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.
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.
Le Stunff
Catherine
C
Pediatric Endocrinology, Hôpital Saint Vincent de Paul, 82 Ave. Denfert Rochereau, 75014 Paris, France.
Dechartres
Agnès
A
Mariot
Virginie
V
Lotton
Chantal
C
Trainor
Cecelia
C
Miraglia Del Giudice
Emanuele
E
Meyre
David
D
Bieche
Ivan
I
Laurendeau
Ingrid
I
Froguel
Philippe
P
Zelenika
Diana
D
Fallin
Dani
D
Lathrop
Mark
M
Roméo
Paul-Henri
PH
Bougnères
Pierre
P
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
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