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3q21.1调节变体可增加高血糖症和骨矿物质密度改变的风险
作者:小柯机器人 发布时间:2021/1/31 22:33:14

美国布罗德研究所Melina Claussnitzer团队发现,3q21.1调节变体能够增加高血糖症和骨矿物质密度改变的风险。相关论文于2021年1月28日在线发表于国际学术期刊《细胞—代谢》。

研究人员表示,骨骼和血糖性状具有共同的病因,但基本的遗传因素仍然未知。

为了确定可能具有多效作用的遗传基因座,研究人员绘制了全基因组关联研究(GWAS)的骨矿物质密度和血糖特征,并确定了3q21的双变量风险基因座。使用序列和表观遗传建模,研究人员确定了腺苷酸环化酶5(ADCY5)内含子因果变体rs56371916的优先级。该SNP改变了SREBP1的结合亲和力,并导致差异化的ADCY5基因表达,从而将染色质格局从平衡变为抑制。这些改变导致成骨细胞和脂肪细胞中脂质代谢的变化。

研究人员通过直接操纵调节子SREBP1、靶基因ADCY5和变体rs56371916验证了这一发现,这两者共同暗示着脂肪酸氧化与成骨细胞分化之间的新联系。通过对多效性GWAS基因座进行系统性功能解剖,这项工作为揭示影响多效性状的生物学机制提供了一个框架。 

附:英文原文

Title: A regulatory variant at 3q21.1 confers an increased pleiotropic risk for hyperglycemia and altered bone mineral density

Author: Nasa Sinnott-Armstrong, Isabel S. Sousa, Samantha Laber, Elizabeth Rendina-Ruedy, Simon E. Nitter Dankel, Teresa Ferreira, Gunnar Mellgren, David Karasik, Manuel Rivas, Jonathan Pritchard, Anyonya R. Guntur, Roger D. Cox, Cecilia M. Lindgren, Hans Hauner, Richard Sallari, Clifford J. Rosen, Yi-Hsiang Hsu, Eric S. Lander, Douglas P. Kiel, Melina Claussnitzer

Issue&Volume: 2021-01-28

Abstract: Skeletal and glycemic traits have shared etiology, but the underlying genetic factors remain largely unknown. To identify genetic loci that may have pleiotropic effects, we studied Genome-wide association studies (GWASs) for bone mineral density and glycemic traits and identified a bivariate risk locus at 3q21. Using sequence and epigenetic modeling, we prioritized an adenylate cyclase 5 (ADCY5) intronic causal variant, rs56371916. This SNP changes the binding affinity of SREBP1 and leads to differential ADCY5 gene expression, altering the chromatin landscape from poised to repressed. These alterations result in bone- and type 2 diabetes-relevant cell-autonomous changes in lipid metabolism in osteoblasts and adipocytes. We validated our findings by directly manipulating the regulator SREBP1, the target gene ADCY5, and the variant rs56371916, which together imply a novel link between fatty acid oxidation and osteoblast differentiation. Our work, by systematic functional dissection of pleiotropic GWAS loci, represents a framework to uncover biological mechanisms affecting pleiotropic traits.

DOI: 10.1016/j.cmet.2021.01.001

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(21)00001-2

期刊信息

Cell Metabolism:《细胞—代谢》,创刊于2005年。隶属于细胞出版社,最新IF:22.415
官方网址:https://www.cell.com/cell-metabolism/home
投稿链接:https://www.editorialmanager.com/cell-metabolism/default.aspx