Details

Autor(en) / Beteiligte

• LE STUNFF, Catherine
• DECHARTRES, Agnès
• ZELENIKA, Diana
• FALLIN, Dani
• LATHROP, Mark
• ROMEO, Paul-Henri
• BOUGNERES, Pierre
• MARIOT, Virginie
• LOTTON, Chantal
• TRAINOR, Cecelia
• DEL GIUDICE, Emanuele Miraglia
• MEYRE, David
• BIECHE, Ivan
• LAURENDEAU, Ingrid
• FROGUEL, Philippe

Titel

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

Ist Teil von

• Diabetes (New York, N.Y.), 2008-02, Vol.57 (2), p.494-502

Ort / Verlag

Alexandria, VA: American Diabetes Association

Erscheinungsjahr

2008

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 Stunff 1 2 , Agnès Dechartres 3 , Virginie Mariot 2 , Chantal Lotton 2 , Cecelia Trainor 4 , Emanuele Miraglia Del Giudice 5 , David Meyre 6 , Ivan Bieche 7 , Ingrid Laurendeau 7 , Philippe Froguel 6 , Diana Zelenika 8 , Dani Fallin 9 , Mark Lathrop 8 , Paul-Henri Roméo 10 and Pierre Bougnères 1 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 Abstract 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 × 10 −12 < P < 2 × 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 × 10 −6 by ANOVA). C/T patients had intermediate values. As shown by the interaction between BMI and genotype ( P = 2.1 × 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. 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 Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 31 October 2007. DOI: 10.2337/db07-1273. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted October 25, 2007. Received September 6, 2007. DIABETES