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, Agnès Dechartres, Virginie Mariot, Chantal Lotton, Cecelia Trainor, Emanuele Miraglia Del Giudice, David Meyre, Ivan Bieche, Ingrid Laurendeau, Philippe Froguel, Diana Zelenika, Dani Fallin, Mark Lathrop, Paul Henri Roméo, Pierre Bougnères

Research output: Contribution to journalArticle

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 p110β.

Original languageEnglish (US)
Pages (from-to)494-502
Number of pages9
JournalDiabetes
Volume57
Issue number2
DOIs
StatePublished - Feb 1 2008

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Le Stunff, C., Dechartres, A., Mariot, V., Lotton, C., Trainor, C., Del Giudice, E. M., Meyre, D., Bieche, I., Laurendeau, I., Froguel, P., Zelenika, D., Fallin, D., Lathrop, M., Roméo, P. H., & Bougnères, P. (2008). 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. Diabetes, 57(2), 494-502. https://doi.org/10.2337/db07-1273