title: Variations in the ghrelin receptor gene associate with obesity and glucose metabolism in individuals with impaired glucose tolerance.
abstract: BACKGROUND
  Ghrelin may influence the development of obesity through its role in the control of energy balance, food intake, and regulation of body weight. The effects of ghrelin are mediated via the growth hormone secretagogue receptor (GHSR).
  
  
  RESULTS
  We genotyped 7 single nucleotide polymorphisms (SNPs) in the GHSR gene and assessed the association between those SNPs and obesity and type 2 diabetes-related phenotypes from 507 middle-aged overweight persons with impaired glucose tolerance participating in the Finnish Diabetes Prevention Study (DPS). Additionally, we performed in silico screening of the 5'-regulatory region of GHSR and evaluated SNPs disrupting putative transcription factor (TF) binding sites in vitro with gelshift assays to determine differences in protein binding between different alleles of SNPs. Rs9819506 in the promoter region of GHSR was associated with body weight (p = 0.036); persons with rs9819506-AA genotype having the lowest body weight. Individuals with rs490683-CC genotype displayed highest weight loss in the whole study population (p = 0.032). The false discovery rate for these results was <10%. Rs490683 and rs509035 were associated with several measures of glucose and insulin metabolism during the follow-up. Rs490683 may be a functional SNP, since gelshift experiments showed differential protein binding between the alleles, with higher binding to the G-allele. Rs490683-C may disrupt a putative binding site for the TF nuclear factor 1 (NF-1), thus rs4906863-GG genotype where the NF-1 site is intact may lead to a higher GHSR gene expression.
  
  
  CONCLUSIONS
  Polymorphisms in the GHSR promoter may modify changes in body weight during long-term lifestyle intervention and affect ghrelin receptor signalling through modulation of GHSR gene expression.
authors.affiliation: Department of Clinical Nutrition, Food and Health Research Centre, University of Kuopio, Kuopio, Finland. ursula.mager@uku.fi
authors.forename: Ursula
authors.initials: U
authors.lastname: Mager
authors.forename: Tatjana
authors.initials: T
authors.lastname: Degenhardt
authors.forename: Leena
authors.initials: L
authors.lastname: Pulkkinen
authors.forename: Marjukka
authors.initials: M
authors.lastname: Kolehmainen
authors.forename: Anna-Maija
authors.initials: AM
authors.lastname: Tolppanen
authors.forename: Jaana
authors.initials: J
authors.lastname: Lindström
authors.forename: Johan G
authors.initials: JG
authors.lastname: Eriksson
authors.forename: Carsten
authors.initials: C
authors.lastname: Carlberg
authors.forename: Jaakko
authors.initials: J
authors.lastname: Tuomilehto
authors.forename: Matti
authors.initials: M
authors.lastname: Uusitupa
mesh_terms: D001835:Body Weight / Q000235:genetics; D014644:Genetic Variation; D005947:Glucose / Q000378:metabolism*; D018149:Glucose Intolerance / Q000235:genetics*; D006801:Humans; D008019:Life Style; D009765:Obesity / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic; D011485:Protein Binding; D054440:Receptors, Ghrelin / Q000235:genetics* / Q000378:metabolism; D015431:Weight Loss / Q000235:genetics
chemical_list: D054440:Receptors, Ghrelin; D005947:Glucose