title: Hepatocyte nuclear factor-6: associations between genetic variability and type II diabetes and between genetic variability and estimates of insulin secretion.
abstract: OBJECTIVE
  The transcription factor hepatocyte nuclear factor (HNF)-6 is an upstream regulator of several genes involved in the pathogenesis of maturity-onset diabetes of the young. We therefore tested the hypothesis that variability in the HNF-6 gene is associated with subsets of Type II (non-insulin-dependent) diabetes mellitus and estimates of insulin secretion in glucose tolerant subjects.
  
  
  METHODS
  We cloned the coding region as well as the intron-exon boundaries of the HNF-6 gene. We then examined them on genomic DNA in six MODY probands without mutations in the MODY1, MODY3 and MODY4 genes and in 54 patients with late-onset Type II diabetes by combined single strand conformational polymorphism-heteroduplex analysis followed by direct sequencing of identified variants. An identified missense variant was examined in association studies and genotype-phenotype studies.
  
  
  RESULTS
  We identified two silent and one missense (Pro75 Ala) variant. In an association study the allelic frequency of the Pro75Ala polymorphism was 3.2% (95% confidence interval, 1.9-4.5) in 330 patients with Type II diabetes mellitus compared with 4.2% (2.4-6.0) in 238 age-matched glucose tolerant control subjects. Moreover, in studies of 238 middle-aged glucose tolerant subjects, of 226 glucose tolerant offspring of Type II diabetic patients and of 367 young healthy subjects, the carriers of the polymorphism did not differ from non-carriers in glucose induced serum insulin or C-peptide responses.
  
  
  CONCLUSIONS
  Mutations in the coding region of the HNF-6 gene are not associated with Type II diabetes or with changes in insulin responses to glucose among the Caucasians examined.
authors.affiliation: Steno Diabetes Center, Gentofte, Copenhagen, Denmark.
authors.forename: A M
authors.initials: AM
authors.lastname: Møller
authors.forename: J
authors.initials: J
authors.lastname: Ek
authors.forename: S M
authors.initials: SM
authors.lastname: Durviaux
authors.forename: S A
authors.initials: SA
authors.lastname: Urhammer
authors.forename: J O
authors.initials: JO
authors.lastname: Clausen
authors.forename: H
authors.initials: H
authors.lastname: Eiberg
authors.forename: T
authors.initials: T
authors.lastname: Hansen
authors.forename: G G
authors.initials: GG
authors.lastname: Rousseau
authors.forename: F P
authors.initials: FP
authors.lastname: Lemaigre
authors.forename: O
authors.initials: O
authors.lastname: Pedersen
mesh_terms: D000328:Adult; D000409:Alanine; D000483:Alleles; D019943:Amino Acid Substitution; D002874:Chromosome Mapping; D002884:Chromosomes, Human, Pair 15; D003001:Cloning, Molecular; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D005091:Exons; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D051559:Hepatocyte Nuclear Factor 6; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D007438:Introns; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D018807:Polymorphism, Single-Stranded Conformational; D011392:Proline; D012042:Registries; D015534:Trans-Activators / Q000235:genetics; D044465:White People / Q000235:genetics
chemical_list: D051559:Hepatocyte Nuclear Factor 6; D018398:Homeodomain Proteins; D007328:Insulin; C496605:ONECUT1 protein, human; D015534:Trans-Activators; D011392:Proline; D000409:Alanine