substrate; PI, phosphatidylinositol; SNP, single nucleotide polymorphism

OBJECTIVE—In search of functional polymorphisms associated with the genetics of insulin resistance, we studied a variant in the promoter of PIK3CB, the gene coding for the catalytic p110β subunit of phosphatidylinositol (PI) 3-kinase, a major effector of insulin action.

RESEARCH DESIGN AND METHODS—The rs361072 C/T variant was selected among single nucleotide polymorphisms of the PIK3CB region because we suspected that its common C allele (allelic frequency ~50% in Europeans) could create a GATA-binding motif and was genotyped in five cohorts of obese (n = 1,876) and two cohorts of nonobese (n = 1,490) European children. To estimate insulin resistance in these children, the homeostasis model assessment for insulin resistance (HOMA-IR) index was measured in strict nutritional conditions. GATA-binding and functional effects of rs361072 were explored in transfected cell lines and in lymphocytes from obese children.

RESULTS—The rs361072 C/T variant was associated with HOMA-IR in the obese children cohorts (1.7 x 10–12 < P < 2 x 10–4 for C/C vs. T/T using regression analysis). HOMA-IR averaged 3.3 ± 0.1 in C/C and 4.5 ± 0.2 in T/T obese children (P = 4.5 x 10–6 by ANOVA). C/T patients had intermediate values. As shown by the interaction between BMI and genotype (P = 2.1 x 10–9), the association of rs361072 with HOMA-IR depended on BMI and was only marginal in nonobese children (P = 0.04). At the molecular level, the C allele of rs361072 was found to create a GATA-binding site able to increase transcription of PIK3CB.

CONCLUSIONS—We postulate that the C allele of rs361072 is a causal variant capable of attenuating insulin resistance in obese children through increased expression of p110β.


Add to CiteULike CiteULike   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?




HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum
Copyright © 2008 by the American Diabetes Association.