The trans-ancestral genomic architecture of glycemic traits

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 x 10(-8)), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution. A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.Peer reviewe

Genetic Drivers of Heterogeneity in Type 2 Diabetes Pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P \u3c 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P &lt; 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.</p

シンキ ゴウセイシタ Arg Gly Asp オ フクンダ ペプチド cyclo RGDf V ワ ユウコウナ ケッカン シンセイ ソガイザイ デ アル

京都大学0048新制・課程博士博士(医学)甲第9236号医博第2424号新制||医||785(附属図書館)UT51-2002-B743京都大学大学院医学研究科分子医学系専攻(主査)教授 開 祐司, 教授 山岡 義生, 教授 今村 正之学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDA

Diabetes Caused by Elastase-Cre-Mediated Pdx1 Inactivation in Mice

発生段階で膵臓の外分泌組織を欠くマウスは、糖尿病になる --機能的膵島作製における外分泌組織との共存の重要性--. 京都大学プレスリリース. 2016-02-18.Endocrine and exocrine pancreas tissues are both derived from the posterior foregut endoderm, however, the interdependence of these two cell types during their formation is not well understood. In this study, we generated mutant mice, in which the exocrine tissue is hypoplastic, in order to reveal a possible requirement for exocrine pancreas tissue in endocrine development and/or function. Since previous studies showed an indispensable role for Pdx1 in pancreas organogenesis, we used Elastase-Cre-mediated recombination to inactivate Pdx1 in the pancreatic exocrine lineage during embryonic stages. Along with exocrine defects, including impaired acinar cell maturation, the mutant mice exhibited substantial endocrine defects, including disturbed tip/trunk patterning of the developing ductal structure, a reduced number of Ngn3-expressing endocrine precursors, and ultimately fewer β cells. Notably, postnatal expansion of the endocrine cell content was extremely poor, and the mutant mice exhibited impaired glucose homeostasis. These findings suggest the existence of an unknown but essential factor(s) in the adjacent exocrine tissue that regulates proper formation of endocrine precursors and the expansion and function of endocrine tissues during embryonic and postnatal stages

Non-functioning pancreatic neuroendocrine tumor accompanied with multiple liver metastases: remorseful case and literature review.

Context Pancreatic neuroendocrine tumor (P-NET) is a rare and slow-growing tumor. Unfortunately, there is no clear consensus on the role and timing of surgery for primary tumor and liver metastases, although current reports refer to liver surgery including LT for unresectable liver metastases. Case report A thirty-nine-year-old man was diagnosed with nonfunctioning pancreatic neuroendocrine tumor (P-NET) in the pancreatic head, with multiple liver metastases. The tumor was 2.5 cm in diameter and he was asymptomatic. Small but multiple metastases were detected in the liver, and no extrahepatic metastases were observed. We initially intended to control the liver metastases before resection of the primary tumor. To begin with, transarterial chemoembolization (TACE) and transcatheter arterial infusion (TAI) were repeated. Thereafter, systemic chemotherapy and biotherapy were introduced according to follow-up assessments. Unfortunately, imaging assessment at about 10 months later revealed that liver metastases were partially enlarged, although some were successfully treated. Therefore, these therapies were switched to other regimens, and TACE/TAI, systemic chemotherapies and biotherapies were repeated. Although liver metastases seemed to be stable for a while, the primary tumor was enlarged even after therapy. At 3.5 years after initial diagnosis, the primary tumor became symptomatic (pain and jaundice). Liver metastases enlarged and massive swelling of the para-aortic lymph nodes was observed. Thereafter, palliative therapy was the main course of action. He died at 4.3 years after initial diagnosis. Conclusion Our young patient could have been a candidate for initial surgery for primary tumor and might have had a chance of subsequent liver transplantation for unresectable metastases. Surgeons still face questions in deciding the best surgical scenario in patients with P-NET with liver metastases

Identification of a novel intracellular interaction domain essential for Bves function.

While Blood vessel epicardial substance (Bves) confers adhesive properties, the molecular mechanism of regulating this activity is unknown. No predicted functional motifs in this highly conserved integral membrane protein, other than the transmembrane domain, have been identified. Here, we report for the first time that Bves interacts with itself through an intracellular interaction domain that is essential for its intercellular adhesion activity. Glutathione-S-transferase (GST) pull-down and SPOTs analyses mapped this domain to amino acids 268-274 in the intracellular C-terminus. Site-directed mutagenesis revealed that lysines 272 and 273 are essential for homodimerization and cell adhesion. Human corneal cells transfected with wild-type Bves trafficked the protein to the cell surface, assembled junction complexes and formed epithelial sheets. In contrast, cells expressing Bves mutated at these positions did not form continuous epithelial sheets or maintain junctional proteins such as ZO-1 and E-cadherin at the membrane. A dramatic reduction in transepithelial electrical resistance was also observed indicating a functional loss of tight junctions. Importantly, expression of mutated Bves in epithelial cells promoted the transformation of cells from an epithelial to a mesenchymal phenotype. This study is the first to demonstrate the essential nature of any domain within Bves for maintenance of epithelial phenotype and function

A phase I study investigating the safety and pharmacokinetics of highly bioavailable curcumin (Theracurmin) in cancer patients.

A growing number of preclinical studies have demonstrated that curcumin could be a promising anticancer drug; however, poor bioavailability has been the major obstacle for its clinical application. To overcome this problem, we developed a new form of curcumin (Theracurmin) and reported high plasma curcumin levels could be safely achieved after a single administration of Theracurmin in healthy volunteers. In this study, we aimed to evaluate the safety of repetitive administration of Theracurmin in cancer patients