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

Abstract

OBJECTIVEMembers 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 METHODSWe 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).RESULTSmRNA 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 were nominally associated with obesity-related quantitative traits in nondiabetic subjects in both adult cohorts. Furthermore, homozygous carriers of the obesity risk alleles had higher BMPR1A mRNA expression in fat than noncarriers.CONCLUSIONSOur data suggest that genetic variation in the BMPR1A may play a role in the pathophysiology of human obesity, possibly mediated through effects on mRNA expression.

Association of serum bone morphogenetic protein 4 levels with obesity and metabolic syndrome in non-diabetic individuals

“…In addition, BMPR1A expression was positively correlated with components of metabolic syndrome including body mass index (BMI), body fat mass, and waist-to-hip ratio (WHR). Because BMP-4 predominantly uses BMPR1A as its receptor, these results suggest that BMP-4/BMPR1A signaling may be involved in the pathogenesis of human obesity [13]. Moreover, BMP-4 signaling has recently been found to regulate pancreatic cell proliferation and differentiation as well as adipogenesis.…”

Inhibition of Bone Morphogenic Protein 4 Restores Endothelial Function in db/db Diabetic Mice

“…BMP4-activated ALK3 signaling mediates endothelial dysfunction induced by BMP4 and promotes remodeling of pulmonary vasculature during hypoxia. 5,13 ALK3 is also involved in the development of obesity 34 and cardiovascular disease. 35 The present results suggest that ALK3 plays a more significant role to mediate BMP4-induced harmful effect on endothelial cells as ALK3 silencing reverses BMP4-stimulated ROS production in cultured endothelial cells.…”

Genetic variation in the Sorbs of eastern Germany in the context of broader European genetic diversity

“…Recently, the Sorbs have been successfully utilized in candidate gene and genome-wide association studies of height and metabolic syndrome traits. [13][14][15][16][17] Although these studies are suggestive of the power of using the Sorbs for mapping, they do not make clear the extent to which Sorbs are a genetic isolate.…”