Decreased STARD10 Expression Is Associated with Defective Insulin Secretion in Humans and Mice.
Decreased STARD10 Expression Is Associated with Defective Insulin Secretion in Humans and Mice.
复制标题
DOI：
10.1016/j.ajhg.2017.01.011
复制
发表时间：
2017-02-02
影响因子：
9.8
通讯作者：
Rutter GA
中科院分区：
文献类型：
--
作者：
Carrat GR;Hu M;Nguyen-Tu MS;Chabosseau P;Gaulton KJ;van de Bunt M;Siddiq A;Falchi M;Thurner M;Canouil M;Pattou F;Leclerc I;Pullen TJ;Cane MC;Prabhala P;Greenwald W;Schulte A;Marchetti P;Ibberson M;MacDonald PE;Manning Fox JE;Gloyn AL;Froguel P;Solimena M;McCarthy MI;Rutter GA
ARAP1(CENTD2)和STARD10附近的基因变异会影响2型糖尿病(T2D)的风险。风险等位基因削弱了葡萄糖诱导的胰岛素分泌，矛盾但具有特征的是，与胰岛素原：胰岛素比率降低有关，表明胰岛素原转化率提高。无论是因果变异的身份，还是导致风险的基因(S)都没有确定下来。ARAP1编码GTP酶激活蛋白，而STARD10是类固醇合成急性调节蛋白(STAR)相关脂转移蛋白家族的成员。通过整合遗传精细作图和表观基因组注释数据，并在β细胞系中进行启动子-报告基因和染色质构象捕捉(3C)研究，我们将该基因座的因果变异(S)定位到一个5kb的区域，该区域与胰岛中活性的拉伸增强子重叠。该区域包含几个高度相关的T2D风险变异体，包括rs140130268内含子。对三个独立受试者的胰岛转录本进行的表达QTL分析表明，T2D风险等位基因携带者的STARD10基因表达水平降低，而ARAP1基因表达水平没有伴随变化。相应地，在小鼠中，StarD10的β细胞选择性缺失导致葡萄糖刺激的钙动力学和胰岛素分泌受损，并概括了在人类GWAs信号中观察到的胰岛素原处理改善的模式。相反，在成年β细胞中过表达StarD10改善了高脂喂养动物的葡萄糖耐量。相反，在β细胞中操作ARap1对小鼠的胰岛素分泌或胰岛素原转化没有影响。人类和小鼠数据的这种融合提供了令人信服的证据，表明与该基因座变异相关的T2D风险是通过减少β细胞中STARD10的表达来调节的。
Genetic variants near ARAP1 (CENTD2) and STARD10 influence type 2 diabetes (T2D) risk. The risk alleles impair glucose-induced insulin secretion and, paradoxically but characteristically, are associated with decreased proinsulin:insulin ratios, indicating improved proinsulin conversion. Neither the identity of the causal variants nor the gene(s) through which risk is conferred have been firmly established. Whereas ARAP1 encodes a GTPase activating protein, STARD10 is a member of the steroidogenic acute regulatory protein (StAR)-related lipid transfer protein family. By integrating genetic fine-mapping and epigenomic annotation data and performing promoter-reporter and chromatin conformational capture (3C) studies in β cell lines, we localize the causal variant(s) at this locus to a 5 kb region that overlaps a stretch-enhancer active in islets. This region contains several highly correlated T2D-risk variants, including the rs140130268 indel. Expression QTL analysis of islet transcriptomes from three independent subject groups demonstrated that T2D-risk allele carriers displayed reduced levels of STARD10 mRNA, with no concomitant change in ARAP1 mRNA levels. Correspondingly, β-cell-selective deletion of StarD10 in mice led to impaired glucose-stimulated Ca2+ dynamics and insulin secretion and recapitulated the pattern of improved proinsulin processing observed at the human GWAS signal. Conversely, overexpression of StarD10 in the adult β cell improved glucose tolerance in high fat-fed animals. In contrast, manipulation of Arap1 in β cells had no impact on insulin secretion or proinsulin conversion in mice. This convergence of human and murine data provides compelling evidence that the T2D risk associated with variation at this locus is mediated through reduction in STARD10 expression in the β cell.