Adipose Tissue Expression and Genetic Variants of the Bone Morphogenetic Protein Receptor 1A Gene (BMPR1A) Are Associated With Human Obesity

Adipose Tissue Expression and Genetic Variants of the Bone Morphogenetic Protein Receptor 1A Gene ( BMPR1A ) Are Associated With Human Obesity Yvonne Böttcher 1 , Hanne Unbehauen 1 , Nora Klöting 1 , Karen Ruschke 1 , Antje Körner 2 , Dorit Schleinitz 3 , Anke Tönjes 1 , 4 , Beate Enigk 3 , Sara Wolf 1 , Kerstin Dietrich 3 , Moritz Koriath 1 , Gerhard Harry Scholz 5 , Yu-Hua Tseng 6 , Arne Dietrich 7 , Michael R. Schön 8 , Wieland Kiess 2 , Michael Stumvoll 1 , Matthias Blüher 1 and Peter Kovacs 3 1 Department of Medicine, University of Leipzig, Leipzig, Germany; 2 University Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany; 3 Interdisciplinary Centre for Clinical Research, University of Leipzig, Germany; 4 Coordination Centre for Clinical Trials, University of Leipzig, Germany; 5 St. Elisabeth Hospital, Medical Department, Leipzig, Germany; 6 Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts; 7 Department of Surgery, University of Leipzig, Leipzig, Germany; 8 Department of Surgery, Städtisches Klinikum Karlsruhe, Germany. Corresponding author: Peter Kovacs, peter.kovacs{at}medizin.uni-leipzig.de . Y.B. and H.U. contributed equally to this study. Abstract OBJECTIVE Members of the family of bone morphogenetic proteins (BMPs) are important regulators of adipogenesis. We examined the role of the BMP receptor 1A gene ( BMPR1A ) in the pathophysiology of human obesity. RESEARCH DESIGN AND METHODS We measured BMPR1A mRNA expression in paired samples of visceral and subcutaneous adipose tissue from 297 subjects and sequenced the BMPR1A in 48 nonrelated white subjects. Twenty-one representative variants including HapMap tagging single nucleotide polymorphisms (SNPs) were then genotyped for association studies in German whites ( n = 1,907). For replication analyses, we used a population of Sorbs from Germany ( n = 900) and German childhood cohorts ( n = 1,029 schoolchildren and 270 obese children). RESULTS mRNA expression of the BMPR1A was significantly increased in both visceral and subcutaneous adipose tissue of overweight and obese subjects compared with lean subjects ( P < 0.05). In a case-control study, four SNPs (rs7095025, rs11202222, rs10788528, and rs7922846) were nominally associated with obesity (adjusted P < 0.05). For three SNPs (rs7095025, rs11202222, and rs10788528), the association with obesity was confirmed in the independent cohort of Sorbs (adjusted P < 0.005). Consistent with this, BMPR1A SNPs we