title: Genetic and evolutionary analyses of the human bone morphogenetic protein receptor 2 (BMPR2) in the pathophysiology of obesity.
abstract: OBJECTIVE
  Human bone morphogenetic protein receptor 2 (BMPR2) is essential for BMP signalling and may be involved in the regulation of adipogenesis. The BMPR2 locus has been suggested as target of recent selection in human populations. We hypothesized that BMPR2 might have a role in the pathophysiology of obesity.
  
  
  METHODS
  Evolutionary analyses (dN/dS, Fst, iHS) were conducted in vertebrates and human populations. BMPR2 mRNA expression was measured in 190 paired samples of visceral and subcutaneous adipose tissue. The gene was sequenced in 48 DNA samples. Nine representative single nucleotide polymorphisms (SNPs) were genotyped for subsequent association studies on quantitative traits related to obesity in 1830 German Caucasians. An independent cohort of 925 Sorbs was used for replication. Finally, relation of genotypes to mRNA in fat was examined.
  
  
  RESULTS
  The evolutionary analyses indicated signatures of selection on the BMPR2 locus. BMPR2 mRNA expression was significantly increased both in visceral and subcutaneous adipose tissue of 37 overweight (BMI>25 and <30 kg/m²) and 80 obese (BMI>30 kg/m²) compared with 44 lean subjects (BMI< 25 kg/m²) (P<0.001). In a case-control study including lean and obese subjects, two intronic SNPs (rs6717924, rs13426118) were associated with obesity (adjusted P<0.05). Combined analyses including the initial cohort and the Sorbs confirmed a consistent effect for rs6717924 (combined P = 0.01) on obesity. Moreover, rs6717924 was associated with higher BMPR2 mRNA expression in visceral adipose tissue.
  
  
  CONCLUSIONS
  Combined BMPR2 genotype-phenotype-mRNA expression data as well as evolutionary aspects suggest a role of BMPR2 in the pathophysiology of obesity.
authors.affiliation: Interdisciplinary Center for Clinical Research, University of Leipzig, Leipzig, Germany.
authors.forename: Dorit
authors.initials: D
authors.lastname: Schleinitz
authors.forename: Nora
authors.initials: N
authors.lastname: Klöting
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Böttcher
authors.forename: Sara
authors.initials: S
authors.lastname: Wolf
authors.forename: Kerstin
authors.initials: K
authors.lastname: Dietrich
authors.forename: Anke
authors.initials: A
authors.lastname: Tönjes
authors.forename: Jana
authors.initials: J
authors.lastname: Breitfeld
authors.forename: Beate
authors.initials: B
authors.lastname: Enigk
authors.forename: Jan
authors.initials: J
authors.lastname: Halbritter
authors.forename: Antje
authors.initials: A
authors.lastname: Körner
authors.forename: Michael R
authors.initials: MR
authors.lastname: Schön
authors.forename: Jost
authors.initials: J
authors.lastname: Jenkner
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Tseng
authors.forename: Tobias
authors.initials: T
authors.lastname: Lohmann
authors.forename: Miriam
authors.initials: M
authors.lastname: Dressler
authors.forename: Michael
authors.initials: M
authors.lastname: Stumvoll
authors.forename: Matthias
authors.initials: M
authors.lastname: Blüher
authors.forename: Peter
authors.initials: P
authors.lastname: Kovacs
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000032:analysis / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000208:ethnology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019143:Evolution, Molecular; D005260:Female; D056726:Genetic Association Studies; D005858:Germany / Q000208:ethnology; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000208:ethnology / Q000235:genetics
chemical_list: C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II; D005947:Glucose