title: 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.
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 p110beta subunit of phosphatidylinositol (PI) 3-kinase, a major effector of insulin action.
  
  
  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 approximately 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 p110beta.
authors.affiliation: Pediatric Endocrinology, Hôpital Saint Vincent de Paul, 82 Ave. Denfert Rochereau, 75014 Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Le Stunff
authors.forename: Agnès
authors.initials: A
authors.lastname: Dechartres
authors.forename: Virginie
authors.initials: V
authors.lastname: Mariot
authors.forename: Chantal
authors.initials: C
authors.lastname: Lotton
authors.forename: Cecelia
authors.initials: C
authors.lastname: Trainor
authors.forename: Emanuele
authors.initials: E
authors.lastname: Miraglia Del Giudice
authors.forename: David
authors.initials: D
authors.lastname: Meyre
authors.forename: Ivan
authors.initials: I
authors.lastname: Bieche
authors.forename: Ingrid
authors.initials: I
authors.lastname: Laurendeau
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.forename: Diana
authors.initials: D
authors.lastname: Zelenika
authors.forename: Dani
authors.initials: D
authors.lastname: Fallin
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.forename: Paul-Henri
authors.initials: PH
authors.lastname: Roméo
authors.forename: Pierre
authors.initials: P
authors.lastname: Bougnères
mesh_terms: D001665:Binding Sites; D001786:Blood Glucose / Q000032:analysis; D015992:Body Mass Index; D002648:Child; D058541:Class II Phosphatidylinositol 3-Kinases; D015331:Cohort Studies; D050981:Erythroid-Specific DNA-Binding Factors / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics*; D009765:Obesity / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D040641:Quantitative Trait Loci; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D001786:Blood Glucose; D050981:Erythroid-Specific DNA-Binding Factors; D007328:Insulin; D012333:RNA, Messenger; D019869:Phosphatidylinositol 3-Kinases; D058541:Class II Phosphatidylinositol 3-Kinases; C502616:PIK3C2B protein, human