title: Analysis of variants and mutations in the human winged helix FOXA3 gene and associations with metabolic traits.
abstract: OBJECTIVE
  The forkhead factor Foxa3 is involved in the early transcriptional events controlling adipocyte differentiation and plays a critical function in fat depot expansion in response to high-fat diet regimens and during aging in mice. No studies to date have assessed the potential associations of genetic variants in FOXA3 with human metabolic outcomes.
  
  
  METHODS
  In this study, we sequenced FOXA3 in 392 children, adolescents and young adults selected from several cohorts of subjects recruited at the National Institute of Child Health and Human Development of the National Institutes of Health based on the availability of dual-energy X-ray absorptiometry data, magnetic resonance imaging scans and DNA samples. We assessed the association between variants present in these subjects and metabolic traits and performed in vitro functional analysis of two novel FOXA3 missense mutations identified.
  
  
  RESULTS
  Our analysis identified 14 novel variants and showed that the common single-nucleotide polymorphism (SNP) rs28666870 is significantly associated with greater body mass index, lean body mass and appendicular lean mass (P values 0.009, 0.010 and 0.013 respectively). In vitro functional studies showed increased adipogenic function for the FOXA3 missense mutations c.185C>T (p.Ser62Leu) and c.731C>T (p.Ala244Val) compared with FOXA3-WT.
  
  
  CONCLUSIONS
  Our study identified novel FOXA3 variants and mutations, assessed the adipogenic capacity of two novel missense alterations in vitro and demonstrated for the first time the associations between FOXA3 SNP rs28666870 with metabolic phenotypes in humans.
authors: Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, MD, USA.
authors: D C
authors: DC
authors: Adler-Wailes
authors: Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, MD, USA.
authors: A T
authors: AT
authors: Alberobello
authors: Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, MD, USA.
authors: X
authors: X
authors: Ma
authors: Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, MD, USA.
authors: L
authors: L
authors: Hugendubler
authors: Section on Growth and Obesity, Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
authors: E A
authors: EA
authors: Stern
authors: Section on Growth and Obesity, Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
authors: Z
authors: Z
authors: Mou
authors: Section on Growth and Obesity, Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
authors: J C
authors: JC
authors: Han
authors: National Institute of Arthritis and Musculoskeletal and Skin Disease, National Institutes of Health, Bethesda, MD, USA.
authors: P W
authors: PW
authors: Kim
authors: Diabetes, Endocrinology and Obesity Branch, Section on Ethnicity and Health, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, MD, USA.
authors: A E
authors: AE
authors: Sumner
authors: Section on Growth and Obesity, Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
authors: J A
authors: JA
authors: Yanovski
authors: Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, MD, USA.
authors: E
authors: E
authors: Mueller
mesh_terms: D015502:Absorptiometry, Photon; D000293:Adolescent; D001823:Body Composition / Q000235:genetics*; D015992:Body Mass Index; D002648:Child; D003430:Cross-Sectional Studies; D059305:Diet, High-Fat; D005260:Female; D014644:Genetic Variation; D051543:Hepatocyte Nuclear Factor 3-gamma / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D009765:Obesity / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014481:United States / Q000453:epidemiology; D055815:Young Adult
chemical_list: C496505:FOXA3 protein, human; D051543:Hepatocyte Nuclear Factor 3-gamma