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肥胖症病理生理学中人类骨形态发生蛋白受体 2 (BMPR2) 的遗传和进化分析。

Genetic and evolutionary analyses of the human bone morphogenetic protein receptor 2 (BMPR2) in the pathophysiology of obesity.

机构信息

Interdisciplinary Center for Clinical Research, University of Leipzig, Leipzig, Germany.

出版信息

PLoS One. 2011 Feb 2;6(2):e16155. doi: 10.1371/journal.pone.0016155.

DOI:10.1371/journal.pone.0016155
PMID:21311592
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3032727/
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.

RESEARCH DESIGN AND 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.

CONCLUSION

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

摘要

目的

人类骨形态发生蛋白受体 2（BMPR2）是 BMP 信号转导所必需的，可能参与脂肪生成的调控。BMPR2 基因座已被认为是人类群体中最近选择的靶点。我们假设 BMPR2 可能在肥胖的病理生理学中发挥作用。

研究设计和方法

在脊椎动物和人类群体中进行了进化分析（dN/dS、Fst、iHS）。在 190 对内脏和皮下脂肪组织的配对样本中测量了 BMPR2 mRNA 的表达。在 48 个 DNA 样本中对该基因进行了测序。对 1830 名德国白种人中与肥胖相关的定量性状进行了 9 个代表性单核苷酸多态性（SNP）的关联研究。在一个独立的 925 名 Sorbs 队列中进行了复制。最后，还研究了基因型与脂肪中 mRNA 的关系。

结果

进化分析表明 BMPR2 基因座存在选择的迹象。与 44 名体重正常（BMI<25 kg/m²）的受试者相比，37 名超重（BMI>25 和 <30 kg/m²）和 80 名肥胖（BMI>30 kg/m²）受试者的内脏和皮下脂肪组织中 BMPR2 mRNA 的表达显著增加（P<0.001）。在一项包括体重正常和肥胖受试者的病例对照研究中，两个内含子 SNP（rs6717924、rs13426118）与肥胖相关（调整后的 P<0.05）。包括初始队列和 Sorbs 的联合分析证实 rs6717924 对肥胖的影响一致（联合 P=0.01）。此外，rs6717924 与内脏脂肪组织中 BMPR2 mRNA 的表达增加相关。

结论

综合 BMPR2 基因型-表型-mRNA 表达数据以及进化方面的研究结果表明，BMPR2 可能在肥胖的病理生理学中发挥作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/383d/3032727/1f90ed420af5/pone.0016155.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/383d/3032727/ffced92186f3/pone.0016155.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/383d/3032727/ed109dd4d47c/pone.0016155.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/383d/3032727/f8160c944f7b/pone.0016155.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/383d/3032727/daf3f06997a1/pone.0016155.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/383d/3032727/1f90ed420af5/pone.0016155.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/383d/3032727/ffced92186f3/pone.0016155.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/383d/3032727/ed109dd4d47c/pone.0016155.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/383d/3032727/f8160c944f7b/pone.0016155.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/383d/3032727/daf3f06997a1/pone.0016155.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/383d/3032727/1f90ed420af5/pone.0016155.g005.jpg

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