Genetic and Evolutionary Analyses of the Human Bone Morphogenetic Protein Receptor 2 (BMPR2) in the Pathophysiology of Obesity

• Published in: PloS one Vol. 6; no. 2; p. e16155
• Main Authors: Schleinitz, Dorit, Klöting, Nora, Böttcher, Yvonne, Wolf, Sara, Dietrich, Kerstin, Tönjes, Anke, Breitfeld, Jana, Enigk, Beate, Halbritter, Jan, Körner, Antje, Schön, Michael R., Jenkner, Jost, Tseng, Yu-Hua, Lohmann, Tobias, Dreβler, Miriam, Stumvoll, Michael, Blüher, Matthias, Kovacs, Peter
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 02.02.2011; Public Library of Science (PLoS)
• Subjects: Adipocytes; Adipogenesis; Adipose tissue; Adipose Tissue - metabolism; Adipose Tissue - pathology; Adult; Aged; Analysis; Bioinformatics; Biological evolution; Biology; Body mass; Body weight; Bone morphogenetic protein receptor type II; Bone morphogenetic protein receptors; Bone Morphogenetic Protein Receptors, Type II - analysis; Bone Morphogenetic Protein Receptors, Type II - genetics; Bone Morphogenetic Protein Receptors, Type II - metabolism; Bone Morphogenetic Protein Receptors, Type II - physiology; Bone morphogenetic proteins; Bones; Cardiovascular disease; Cohort Studies; Coronary vessels; Data processing; Deoxyribonucleic acid; Diabetes; Diabetes Mellitus, Type 2 - ethnology; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; DNA; European Continental Ancestry Group - ethnology; European Continental Ancestry Group - genetics; Evolution; Evolution, Molecular; Evolutionary design method; Fasting; Fats; Female; Gene expression; Genes; Genetic aspects; Genetic Association Studies; Genetics; Genomes; Genotypes; Germany - ethnology; Glucose - metabolism; Haplotypes; Human populations; Humans; Hypertension; Hypotheses; Insulin; Insulin Resistance - genetics; Insulin Resistance - physiology; Interdisciplinary aspects; Kinases; Loci; Male; Measurement; Medicine; Messenger RNA; Middle Aged; Nucleotide sequence; Obesity; Obesity - ethnology; Obesity - genetics; Obesity - metabolism; Obesity - pathology; Overweight; Phylogenetics; Polymorphism, Single Nucleotide; Population; Populations; Proteins; Replication; Research design; Rodents; Signaling; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Statistical analysis; Statistical methods; Stem cells; Studies; Type 2 diabetes; Vertebrates; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0016155

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. 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. 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. Combined BMPR2 genotype-phenotype-mRNA expression data as well as evolutionary aspects suggest a role of BMPR2 in the pathophysiology of obesity.