title: The FOXO3A rs2802292 G-allele associates with improved peripheral and hepatic insulin sensitivity and increased skeletal muscle-FOXO3A mRNA expression in twins.
abstract: OBJECTIVE
  The minor G-allele of FOXO3A rs2802292 has been associated with longevity. We aimed to investigate whether a phenotype related to healthy metabolic aging could be identified in individuals carrying the longevity-associated FOXO3A rs2802292 G-allele.
  
  
  METHODS
  rs2802292 was genotyped in a phenotypically well-characterized population of young and elderly twins (n = 190) and in the population-based Inter99 cohort (n = 5768). All participants underwent oral glucose tolerance tests, and the twin population was additionally examined with an iv glucose tolerance test and a hyperinsulinemic, euglycemic clamp. Basal and insulin-stimulated FOXO3A mRNA expression was assessed in skeletal muscle biopsies from the twin population.
  
  
  RESULTS
  In the twin sample, carriers of the minor G-allele of rs2802292 showed reduced fasting plasma insulin [per allele effect (β) = -13% (-24; -1) (95% confidence interval), P = 0.03] and lower incremental area under the curve 0-120 min for insulin after an oral glucose load [β = -14% (-23; -5), P = 0.005]. The G-allele was associated with increased peripheral insulin action [glucose disposal rate clamp, β = 0.85 mg · kg(fat-free mass)(-1) · min(-1)() (0.049; 1.64), P = 0.04] and lower hepatic insulin resistance index [β = -13% (-25; -1), P = 0.03]. Furthermore, carriers of the G-allele had increased basal FOXO3A mRNA expression in skeletal muscle compared with T-allele carriers [β = 16% (0; 33), P = 0.047]. In the Inter99 sample, we found an association with reduced incremental area under the curve 0-120 min for insulin after an oral glucose load [β = -3% (-5; -0.07), P = 0.04], but this association was not significant after adjustment for body mass index.
  
  
  CONCLUSIONS
  Our data indicate that the minor G-allele of FOXO3A rs2802292 is associated with enhanced peripheral and hepatic insulin sensitivity in our small twin cohort, which may be mediated through increased FOXO3A mRNA expression, although no major metabolic impact of rs2802292 was found in the large Inter99 cohort.
authors.affiliation: Hagedorn Research Institute, Gentofte, Copenhagen, Denmark. kabs@hagedorn.dk
authors.forename: Karina
authors.initials: K
authors.lastname: Banasik
authors.forename: Rasmus
authors.initials: R
authors.lastname: Ribel-Madsen
authors.forename: Anette P
authors.initials: AP
authors.lastname: Gjesing
authors.forename: Lise
authors.initials: L
authors.lastname: Wegner
authors.forename: Asa
authors.initials: A
authors.lastname: Andersson
authors.forename: Pernille
authors.initials: P
authors.lastname: Poulsen
authors.forename: Anders
authors.initials: A
authors.lastname: Borglykke
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Witte
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
authors.forename: Allan
authors.initials: A
authors.lastname: Vaag
mesh_terms: D015502:Absorptiometry, Photon; D000328:Adult; D000368:Aged; D000483:Alleles; D019540:Area Under Curve; D001786:Blood Glucose / Q000235:genetics / Q000378:metabolism; D001823:Body Composition; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D005838:Genotype; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014427:Twins / Q000235:genetics
chemical_list: D001786:Blood Glucose; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D007328:Insulin; D012333:RNA, Messenger