Expression of the Bone Morphogenetic Protein Receptor 1A Gene (BMPR1A) in Adipose Tissue and BMPR1A Genetic Variation are Associated with Human Obesity

Abstract

Family of bone morphogenetic proteins (BMP) is involved in regulation of adipogenesis. We measured the mRNA expression of BMP members in paired samples of visceral and subcutaneous adipose tissue from 198 subjects and examined its relation to obesity. Amongst others, mRNA expression of the human bone morphogenetic protein receptor 1A (BMPR1A) was significantly increased in both visceral and subcutaneous adipose tissue of 51 overweight (BMI>25 and <30kg/m2) and 91 obese (BMI>30kg/m2) subjects compared with 56 lean subjects (BMI<25kg/m2) (P<0.05 and P<0.001, respectively). BMPR1A is one of the three specific BMP-receptors which are essential for the bone morphogenetic protein signalling. The BMPR1A gene maps to human chromosome 10q23 and spans about 168 kb. To determine whether genetic variants within the BMPR1A are associated with mRNA expression in fat and whether these variants affect the pathophysiology of human obesity and type 2 diabetes (T2D), we sequenced the BMPR1A (13 exons, exon-intron boundaries, 5′ and 3′ UTRs) in DNA samples from 48 non-related Caucasian subjects to identify genetic variants. Twenty representative variants including HapMap tagging SNPs (single nucleotide polymorphisms) (www.hapmap.org) were genotyped for subsequent association studies on quantitative traits in 1808 German Caucasians with detailed metabolic testing (896 subjects without T2D and 912 subjects with T2D). In a case control study including 461 lean (BMI<25kg/m2) and 678 obese (BMI>30kg/m2) subjects, four SNPs (rs7095025, rs7922846, rs11202222 and rs10788528) were significantly associated with obesity (all P<0.05, adjusted for age and sex). Consistent with this, we found significant associations between BMPR1A SNPs and obesity/diabetes related quantitative traits (body mass index (BMI), circulating serum leptin, fasting plasma glucose, 2-hr plasma glucose in oral glucose tolerance test; all P<0.05, adjusted for age, sex and BMI) in 896 subjects without T2D. Finally, the rs17426348 was moderately associated with T2D in 912 cases with T2D and 718 healthy controls with normal glucose tolerance (P=0.05, adjusted for age, sex and BMI). In conclusion, association of both, BMPR1A expression in fat and BMPR1A genetic variation with obesity suggest that this gene may play a role in the pathophysiology of human obesity and T2D.