Association Analysis Indicates that a variant GATA-binding site in the PIK3CB Promoter Is a Cis-Acting expression Quantitative Trait Locus (eQTL) for this Gene and Attenuates Insulin Resistance (IR) 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 Bougnères (bougneres{at}paris5.inserm.fr)1,2
- 1Pediatric Endocrinology, Pôle d'Endocrinologie Enfants-Adultes Cochin-St Vincent de Paul, APHP, Hôpital Saint Vincent de Paul, Paris V University, Paris, France
- 2INSERM U561, Hôpital Saint Vincent de Paul, Paris, France
- 3 Service de Biostatistique, Hôpital Necker, Paris, France
- 4Laboratory of Molecular Biology, NIDDKD, National Institute of Health, Bethesda, MD 20892, USA
- 5Department of Pediatrics, Second University of Naples, Italy
- 6CNRS UMR8090, Pasteur Institute, Lille, France
- 7INSERM U745, Faculty of Pharmacy, Paris V, Paris, France
- 8Centre National de Génotypage, Genomic Center of the Commissariat de l'Energie Atomique, Evry, France
- 9Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21025, USA
- 10Institut de Radiobiologie Cellulaire et Moléculaire, Département des Sciences du Vivant of the Commissariat de l'Energie Atomique, Fontenay aux Roses, France
Abstract
Objective: In search of functional polymorphisms associated with the genetics of IR, we studied a variant in the promoter of PIK3CB, the gene coding for the catalytic p110β subunit of phosphatidyl-inositol-3 kinase (PI3K), a major effector of insulin action.
Research Design and Methods: The rs361072 C/T variant was selected among SNPs 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 5 cohorts of obese (N = 1,876) and 2 cohorts of non-obese (N = 1,490) European children. To estimate IR in these children, the homeostasis model assessment index (HOMA-IR) 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 non-obese 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 IR in obese children through increased expression of p110β.
Footnotes
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- Received September 6, 2007.
- Accepted October 25, 2007.
- Copyright © American Diabetes Association
